UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`
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`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.
`Patent Owner
`
`Patent No. 8,268,299
`Issue Date: September 18, 2012
`Title: SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`
`
`
`Inter Partes Review No.: IPR2017-01053
`
`
`
`
`
`PETITIONER’S RESPONSE TO PATENT OWNER’S MOTION FOR
`OBSERVATIONS ON CROSS-EXAMINATION OF PETITIONER’S
`REPLY WITNESS DR. ERNING XIA
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`
`
`
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.
`Patent Owner
`
`Patent No. 8,268,299
`Issue Date: September 18, 2012
`Title: SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`
`
`
`Inter Partes Review No.: IPR2017-01053
`
`
`
`
`
`PETITIONER’S RESPONSE TO PATENT OWNER’S MOTION FOR
`OBSERVATIONS ON CROSS-EXAMINATION OF PETITIONER’S
`REPLY WITNESS DR. ERNING XIA
`
`
`
`
`
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`Petitioner Argentum Pharmaceuticals LLC (“Petitioner”) hereby responds to
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`Alcon Research Ltd.’s motion for observations on the deposition of Petitioner’s
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`expert Dr. Erning Xia (Paper 43, hereafter “Mot.”). Office Patent Trial Practice
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`Guide, 77 Fed. Reg. 48756 at 48767-68 (August 14, 2012).
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`Observation #1: Patent Owner’s assertion that Dr. Xia’s testimony
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`contradicts Petitioner’s argument that a POSA “would have arrived at the claims of
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`the ‘299 Patent via routine optimization” is unsupported. First, Counsel’s final
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`question to Dr. Xia was a compound question (“Is that the only place the POSA
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`may have ended up or could the POSA have ended up at…different
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`formulation?”), such that Dr. Xia’s answer in the affirmative could just as easily be
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`understood to be confirming the first part of the question versus the second.
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`Counsel did not clarify which part of this question Dr. Xia was answering.
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`ALCON2166, 107:7-11. Second, there is no foundation in Counsel’s question for
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`what was meant by “different formulation.” The combined cited art provides a
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`variety of (different) obvious formulations meeting the claimed limitations. See,
`
`e.g., Pet., 15 and Reply, 12 (arguing that Chowhan discloses a range of
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`borate/polyol concentrations falling within the claimed range). These observations
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`are relevant because they do not support Patent Owner’s characterization of Dr.
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`Xia’s testimony as contradicting Petitioner’s routine optimization argument.
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`
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`1
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`
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`Observation #2: Patent Owner’s assertions that Dr. Xia is not a
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`microbiologist and does not know if zinc is a necessary micronutrient for bacterial
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`growth is taken out of context and not relevant to Dr. Xia’s qualification to opine
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`on Alcon’s argument that “the POSA would affirmatively be concerned that zinc
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`compositions with less zinc than the 0.48 mM in Xia’s Example 18 would fail
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`PET.” In making this assertion Patent Owner overlooks Dr. Xia’s over 30 years of
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`experience in not just ophthalmic formulations (110 patents, 36 publications), but
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`in ophthalmic preservative systems, including the very zinc preserved ophthalmic
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`formulations of the Xia reference, of which he is an inventor. EX1002 ¶¶6-13;
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`EX1015. Patent Owner overlooks Dr. Xia’s clarification that zinc “by itself” is not
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`a foodstuff (ALCON2166 50:15-19) in an ophthalmic formulation. Id. 40:7-14.
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`Patent Owner further overlooks Dr. Xia’s testimony (id., 49:19-50:6, 51:2-6;
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`EX1093, ¶¶13-24) and Dr. Zhanel’s testimony (Alcon’s own microbiology expert)
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`(EX1048, 49:6-9; 50:8-10, 50:13-16; 55:17-22; 114:15-21) that non-ophthalmic
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`compositions (such as those in Winslow, McCarthy, and Zeelie) cannot predict
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`PET for ophthalmic compositions and a 48 hour test cannot predict PET. Finally,
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`Patent Owner overlooks their own admission that Xia teaches zinc concentrations
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`lower than 0.48 mM and that preservation may be achieved “using zinc and ‘less
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`than a preservative-effective amount of a primary preservative agents’…” (POR, 9,
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`17; ALCON2023, ¶¶29, 60; ALCON2025, ¶¶22, 26), which contradicts Alcon’s
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`
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`2
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`
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`present argument, and supports Petitioner’s argument that “a POSA would
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`combine zinc with another preservative agent—in this case, the borate-polyols as
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`taught by Chowan and already present in both the Xia and Schneider
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`formulations.” Reply, 8 (citing EX1093, ¶¶28-38).
