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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`APOTEX CORP.,
`Petitioner
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`v.
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`ALCON RESEARCH, LTD.,
`Patent Owner.
`
`
`Case IPR2013-00428
`U.S. Patent No. 8,268,299
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`PATENT OWNER ALCON RESEARCH, LTD.’S
`PRELIMINARY RESPONSE TO PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,268,299
`UNDER 35 U.S.C. §§ 311–319 AND 37 C.F.R. §§ 42.1–.80, 42.100–.123
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`TABLE OF CONTENTS
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`BACKGROUND ....................................................................................................... 3
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`ARGUMENT ............................................................................................................. 6
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`I.
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`II.
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`Apotex’s Petition Is Based on an Unreasonable Construction of
`“Self-Preserved.” ............................................................................................. 8
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`Apotex Has Failed To Show a Substantial Likelihood that Any Claim Is
`Unpatentable. ................................................................................................. 13
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`CONCLUSION ........................................................................................................ 23
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`U.S. Patent No. 8,268,299 (“the ’299 patent”) is directed to “multi-dose,
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`self-preserved ophthalmic compositions.” When ophthalmic compositions—such
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`as eye drops—are administered to a patient, it is critical that the compositions not
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`contain harmful microorganisms that can cause sight-threatening eye infections.
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`Eye drops that are packaged in multi-dose containers must therefore be able to
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`resist the growth of microbes from the time the container is opened until the last
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`dose is used. Traditionally, that resistance to microbial growth has been provided
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`by preservative chemicals that are included in the compositions. Conventional
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`ophthalmic preservatives, however, have disadvantages; in particular, they can be
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`toxic to parts of the eye and thus cause side effects. Every claim of the ’299 patent
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`is directed to ophthalmic compositions that are “self-preserved”—that is, they “do
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`not contain a conventional antimicrobial preservative.” APO 1001, col. 3, ll. 27–
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`29.
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`Apotex Corp.’s (“Apotex’s”) Petition for inter partes review of the claims of
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`the ’299 patent attempts to write the “self-preserved” limitation out of the claims
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`altogether. Despite the fact that the specification expressly defines “self-
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`preserved” to mean that the compositions “do not contain a conventional
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`antimicrobial preservative,” APO 1001, col. 3, ll. 27–29, Apotex premises its
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`Petition on the proposition that “[t]he specification of the ’299 patent does not
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`define the term ‘self-preserved.’” Pet. at 5. Having ignored the specification’s
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`definition for this claim term, Apotex then proceeds to define “self-preserved” to
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`mean that a composition “can be administered to patients in a multi-dose container
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`and need not be maintained aseptically because of [the composition’s]
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`antimicrobial properties”—without regard to whether the composition achieves
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`those properties by using conventional antimicrobial preservatives. Pet. at 5.
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`Apotex’s definition, however, is fundamentally inconsistent with the definition of
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`this term set forth in the specification, and as a result, is incorrect and
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`unreasonable. Therefore, it cannot be the “broadest reasonable interpretation
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`consistent with the specification” that is to be used in IPR proceedings. In re
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`Abbott Diabetes Care Inc., 696 F.3d 1142, 1148 (Fed. Cir. 2012); see 37 C.F.R.
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`§ 42.100(b).
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`Because Apotex has based its Petition on an erroneous construction of “self-
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`preserved,” it has failed to demonstrate, as it must, that it has a reasonable
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`likelihood of success in showing that the challenged claims are obvious over the
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`prior art. “Self-preserved” is a limitation of every claim and is emphasized
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`throughout the specification as an important aspect of the invention, and yet not
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`one of Apotex’s proposed Grounds for unpatentability describes where this
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`limitation is present in the cited art. The result of Apotex’s failure to apply the
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`proper construction of this claim term is that each of its proposed Grounds for
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`unpatentability effectively fails to account for an express claim limitation and fails
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`2
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`to show that the claims as a whole containing this express limitation would have
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`been obvious over the prior art. Accordingly, Apotex’s Petition fails to show that
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`the person of ordinary skill in the art would have used the particular ingredients
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`and quantities in the challenged claims to make a self-preserved composition—as
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`that term is properly construed—or that the person of ordinary skill would have
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`had a reasonable expectation of success in making such a self-preserved
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`composition. The Petition should therefore be denied.
