IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC,
`MYLAN PHARMACEUTICALS INC., and MYLAN INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`
`
`Case IPR2015-00902 (Patent 8,669,290 B2)
` Case IPR2015-00903 (Patent 8,129,431 B2)1
`
`
`
`
`
`REPLY DECLARATION OF PAUL A. LASKAR, PH.D.
`
`
`1 A word-for-word identical paper has been filed in each proceeding identified in the
`
`heading. IPR2015-01871 has been joined with IPR2015-00903 and includes
`
`Petitioners Lupin Ltd. and Lupin Pharmaceuticals Inc. in addition to the parties
`
`identified above.
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC,
`MYLAN PHARMACEUTICALS INC., and MYLAN INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`
`
`Case IPR2015-00902 (Patent 8,669,290 B2)
` Case IPR2015-00903 (Patent 8,129,431 B2)1
`
`
`
`
`
`REPLY DECLARATION OF PAUL A. LASKAR, PH.D.
`
`
`1 A word-for-word identical paper has been filed in each proceeding identified in the
`
`heading. IPR2015-01871 has been joined with IPR2015-00903 and includes
`
`Petitioners Lupin Ltd. and Lupin Pharmaceuticals Inc. in addition to the parties
`
`identified above.
`
`
`
`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
`
`I.
`
`List of documents I considered in formulating my opinion in this
`declaration
`
`1.
`
`In formulating my opinion below, I have considered all documents cited
`
`in this Declaration.
`
`II.
`
`The Disclosure of Fu includes Tyloxapol
`
`2.
`
`Patent Owners’ experts take the position that Fu does not disclose
`
`tyloxapol to a skilled artisan. (EX2082, ¶¶ 92, 94, 180 / ¶¶ 84, 86, 136; EX2105, ¶
`
`94 / ¶ 92).2 I disagree. Fu teaches that the “nonionic ethoxylated octylphenol
`
`surfactant is an octylphenoxypoly(ethyleneoxy)ethanol with a mole ratio of
`
`ethylene oxide to octylphenol of between 3:1 and 40:1.” (See, e.g., EX1011, Claim
`
`3).3 Therefore, Fu teaches a series of ethoxylated octylphenol surfactant. (See also
`
`EX1079, 112:7-16 (Patent Owner’s expert admitting that given these mole ratios,
`
`Fu discloses a “series of octoxynols”)).
`
`3.
`
`Tyloxapol falls within the series disclosed by Fu. The mole ratio of
`
`ethylene oxide to octylphenol of tyloxapol is 8-10 to 1. (See EX2105, ¶ 86 / ¶ 84
`
`
`2 Citations to the Declarations of Dr. Williams and Dr. Davies are to the paragraph
`
`number(s) to their declarations in IPR2015-00902, followed by the paragraphs
`
`number(s) to their declarations in IPR2015-00903, with a slash separating the two.
`
`3 Citations to the exhibits of record will be to the exhibit numbers in IPR2015-00902
`
`unless stated otherwise.
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`1
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`Page 2
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`(providing n and m values of tyloxapol);4 EX1091, col. 1, lines 45-61 (“A preferred
`
`compound of this group is the product containing ten ether groups per p-tertiary-
`
`octylphenol nucleus which is known under the brand names, Superinone and
`
`Triton WR-1339, chemically as oxyethylated tertiary octylphenol formaldehyde
`
`polymer or p-isooctylpoly-oxyethylenephenol formaldehyde polymer, and,
`
`generically as tyloxapol”) (emphasis added). Thus, a skilled artisan would
`
`conclude that tyloxapol falls within the disclosure of Fu.
`
`III. Tyloxapol is an Antioxidant
`
`4.
`
`I understand that Patent Owners’ experts have stated that since Ogawa
`
`Example 6 is a bromfenac formulation, the bromfenac in the solution is susceptible
`
`to oxidation. (EX2105, ¶ 74 / ¶ 72) (“Ogawa Example 6 is a bromfenac
`
`formulation, and bromfenac is susceptible to oxidation”). Moreover, Patent
`
`Owners’ experts have identified the surfactant polysorbate 80 as the source of
`
`bromfenac’s degradation in Ogawa providing a motivation to replace the
`
`
`4 The values reported by Dr. Davies are consistent with Schott (EX1019 / EX1024).