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`Observation #3: Patent Owner mischaracterizes Dr. Xia’s testimony
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`regarding EX1093, ¶24. Paragraph 24 states “I believe a POSA would avoid high
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`zinc concentrations knowing zinc at 0.25 w/v% is an astringent and use Xia’s
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`express teaching of zinc concentrations as low as 0.074 mM to determine an
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`optimum zinc concentration in an ophthalmic solution that passes standard PET.”
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`EX1093, ¶24. Dr. Xia’s testimony that “high” in the sentence refers to 0.25 w/v%
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`and that 0.25 w/v% is not in the zinc concentration range taught by Xia
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`(ALCON2166, 53:21-25) does not contradict Petitioner’s argument. Rather, Dr.
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`Xia’s testimony is consistent with Petitioner’s argument that “a POSA would have
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`been concerned with using too high a level of zinc, and would therefore have
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`engaged in optimization to find the lowest suitable zinc concentration.” Reply, 5
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`(citing EX1093, ¶12). Dr. Xia’s testimony is also consistent with Dr. Majumdar’s
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`testimony that a POSA would avoid zinc concentrations that cause astringency
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`(i.e., 0.25 w/v%) and that all else being equal, a POSA would opt for the lowest
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`preservative concentration that passes PET (EX1045, 51:24-52:10, 79:9-16; see
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`also 1093, ¶12).
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`3
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`
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`Observation #4: Patent Owner mischaracterizes Dr. Xia’s testimony
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`concerning the phrase “are useful” in EX1093, ¶11 in relation to 0.001% and
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`0.005% zinc concentrations as he testified the phrase “means it may need some
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`help from other ingredients.” ALCON2166, 73:1-5 (emphasis added). Patent
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`Owner also overlooks Dr. Zhanel’s testimony that “the POSA cannot find a very
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`specific statement that says do not go lower with zinc than 0.0065 percent if you
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`expect to pass preservative efficacy” (EX1048, 123:12-124:14), which contradicts
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`Patent Owner’s argument. Furthermore, Patent Owner overlooks their own
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`admission that Xia teaches zinc concentrations lower than 0.48 mM and that
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`preservation may be achieved “using zinc and ‘less than a preservative-effective
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`amount of a primary preservative agents’…” (POR, 9, 17; ALCON2023, ¶¶29, 60;
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`ALCON2025, ¶¶22, 26), which contradicts Patent Owner’s current argument and
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`supports Petitioner’s argument that “a POSA would combine zinc with another
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`preservative agent—in this case, the borate-polyols as taught by Chowan and
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`already present in both the Xia and Schneider formulations.” Reply, 8 (citing
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`EX1093, ¶¶28-38).
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`Observation #5: Alcon’s assertion that Dr. Xia’s testimony demonstrates
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`that the POSA would not have considered borate-polyol complexes to fall within
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`Xia’s definition of “primary preservative agent” mischaracterizes the testimony
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`4
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`
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`and overlooks other relevant testimony in the same passage that was not quoted as
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`well as relevant parts of the record. Counsel directly asked Dr. Xia:
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`Q…The POSA would not have known whether it was possible
`to use borate-polyol complexes as the sole preservative in an
`ophthalmic composition and achieve preservative efficacy?
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`
`
`A. I disagree because a POSA in this area, if you are using
`polymer—sorry—borate-polyol complex as preservative
`enhancers, you must read Chowhan’s may six, seven patent
`applications talking about complex.
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`So one of the reference I cite, Chowhan’s clearly teach that, that
`borate-polyol complex can be used for unpreserved ophthalmic
`solutions.
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`ALCON2166, 76:4-16.