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`BACKGROUND
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`The ’299 patent is directed to “multi-dose, self-preserved ophthalmic
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`compositions.” APO 1001, Abstract. An example of such a composition is a
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`pharmaceutical eye drop sold in a bottle containing more than one dose. See APO
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`1001, col. 1, ll. 33–46. A patient may administer medication from one such bottle
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`every day for weeks at a time. Each time the patient opens the bottle and applies
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`an eye drop to their eye, the potential for microbial contamination of the drug
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`product exists. This can occur in a variety of ways; for example, a user may
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`inadvertently touch the tip of the bottle with a finger or eyelash, providing a
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`potential source of microbial contamination. Thus, even if an eye drop is
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`manufactured under sterile conditions, it must be able to resist the growth of both
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`bacteria and fungi that, if allowed to multiply, could cause an eye infection. That
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`3
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`resistance to the growth of bacteria and fungi is referred to generally as
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`“preservative efficacy.”
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`Because of the serious, sight-threatening conditions that can develop if a
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`patient uses contaminated eye drops, multi-dose ophthalmic compositions are
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`required to meet published preservative efficacy standards, such as the USP 27
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`requirements referred to in the claims. Preservative efficacy standards measure the
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`extent to which a composition can reduce the concentration of particular microbes
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`over specified periods of time. For example, the USP 27 standard requires (among
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`other things) that a composition that is inoculated with particular bacterial species,
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`and then incubated, exhibit a one-log (90%) reduction in the bacteria after one
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`week, a three-log (99.9%) reduction in bacteria after three weeks, and no increase
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`in bacteria after day 14. Id. col. 7, ll. 33–35.
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`Prior art multi-dose ophthalmic compositions have generally met
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`preservative efficacy requirements by including an antimicrobial preservative—a
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`chemical ingredient specifically intended to prevent the proliferation of bacteria,
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`fungi, and/or other microbes. Id. col. 1, ll. 56–59. However, such preservatives
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`have disadvantages; the tissues of the eye are sensitive to exogenous chemical
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`agents, and so ingredients that inhibit or kill microbes may also cause irritation or
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`damage to these sensitive tissues. Id. col. 1, ll. 60-67.
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`4
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`The invention disclosed and claimed in the ’299 patent enables compositions
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`to meet preservative efficacy standards without a conventional ophthalmic
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`preservative. E.g., id. col. 3, l. 33 – col. 4, l. 25. The invention accomplishes this
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`by using a combination of particular concentrations of zinc chloride, boric acid,
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`sorbitol, and propylene glycol, in a solution that also has a limited concentration of
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`negatively charged ions, known as “anions,” which the Alcon inventors found to
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`interfere with preservative effects. E.g., id. col. 4, ll. 41–53, col. 5, ll. 14–31, col.
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`6, ll. 6–53, col. 15, ll. 36–55. Every claim of the ’299 patent requires this
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`particular combination of ingredients. Id. cols. 25–28. When the various
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`ingredients are put together in the specific way that the claims require, the resulting
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`solution meets preservative efficacy requirements—another requirement of every
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`claim of the patent. E.g., id. col. 15, ll. 36–55. Finally, every claim of the ’299
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`patent requires the composition to be “self-preserved”—that is, they “do not
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`contain a conventional antimicrobial preservative.” Id., col. 3, ll. 28–29.
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`The ’299 patent is commercially embodied in Alcon’s TRAVATAN Z®
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`product, an eye drop used to treat glaucoma (a serious eye disease that leads to
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`blindness) and ocular hypertension (elevated pressure of the fluid within the eye, a
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`precursor to glaucoma). Several of the dependent claims of the ’299 patent are
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`directed specifically to TRAVATAN Z, in particular to the use of the preservative
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`system described above with travoprost (the active ingredient in TRAVATAN Z)
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`5
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`as well as to certain other aspects of the TRAVATAN Z formulation. Because
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`glaucoma and ocular hypertension are both chronic conditions, patients with either
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`condition are likely to require treatment for the rest of their lives. Those who are
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`prescribed TRAVATAN Z are likely to use it every day for years on end. The
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`invention claimed in the ’299 patent enables TRAVATAN Z to adequately prevent
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`microbial growth without a conventional ophthalmic preservative, and thus to meet
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`the needs of patients with glaucoma and ocular hypertension while avoiding the
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`potential for adverse side effects caused by the use of a conventional preservative.