`
`Using Schott, which states that “[t]yloxapol is essentially an oligomer of octoxynol
`
`9” including explaining that “[d]espite the methylene bridges, it has practically the
`
`same hydrophilic-lipophilic balance as octoxynol,” the mole ratio of ethylene oxide
`
`to octylphenol of tyloxapol is 9.6 to 1.
`
`2
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`Page 3
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`
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`surfactant. (Id. (“A person of ordinary skill in the art would expect bromfenac to
`
`
`
`
`
`
`
`degrade in the presence of . . . polysorbate 80.”)).5
`
`5.
`
`I made a similar observation about the
`
`; see also EX2114, 157:18-22 (
`
`6.
`
`I also explained during my deposition,
`
`).
`
`
`5 In that same section, Dr. Davies also takes the position that tyloxapol would also
`
`lead to the generation of peroxides and hydroperoxides. I disagree, and I will address
`
`Dr. Davies’ contentions later in this declaration.
`
`3
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`Page 4
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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` (EX2114, 157:13-18
`
`(emphasis added)).
`
`7.
`
`Knowing that polysorbate 80 was the cause of oxidative degradation,
`
`the skilled artisan would have replaced the polysorbate 80 with another non-ionic
`
`surfactant that did not share polysorbate 80’s liability. The skilled artisan would
`
`have known that tyloxapol, like polysorbate 80, is not only a non-ionic surfactant
`
`commonly used in ophthalmic solutions but, unlike polysorbate 80, it also has
`
`antioxidant properties.
`
`
`
` (EX2114, 183:1-7).
`
`8.
`
`Put another way, polysorbate 80 is an oxidizing agent (whereas
`
`tyloxapol is an antioxidant).6 Moreover, Patent Owner’s experts agree with my
`
`conclusions that polysorbate 80 generates peroxides which negatively impacts the
`
`stability of Example 6 of Ogawa, and that the stability of the bromfenac solutions
`
`disclosed in Ogawa can be improved by replacing polysorbate 80. (EX2105, ¶ 74
`
`/ ¶ 72).
`
`
`
`
`6 Polysorbate 80 is an oxidizing agent because it degrades to produce peroxides and
`
`hydroperoxides. (See also EX2105, ¶ 74 / ¶ 72).
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`4
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`Page 5
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`9.
`
`Consistent with these conclusions, Dr. Williams, Patent Owner’s other
`
`expert has stated that based on the teachings of Ogawa, a skilled artisan would have
`
`considered other antioxidants “to even further improve bromfenac’s chemical
`
`stability.” (EX2082, ¶ 124 / ¶ 114). As Patent Owner’s expert states:
`
`A person of ordinary skill[] considering the teachings of Ogawa—said
`
`by Dr. Laskar to constitute the closest prior art—would have been led
`
`to consider antioxidants, other than those disclosed in Ogawa, to even
`
`further improve bromfenac’s chemical stability. For example, U.S.
`
`Patent No. 5,856,345 to Doi discloses antioxidants to stabilize aqueous
`
`solutions of pranoprofen, also an NSAID (EX2025 at abstract).
`
`(EX2082, ¶ 124 / ¶ 114).
`10. Patent Owner’s expert, Dr. Davies believes a skilled artisan would not
`
`have
`
`turned
`
`to
`
`tyloxapol because he believes
`
`that
`
`tyloxapol generates
`
`hydroperoxides/peroxides (i.e., it is an oxidizing agent). (EX2105, ¶ 74 / ¶ 72).
`
`This is where Dr. Davies and I disagree, tyloxapol does not generate
`
`hydroperoxides/peroxides but is in fact, as described by numerous references, a
`
`general purpose antioxidant.