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`Further, Alcon’s characterization that primary preservatives must be able to be
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`used alone contradicts the express definition of primary preservative in Xia that
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`does not require such activity: “Primary preservative agents are defined as non-
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`zinc containing compounds that derive their preservative activity through a
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`chemical or physiochemical interaction with microbial organisms.” EX1003, 4;
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`EX1093 ¶30. It also contradicts Alcon’s own assertions that Polymer JR is a
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`primary preservative (POR, 9, 17), although it cannot be used alone to pass PET
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`(ALCON2166, 73:6-11).
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`
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`5
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`
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`Observation #6: Alcon’s heavily redacted presentation of Dr. Xia’s
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`testimony is misleading and does not support their argument that Chowhan “would
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`not motivate a POSA to select a different polyol” from mannitol. First, the
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`excerpts concern Schneider and Xia rather than Chowhan, and overlook Dr. Xia’s
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`testimony supporting Petitioner’s arguments (Pet. 16-18, 47, 52; Reply, 12-14, 16).
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`In the same passage of his deposition cited by Alcon and immediately following,
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`Dr. Xia testified:
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`1) a POSA would use different polyols during optimization to improve the
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`combined Schneider/Xia formulation (ALCON2166, 63:17-24);
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`2) mannitol does not need to cause problems for a POSA to switch to
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`sorbitol; the chemical structures of the two compounds are very similar and should
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`behave similarly (id., 65:4-16); and
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`3) none of the references, including Schneider, advise against using sorbitol,
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`and Chowhan “named four polyols that they’re all under the FDA GRAS list,
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`generally recognized as safe ingredients,” providing added impetus for their use
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`(id., 66:3-67:6, 69:7-14). The four polyols named by Chowhan include sorbitol
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`and propylene glycol. Reply, 12; EX1004, 2:5-12; EX1093 ¶39. Dr. Xia’s
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`testimony therefore supports Petitioner’s arguments that a POSA would have been
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`motivated to replace mannitol with sorbitol and propylene glycol based on
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`Chowhan.
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`6
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`Observation #7: Patent Owner mischaracterizes Dr. Xia’s deposition
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`testimony to assert it is consistent with Alcon’s argument and contradicts
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`Petitioner’s argument that “flawed is Alcon’s demand that a POSA would need a
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`particular reason to select ‘propylene glycol and sorbitol over other polyols’ and
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`‘instead of mannitol.’” Dr. Xia’s cited deposition testimony was regarding just
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`three polyols – glycerin, propylene glycol, and mannitol. ALCON2166, 86:18-25.
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`Regarding sorbitol versus mannitol and in the same line of questioning, Dr. Xia
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`testified that a POSA would understand that “sorbitol and mannitol were equally as
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`good at forming borate-polyol complexes.” ALCON2166, 89:20-24. Dr. Xia
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`further testified in his second declaration that the ’299 Patent recites three
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`compositions “representative of the invention” that “each include mannitol and not
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`sorbitol.” EX1093, ¶52. Petitioner’s Reply likewise states Alcon’s arguments are
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`flawed because “[t]he patent claims do not exclude other polyols, and the ’299
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`Patent highlights compositions that include mannitol but not sorbitol” as
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`representative of the ’299 invention. Paper 35, 13-14.
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`Observation #8: Patent Owner mischaracterizes Dr. Xia’s testimony as
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`consistent with Alcon’s position that “the POSA following Chowan’s teaching
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`would be led to develop a composition containing a high concentration of borate-
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`polyol anions.” Dr. Xia states in his declaration a POSA understood not only that
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`sorbitol and propylene glycol each complex with boric acid (EX1093, ¶44-45), but
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`7
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`also appreciated “the differing amount by which sorbitol and mannitol increased
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`the acidity of a borate/polyol complex over propylene glycol” (id., ¶47). A POSA
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`understood borate-propylene glycol complexes provided only a “minor increase” in
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`anions over uncomplexed boric acid. Id., ¶48. Contrary to what Alcon implies in
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`this observation, a high concentration of borate-polyol complexes does not equate
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`with a high concentration of borate-polyol anions. Id., ¶48. Dr. Xia further
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`explained in his declaration that the borate-polyol concentration provided by
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`claims 1-13 and 15-21 of the ‘299 Patent are “far broader than Chowhan’s
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`preferred range.” Id., ¶55. This is consistent with Petitioner’s argument that “the
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`prior art motivated the POSA to combine zinc and borate-polyol formulations
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`having minimal or even no other Anionics.” Paper 35, 17.