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`A key aspect of TRAVATAN Z’s ongoing success, and of the benefits it brings to
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`patients, is that it is a self-preserved composition in accordance with the ’299
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`patent.
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`ARGUMENT
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`In order for an IPR to be initiated, Apotex must show that “there is a
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`reasonable likelihood that [it] will prevail with respect to at least 1 of the claims
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`challenged in the petition”—that is, a reasonable likelihood that at least one of the
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`claims of the ’299 patent is invalid for the reasons Apotex articulates. 35 U.S.C.
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`§ 314(a). As part of making this showing, for each claim in the ’299 patent,
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`Apotex is required to “specify” in its Petition “where each element of the claim is
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`found in the prior art patents or printed publications relied upon.” 37 C.F.R.
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`§ 42.104(b)(4); Wowza Media Sys., LLC v. Adobe Sys., Inc., IPR2013-00054,
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`6
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`
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`Paper No. 12, at 15 (P.T.A.B. Apr. 8, 2013). If a Petition fails to show how the
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`asserted prior art discloses or leads to each and every limitation of the claims, the
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`Petition should be denied. Wowza, IPR2013-00054, Paper No. 12, at 15; Veeam
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`Software Corp. v. Symantec Corp., IPR2013-00144, Paper No. 11, at 11–12
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`(P.T.A.B. Aug. 7, 2013).
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`Every asserted ground of invalidity in Apotex’s Petition suffers the same
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`fatal flaw: Apotex fails to address the “self-preserved” limitation of the claims, as
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`properly construed. While it purports to apply the “broadest reasonable
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`interpretation” of the term “self-preserved,” it bases its invalidity arguments on a
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`definition of “self-preserved” that directly contradicts the specification. That is
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`incorrect, and unreasonable, as a matter of law. And because Apotex’s definition
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`effectively strips from each and every claim the requirement that the claimed
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`compositions not contain a conventional ophthalmic preservative, its asserted
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`Grounds of invalidity are all facially deficient—they are all missing a material
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`limitation. Apotex has therefore failed to show a reasonable likelihood that any
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`claim of the ’299 patent is obvious, and its Petition should be denied in its entirety.
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`Alcon’s arguments herein are limited to the single issue of the construction
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`of “self-preserved.” Regardless of that claim construction, however, Alcon also
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`disagrees with Apotex’s obviousness allegations, and reserves the right to respond
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`to them and to present additional evidence and arguments should the Board
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`7
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`
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`institute an IPR. See 37 C.F.R. § 42.107; Athena Automation Ltd. v. Husky
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`Injection Molding Sys. Ltd., IPR2013-00290, Paper 13 (P.T.A.B. Sept. 3, 2013).1
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`I.
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`Apotex’s Petition Is Based on an Unreasonable Construction of “Self-
`Preserved.”
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`In an IPR—as in any other proceeding before the PTO—patent claims “are
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`to be given their broadest reasonable interpretation consistent with the
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`specification.” In re Sneed, 710 F.2d 1544, 1548 (Fed. Cir. 1983) (emphasis
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`added); see Abbott, 696 F.3d at 1149; 37 C.F.R. § 42.100(b). Indeed, the Federal
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`Circuit has explained that in selecting the broadest reasonable interpretation, “it
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`would be unreasonable for the PTO to ignore any interpretive guidance afforded by
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`1 Contrary to Apotex’s arguments, there is nothing obvious about the claims of the
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`’299 patent. The PTO has already considered the principal references on which
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`Apotex relies (Xia and Chowhan) and has allowed the claims over them. See APO
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`1008 at 378–79. And in the event that an inter partes review is initiated, Alcon
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`will adduce extensive evidence of nonobviousness, including that the person of
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`ordinary skill in the art would not have had reason to use the very particular
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`ingredients and concentrations of those ingredients that are claimed in the ’299
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`patent and would not have reasonably expected that the claimed formulations
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`would meet the claimed preservative efficacy requirements, as well as other factors
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`that show the nonobviousness of the claimed invention.