`
`11. Turning to Dr. Davies’ mistaken belief that tyloxapol is an oxidizing
`
`agent: Rather than simply reviewing the relevant tyloxapol art (since he has never
`
`worked with tyloxapol), to support his proposition that tyloxapol (like polysorbate
`
`80) is an oxidizing agent, Dr. Davies cites to EX2097 at 1678 and EX2120 at 393-
`
`5
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`Page 6
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`94. For example, Dr. Davies refers to the propensity of diphenylmethane (the
`
`structure depicted below) to produce peroxides/hydroperoxides:
`
`12. For reference, the structure of tyloxapol is shown below:
`
`
`
`(EX1089, 9902).
`
`
`
`6
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`Page 7
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`13. Putting aside whether a skilled artisan would have considered these
`
`compounds or the art analogous,7 Dr. Davies’ reference does not discuss tyloxapol.8
`
`Neither one of Dr. Davies’ two references actually discusses tyloxapol. Moreover,
`
`Dr. Davies’ conclusion (i.e., that tyloxapol produces peroxides/hydroperoxides and
`
`hence is an oxidizing agent) is contrary to the numerous prior art references
`
`explicitly discussing tyloxapol and its antioxidant properties, including actual
`
`experimental data of record refuting any notion that tyloxapol is an oxidizing agent.
`
`Indeed, even Patent Owners’ other expert, Dr. Williams, has provided a reference
`
`(Doi) that teaches that the class of compounds to which tyloxapol belongs to not
`
`only have antioxidant properties, but that he would look to Doi “to even further
`
`improve bromfenac’s chemical stability” of Ogawa. (EX2082, ¶ 124 / ¶ 114).
`
`14. Turning to the prior art: As of the relevant priority date, tyloxapol’s
`
`general purpose antioxidant properties for a variety of chemical species over a
`
`
`7 While I do not dispute that skilled artisans can make conclusions based on
`
`reviewing analogous compounds, the reference only provides information for non-
`
`aqueous solvents including showing that in some cases the propensity of
`
`diphenylmethane to produce hydroperoxide/peroxide radicals is zero (i.e., 2-
`
`methylpropan-3-ol).
`
`8 This is also true for the other reference Dr. Davies relies upon.
`
`7
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`Page 8
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`broad spectrum of applications would have been well known to the skilled artisan.
`
`Indeed, its antioxidant properties were so well known, that they were referenced in
`
`well-known treatises like the Merck Index and Remington: The Science and
`
`Practice of Pharmacy. (EX1089, 9902; EX1106, 1415).
`
`15. U.S. Patent No. 5,856,345 to Doi (EX2025) was a reference provided
`
`by Patent Owner’s expert, Dr. Williams. Although Doi teaches another NSAID,
`
`Dr. Williams has testified that “[a] person of ordinary skill[] considering the
`
`teachings of Ogawa [would look to Doi’s antioxidants] . . . to even further improve
`
`bromfenac’s chemical stability.” (EX2082, ¶ 124 / ¶ 114). Specifically, Doi
`
`teaches NSAIDs in ophthalmic preparation (“eye drops”) can be stabilized with the
`
`inclusion of alkylphenols. (EX2025, col. 3, lines 7-9, col. 3, lines 36-39).
`
`16. An “example” of an alkylphenol in Doi includes 2,2'-methylenebis(4-
`
`methyl-6-tert-butylphenol), (EX2025, col. 3, lines 51-52), which is depicted below:
`
`17. Tyloxapol belongs to the alkylphenol class of compounds because it is
`
`made from the alkylphenol p-(1,1,3,3-tetramethybutyl) phenol also referred to as
`
`
`
`8
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`Page 9
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`p-tertiary-octylphenol. (EX1091, col. 1, lines 45-61 (“A preferred compound of
`
`this group is the product containing ten ether groups per p-tertiary-octylphenol
`
`nucleus which is known under the brand names, ‘Superinone’ and ‘Triton WR-
`
`1339,’ chemically as oxyethylated tertiary octylphenol formaldehyde polymer or
`
`p-isooctylpoly-oxyethylenephenol formaldehyde polymer, and, generically as
`
`tyloxapol”); EX1089, 9902 (disclosing that tyloxapol is made from p-(1,1,3,3-
`
`tetramethybutyl) phenol); EX1106, 1415 (same)).