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`Observation #9: Patent Owner’s assertion that Dr. Xia’s deposition
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`testimony is contradictory is incorrect and misleading. Dr. Xia testified that
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`European PET requires testing at 1-day, 7-days, 14-days, and 21-days and “you
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`[have] got to pass all days, all data points.” ALCON2166, 52:1-10. Dr. Xia also
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`testified in his declaration that testing under the USP 27 standard occurs at 7-days,
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`14-days, and 28 days. EX1093, ¶17. During examination by counsel for Alcon,
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`Dr. Xia was asked if “testing under both [USP 27 and European] preservative
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`efficacy criteria…[w]hat if there is a growth in pseudomonas after one day, does
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`that allow you to predict the results at seven days?” ALCON2166, 52:11-20
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`
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`8
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`
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`(emphasis added). Dr. Xia answered the “formulation is gone…[t]he formulation
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`failed[,]” because it did not pass both USP 27 and European PET. Id., 52:21-53:2.
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`When asked by counsel for the Petitioner “if you test the bacteria concentration
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`after one day and it has gone up, instead of down, that would for sure fail the
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`European standard, right?”, Dr. Xia consistently testified “[y]es, for European,
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`one day, you can reject your formulations, but in United States, in USP, it's seven
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`days.” Id., 115:15-17 (emphasis added). When asked by counsel for the Petitioner
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`“[i]f you measure your bacteria concentration after one day and it has gone up, do
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`you know whether it will pass or fail the USP test measurement at 7 days, 14 days,
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`28 days?” (id., 115:20-23), Dr. Xia again consistently testified “[y]ou cannot
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`predict that” (id., 115: 24). Dr. Xia’s testimony is consistent and reflects his
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`credibility and expertise on the different requirements by European PET and USP
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`27 PET.
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`Observation #10: Patent Owner mischaracterizes the record and Dr. Xia’s
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`testimony in asserting it undermines Dr. Xia’s credibility and contradicts
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`Petitioner’s argument that “[w]ithout any optimization, the art already provides for
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`a pH within 5.5-5.9 for a travoprost and HCO-40 containing ophthalmic solution.”
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`Counsel’s question related to a pH of 5.5 to 5.7, but the ’299 Patent does not
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`include a claim to a pH of 5.5-5.7. Claims 7, 12, 23, 26, and 27 of the ’299 Patent
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`recite “a pH from 5.5-5.9.” Schneider discloses a specific working example
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`9
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`
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`containing both travoprost and HCO-40 (Example 2, Formulation A) where the pH
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`is “6 ± 0.2.” EX1007, 9:21-42; EX1002, ¶37; EX1093, ¶58. Dr. Xia testified that
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`a POSA would understand this discloses a pH from 5.8 to 6.2. EX1002, ¶37;
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`EX1093, ¶58. Even Alcon’s expert admitted this example of Schneider teaches a
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`pH of 5.8. EX1045, 95:24-96:4. Thus, Dr. Xia’s testimony remains credible and
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`is consistent with Petitioner’s argument.
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`Observation #11: Patent Owner mischaracterizes the testimonial record as
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`well as Petitioner’s Reply to challenge Dr. Xia’s credibility and to assert his
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`deposition testimony is inconsistent with Petitioner’s argument. In regard to the
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`three references cited by microbiology expert Dr. Zhanel to assess the potential of
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`zinc to pass PET in an ophthalmic composition, Dr. Xia explained that because
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`“ophthalmic compositions include a variety of ingredients that may affect
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`preservative efficacy” then “non-ophthalmic compositions cannot predict PET
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`outcome for ophthalmic compositions.” EX1093, ¶19. Dr. Xia further explained
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`that the tests performed in Dr. Zhanel’s three cited references “are all very different
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`from a standard PET.” Id., ¶20. In addition, Dr. Xia discussed how one used “a
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`non-standard medium (Dolloff medium) and admitted the testing was affected by
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`the medium” and the other two “performed microorganism ‘kill’ tests, not
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`microorganism “inhibition” tests” where “killing tests (e.g., MBC or minimum
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`lethal concentration) cannot predict the outcome of PET.” Id., ¶20-21. He
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`
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`10
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`
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`highlights in his second deposition that “Example 18 [of EX1003] demonstrates
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`that zinc (without Polymer JR) at 0.48 mM passed PET rebutting Dr. Zhanel’s
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`conclusions that higher zinc concentrations of 0.5 mM and 0.76 mM are not
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`effective against E. coli or P. aeruginosa, respectively.” Id., ¶22. Petitioner’s
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`Reply at pages 5-6 reiterates each of these points. The deposition testimony cited
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`by Alcon in this observation is therefore consistent with Petitioner’s argument and
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`Dr. Xia’s testimony remains credible.