`
`18. The structure of tyloxapol is depicted below and the structural
`
`similarities to 2,2'-methylenebis(4-methyl-6-tert-butylphenol) (above) would have
`
`been clear to the skilled artisan.
`
`
`
`19. Moreover, in reference to tyloxapol’s p-(1,1,3,3-tetramethybutyl)
`
`phenol component (e.g.., alkylphenol), the prior art explains that tyloxapol “retains
`
`functional groups to the original alcohol monomer, and these may confer its
`
`antioxidant capacity.”
`
`
`
`(EX1094, 1221:2:2-1222:1:1
`
`(emphasis added)).
`
`9
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`Page 10
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`Therefore, to a skilled artisan, tyloxapol is within the alkylphenols disclosed by
`
`Doi for use in ophthalmic preparations.
`
`20. Again, Patent Owner’s expert, Dr. Williams, has testified “[a] person
`
`of ordinary skill[] considering the teachings of Ogawa [would look to Doi’s
`
`antioxidants] . . . to even further improve bromfenac’s chemical stability.”
`
`(EX2082, ¶ 124 / ¶ 114). Doi shows that the alkylphenol class of compounds,
`
`within which tyloxapol is included, have antioxidant properties, and Dr. Williams
`
`has admitted that inclusion of such compounds in ophthalmic preparations would
`
`have led to improvements in the bromfenac solutions of Ogawa. (EX2082, ¶ 124 /
`
`¶ 114).
`
`21. Other prior art references also discuss the antioxidant abilities of
`
`tyloxapol. For example, the Merck Index—a well-known treatise referenced by
`
`pharmaceutical formulators—teaches that tyloxapol is used as “an ophthalmic
`
`excipient.” (EX1089, 9902). In addition, the Merck Index also explains that
`
`tyloxapol is “oxidized by metals.” (EX1089, 9902) (emphasis added). When a
`
`first species (i.e., tyloxapol in the context of the Merck Index entry) is “oxidized
`
`by” a second species (i.e., metals in the context of the Merck Index entry), it means
`
`the first species is an antioxidant in that context. (See also EX2082, ¶ 53 / ¶ 44
`
`(identifying sodium sulfite as an antioxidant); EX1080, 114:6-16 (explaining that
`
`sodium sulfite (i.e., first species/antioxidant) can be “oxidized by” chromic acid
`
`10
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`(i.e., second species)). Therefore, the Merck Index teaches both that tyloxapol has
`
`antioxidant properties and that it is used in ophthalmic preparations.
`
`22. Remington: The Science and Practice of Pharmacy (19th Ed) (EX1106)
`
`teaches, much like the Merck Index, that tyloxapol is “oxidized by metals.”
`
`(EX1106, 1415). For the same reason as discussed above with the Merck Index,
`
`the reference to tyloxapol being “oxidized by metals” would have shown to a
`
`skilled artisan that tyloxapol is an antioxidant. Moreover, the statements in
`
`Remington would have been relevant to a skilled artisan. (EX1079, 24:8-15 (Patent
`
`Owners’ expert testifying that he uses Remington “quite frequently”); see also id.,
`
`16:7-14 (agreeing that all of his answers are from the perspective of a skilled artisan
`
`unless he states otherwise). Therefore, Remington also discusses tyloxapol’s
`
`antioxidant properties.
`
`23. U.S. Patent App. Pub. No. 2003/0053956 (EX1105) (“the ’956
`
`application”) and its equivalent PCT International Patent App. Pub. No. WO
`
`02/058610 (EX1148) (“WO ’610”) disclose liquid preparations for nasal and/or
`
`pharyngeal applications. (EX1105, Abstract; EX1148, Abstract). In addition to
`
`explaining that tyloxapol is an surfactant (“dispersant agent”), the ’956 application
`
`and WO ’610 teach that it is an antioxidant and free radical scavenger: “[a]lkylaryl
`
`polyether alcohol polymers such as tyloxapol are known to be active as mucolytics,
`
`antioxidants, free radical scavengers, and as dispersant agents.” (EX1105, ¶
`
`11
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`Page 12
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`[0032] (emphasis added); see also EX1148, 6:25-28 (same)). Moreover, as the
`
`’956 application explains, tyloxapol is a “free radical scavenger” meaning that it
`
`will quench species such as peroxides and hydroperoxides.
`
`24.
`
`Indeed, the ’956 application and WO ’610 teach the entire class of
`
`“[a]lkylaryl polyether alcohol polymers . . . are known to be active as. . .
`
`antioxidants, free radical scavengers . . .” (Id.) The ’956 application and WO
`
`’610 provide the structure of the alkylaryl polyether alcohol polymers:
`
`
`
`“Wherein R is an ethylene, R1 is tertiary octyl, X is greater than 1 . . . .”
`
`(EX1105, ¶¶ [0081-82]; EX1148, 9:21-35) (emphasis added). This indicates that
`
`the entire class of compounds have antioxidant activity (i.e., as X increases).
`
`Moreover, the structure is very similar to the 2,2'-methylenebis(4-methyl-6-tert-
`
`butylphenol) disclosed in Doi, (see supra ¶ 16), which further shows that the skilled
`
`artisan reading Doi’s statement that alkylphenols have antioxidant properties would
`
`have understood those properties to extend to tyloxapol.
`
`25. Furthermore, properties of materials used in nasal solution would have
`
`been relevant to ophthalmic preparations. (EX1001 (‘290 patent), col. 4, lines 10-
`
`12
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`Page 13
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`13; EX1004, col. 4, lines 60-62; see also, EX1079, 20:13-21 (patent owners’ expert
`
`testifying that “I -- I study -- these often involve solution formulations and
`
`suspension formulations especially the one for the inhalation and nasal so the
`
`characteristics are the same, but my application at the current time is not necessarily
`
`for the eye but for the lungs and nasal so the properties of the materials I mean,
`
`tool [sic] me -- to a person of skill in the art would be quite similar.”) (emphasis
`
`added).9 Therefore, the ’956 application discusses tyloxapol’s antioxidant
`
`properties in a relevant art space.
`
`26. Kennedy
`
`(EX1092) discloses
`
`“pharmaceutical
`
`compositions
`
`containing alkylaryl polyether alcohol polymer tyloxapol” for treating respiratory
`
`inflammation. (EX1092, col. 1, lines 20-23). Art in the respiratory space would
`
`have been relevant. (See also EX1079, 19:21-20:21 (patent owners’ expert
`
`testifying about the relevance of the inhalation formulations medications designed
`
`for “lungs” because “the properties of the materials I mean, tool [sic] me -- to a
`
`person of skill in the art would be quite similar.”). In addition to discussing
`
`tyloxapol’s surfactant properties, Kennedy also discusses its antioxidant properties:
`
`It has recently been shown that a previously known class of drugs, the
`
`alkylaryl polyether alcohol polymers, are potent antioxidants useful
`
`
`9 See also EX1105, ¶¶ [0180]-[0190]; EX1148, 28:27-30:20 discussing excipients,
`
`pH ranges, and other parameters in common with ophthalmic preparations.
`
`13
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`Page 14
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`in the treatment of mammalian diseases. Alkylaryl polyether alcohol
`
`polymers are used commercially as surface active detergents and
`
`wetting agents. The best known of this class is tyloxapol, a polymer
`
`of 4-(1,1,3,3-tetramethylbutyl)phenol with formaldehyde and oxirane.
`
`(EX1092, col. 4, lines 46-56 (emphasis added)).
`
`27. Moreover, a skilled artisan would find Kennedy’s discussion of the
`
`detrimental impact of oxygen radicals (which would include partially reduced O2
`
`species) and the antioxidant ability of tyloxapol to limit such radicals to be relevant.