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`Observation #12: Alcon’s assertion that Dr. Xia’s testimony demonstrates
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`that Systane Free includes AMP is not relevant to Petitioner’s Reply arguments.
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`Petitioner used marketing materials for Systane® Free—Alcon’s own ophthalmic
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`product—to rebut Alcon’s assertions that a POSA would have no reason to think
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`that borate-polyol complexes work effectively with zinc or provide sufficient
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`preservation against both fungi and bacteria to pass USP27. Reply, 10-11. The
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`Exhibits Alcon questioned Dr. Xia about show on their face that 1) “borate and
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`sorbitol combine with the divalent zinc ion, creating a hostile environment for
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`microorganisms within the solution and effectively preventing microbial growth
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`within the bottle” (EX1042,2); 2) “Systane® Free meets all USP preservative
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`efficacy standards” (id.) and that AMP is a “pH adjuster” (EX1110). In any case,
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`Dr. Xia, who did not provide declaration testimony on any Systane Free materials,
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`only agreed at his deposition that the Systane® Free promotional materials disclose
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`11
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`
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`“AMP is a buffering agent. It’s not a preservative here.” ALCON2166, 95:1-3, 13-
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`22; 96:12-15.
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`Observation #13: Patent Owner mischaracterizes Dr. Xia’s testimony to
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`assert Petitioner and Dr. Xia apply a legally incorrect standard for a POSA. When
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`asked if a POSA is “trying to come up with something that’s patentable,” Dr. Xia
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`stated this was “not necessary” as it “involves unexpected results.” ALCON2166,
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`10:19-11:6. Regarding a POSA’s “ordinary creativity”, Dr. Xia testified “it means
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`not just focused on the examples. You have to be analytical and try to learn from
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`the examples, especially bad examples.” Id., 7:10-20. This is consistent with his
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`declaration testimony that a “POSA is presumed aware of all pertinent art and is a
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`person of ordinary creativity[,]…would consider a reference for all it discloses or
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`suggests, whether expressly spelled out or not, and would not look only to
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`examples and preferred embodiments[, and]…would consider what the combined
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`references would suggest, and not just the individual references.” EX1093, ¶8.
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`Dr. Xia further explained “Alcon and Dr. Majumdar’s assessment is based only on
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`treating the POSA a rigid and uncreative person with an unrealistically narrow
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`understanding of the references’ express teachings.” EX1093, ¶41.
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`12
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`Dated: May 25, 2018
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`Respectfully submitted,
`
`By: /Michael R. Houston/
`Michael Houston
`Registration No. 58,486
`FOLEY & LARDNER LLP
`321 North Clark Street, Suite 2800
`Chicago, Illinois 60654
`Telephone: 312-832-4500
`Facsimile: 312-832-4700
`mhouston@foley.com
`
`Counsel for Petitioner
`Argentum Pharmaceuticals LLC
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`13
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`CERTIFICATION OF SERVICE
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`The undersigned hereby certifies that a copy of the foregoing
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`PETITIONER’S RESPONSE TO PATENT OWNER’S MOTION FOR
`
`OBSERVATIONS ON CROSS-EXAMINATION OF PETITIONER’S
`
`REPLY WITNESS, DR. ERNING XIA was served on May 25, 2018, on
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`Counsel for Patent Owner via electronic mail to the following:
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`Dated: May 25, 2018
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`dkrinsky@wc.com
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`csuarez@wc.com
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`TravZ-IPR@wc.com
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`By: /Michael R. Houston/
`Michael Houston
`Registration No. 58,486
`Counsel for Petitioner
`
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`
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