`
`(EX1092, 1:27-61). As discussed above, Patent Owner’s expert (Dr. Williams) has
`
`admitted that the skilled artisan would have been guided by the teachings of Doi to
`
`improve the stability of Ogawa’s bromfenac solutions. (EX2082, ¶ 124 / ¶ 114).
`
`Doi teaches that the presence of oxygen leads to degradation, and teaches that
`
`methods to limit oxygen’s presence enhances stability. (EX2025, col. 3, lines 57-
`
`65).
`
`28. A person of ordinary skilled in the art would have understood that
`
`based on the teachings of Doi, methods to limit oxygen and quench any ensuing
`
`14
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`Page 15
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`radicals10 (which would include partially reduced species) would be relevant.11 As
`
`Kennedy teaches, tyloxapol’s antioxidant abilities include the ability to quench
`
`oxygen radicals.12 Therefore, Kennedy teaches that tyloxapol is a “potent
`
`antioxidant” and it’s “best known of [its] . . . class” in a relevant art space.
`
`(EX1092, col. 4, lines 46-56).
`
`29. Ghio (EX1093) discusses diseases of the respiratory system such as
`
`cystic fibrosis. Again, art in the respiratory space would have been relevant. (See
`
`also EX1079, 19:21-20:21 (patent owners’ expert testifying about the relevance of
`
`the “inhalation” formulations medications designed for “lungs” because “the
`
`properties of the materials I mean, tool [sic] me -- to a person of skill in the art
`
`would be quite similar.”). Ghio teaches not only tyloxapol’s surfactant properties
`
`but also its antioxidant properties:
`
`
`10 The ensuing radicals lead to oxidative degradation since they are considered
`
`activated forms of oxygen.
`
`11 Moreover, Doi teaches that his solutions may be used together or separately.
`
`(EX2025, col. 3, lines 5-6).
`
`12 See also EX1105, ¶ [0032] (discussing that tyloxapol acts as a “free radical
`
`scavenger”).
`
`15
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`Page 16
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`As can be explained below, this invention describes how alkylaryl
`
`polyether alcohol polymers are useful as antioxidants in blocking
`
`oxidant reactions and biologic injury from partially reduced O2
`
`species.13 Alkylaryl polyether alcohol polymers are known and used
`
`commercially as surface active detergents and wetting agents . . . . The
`
`best known of this class is tyloxapol. . . .
`
`(EX1093, col. 2, lines 38-50). Therefore, Ghio discusses tyloxapol’s antioxidant
`
`properties.
`
`30. Finally, the experimental data of Yasueda (EX1012) shows tyloxapol
`
`cannot be an oxidizing agent (like polysorbate 80) as Dr. Davies contends.
`
`Experiment 4 of Yasueda demonstrated that the amount of pranlukast in the
`
`solution with polysorbate 80 (i.e., Formulation D) decreased by 15% after two
`
`weeks of storage, and only by 0.5%, on average, during the same time period when
`
`using tyloxapol (i.e., Formulation A). (EX1012, col. 6, line 55–col. 7, line 43,
`
`Tables 4 and 5).
`
`31.
`
`In order to improve the performance of the polysorbate 80 formulation,
`
`antioxidant BHT had to be added (i.e., Formulation E). (EX1079, 23:16-24:7
`
`
`
`(testifying that BHT is an antioxidant stabilizer); EX1061, 270:3-5 (same).
`
`
`13 See discussion above about the teachings of Doi as they relate to partially reduced
`
`O2 species.
`
`16
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`Page 17
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`32. Contrary to Dr. Davies opinion that tyloxapol is also an oxidizing
`
`agent, Yasueda (EX1012) shows that the tyloxapol solutions did not need the
`
`antioxidant BHT to improve its performance. Therefore, tyloxapol cannot be
`
`considered an oxidizing agent in view of Yasueda.
`
`33. Moreover, the addition of tyloxapol to Ogawa Example 6 would not
`
`mean that the skilled artisan would have removed other components (e.g, the
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`antioxidant sodium sulfite). A POSA would have known of the benefits of adding
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`the antioxidant sodium sulfite based on Ogawa’s explanation. (See, e.g., EX1004,
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`col. 8, lines 48-51; EX2105, ¶ 41). Thus, the skilled artisan would been motivated
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`to only replace polysorbate 80 of Ogawa Example 6 with tyloxapol (while leaving
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`the other components alone) with a reasonable expectation that the tyloxapol would
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`have resulted in improved properties. Optimizing this tyloxapol containing
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`formulation would have been a matter of routine experimentation.
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`34. Likewise, even Patent Owners’ expert do not state that the inclusion of
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`additional antioxidants as suggested in Doi would have meant removing other
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`components of Example 6 of Ogawa. (See, e.g., EX2082, ¶ 124 / ¶ 114 (stating
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`that a POSA would have considered other antioxidants “other than those disclosed
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`in Ogawa” but makings no affirmative statement that the inclusion of such other
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`17
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`Page 18
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`antioxidants would have been to the exclusion of what had already been used in the
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`Example 6 of Ogawa). Doi itself recognizes the possibility of having more than
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`one antioxidant. (EX2025, 2:1-4, 10:39-43).
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`IV. Benzalkonium Chloride and Acidic NSAIDs Form Complexes
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`35. Example 5 of Fu compares six different formulations. Each
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`formulation explicitly contains four components: water; ketorolac; benzalkonium
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`chloride; and one of the three surfactants octoxynol 40, polysorbate 80, or Myrj 52.
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`(EX1011, Example 5).
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`36. According to Fu, those four components are included in the
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`formulations of the purported invention of Fu, although other excipients are
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`optionally added. Fu states:
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`The formulations of the present invention include an NSAID active
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`agent in an effective amount for ophthalmic treatment, a quaternary
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`ammonium preservative, a stabilizing amount of an ethoxylated
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`octylphenol as a nonionic surfactant, optionally including other
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`excipients such as a chelating agent, a tonicifier, a buffering system, a
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`viscosity agent as well as other stabilizing agents.
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`(EX1011, col. 6, lines 15-22). Fu repeatedly makes a similar statement. (EX1011,
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`col. 7, lines 8-26, col. 10, lines 12-34). Example 5 of Fu does not state those other
`
`excipients are included.
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`37. As an example, the formulations containing water, ketorolac,
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`benzalkonium chloride, and polysorbate 80 turned turbid. I agree with the
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`18
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`Page 19
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`Protective Order Material FRE 615 Reply Declaration of Dr. Paul A. Laskar (EX1104)
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`inventors of Fu that the ketorolac-benzalkonium chloride complex is the cause of
`
`the turbidity. (EX1011, col. 18, lines 23-26).
`
`38. Dr. Davies states that bromfenac is freely soluble in water, (EX2105,
`
`¶ 49), and “thus any solubilizing effect of polysorbate 80 or tyloxapol would not
`
`be required to dissolve or solubilize bromfenac sodium.” (EX2105, ¶ 56). Dr.
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`Davies’s statement misses the point, because the use of the non-ionic surfactant, as
`
`can be evidenced from Fu, was to address the complex formed between ketorolac
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`and benzalkonium chloride. (EX1011, col. 19, lines 19-22). Thus, the relevant
`
`inquiry is the non-ionic surfactants function with respect to the complex that is
`
`formed between the NSAID and benzalkonium chloride.
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`V.
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`Conclusion
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`39.
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`I hereby declare that all statements made herein of my own knowledge
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`are true and that all statements made on information and belief are believed to be
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`true; and further that these statements were made with the knowledge that willful
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`false statements and the like so made are punishable by fine or imprisonment, or
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`both, under Section 1001 of Title 18 of the United States Code.
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`Respectfully Submitted,
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`
`Dr. Paul A. Laskar
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`Date: March 18, 2016
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`19
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`Page 20
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