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`8
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`
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`the [patent’s] written description,” such as “an express definition in the[]
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`specification.” In re Morris, 127 F.3d 1048, 1054, 1056 (Fed. Cir. 1997). In other
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`words, the requirement to use a “broad” interpretation does not absolve the PTO of
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`its responsibility to “look to the specification to see if it provides a definition for
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`claim terms,” and to use that definition if it is present. In re ICON Health &
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`Fitness, Inc., 496 F.3d 1374, 1379 (Fed. Cir. 2007). Thus, if “‘the patentee acted
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`as his own lexicographer and clearly set forth a definition of the disputed claim
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`term,’” that express definition will control in an IPR just as in infringement
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`litigation. Sony Corp. of Am. v. Network-1 Security Sol’ns, Inc., IPR2013-00092,
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`Paper 21, at 7 (P.T.A.B. May 24, 2013) (quoting CCS Fitness, Inc. v. Brunswick
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`Corp., 288 F.3d 1359, 1366 (Fed. Cir. 2002)).
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`In this case, the ’299 patent explains at length what it means by “self-
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`preserved” and then sets forth an express definition of the term:
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`The compositions of the present invention are multi-dose
`products that do not require a conventional antimicrobial preservative
`(e.g., benzalkonium chloride), and yet are preserved from microbial
`contamination. Such compositions have been referred to in the art as
`being “preservative free” (see, e.g., U.S. Pat. No. 5,597,559 issued to
`Ojenik, et al.). Compositions that are preserved from microbial
`contamination as a result of the inherent antimicrobial activity of one
`or more components of the composition are also referred to in the art
`as being “self-preserved” . . . .
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`9
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`The multi-dose compositions of the present invention, which do
`not contain a conventional antimicrobial preservative, are referred to
`herein as being “self-preserved.”
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`APO 1001, col. 3 ll. 10–19, 27–29 (emphasis added). Because that definition
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`clearly and expressly sets forth that the term “self-preserved” as used “herein,” i.e.,
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`in the ’299 patent, refers to compositions “which do not contain a conventional
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`antimicrobial preservative,” that definition is the only reasonable interpretation of
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`the term. Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005) (en banc);
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`Berk-Tek LLC v. Belden Techs., Inc., IPR2013-00059, Paper 12, at 7 (P.T.A.B.
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`May 2, 2013) (applying Phillips to determination of broadest reasonable
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`interpretation in IPR); M.P.E.P. § 2111.01 (8th ed., rev. 9, Aug. 2012).2
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`
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`Apotex ignores this definition. Indeed, it states outright that “[t]he
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`specification of the ’299 patent does not define the term ‘self-preserved.’” Pet. at
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`2 For purposes of this Preliminary Response, Alcon does not take a position, and
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`the Board need not resolve, whether the express definition of “self-preserved”
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`differs from the ordinary and customary meaning of the term. Cf. Berk-Tek,
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`IPR2013-00059, at 6 (referring to patentee as “lexicographer” when the patentee
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`“set[s] forth a special meaning for a term” that differs from the “ordinary and
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`customary meaning”). Either way, the express definition is controlling and
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`constitutes the broadest reasonable interpretation.
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`10
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`5. That is simply wrong. To be clear, Apotex does not argue that the language
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`quoted above is not a definition or otherwise take this language into account in any
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`way. Rather, in its discussion of the term “self-preserved,” Apotex fails to cite this
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`language—or indeed any part of the specification—at all. Instead, Apotex defines
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`“self-preserved” to mean “a solution that is not susceptible to significant microbial
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`growth because of the solution’s antimicrobial properties”—which would include
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`solutions that are not susceptible to significant microbial growth because they
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`contain a conventional ophthalmic preservative. Id. Indeed, Apotex emphasizes
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`that its interpretation “encompasses solutions that can be administered to patients
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`in a multi-dose container and need not be maintained aseptically because of their
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`antimicrobial properties”—i.e., any solutions that meet preservative efficacy
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`requirements. Id. Not only does this ignore the patent’s definition of “self-
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`preserved,” but because the requirement that the composition “exhibit[] sufficient
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`antimicrobial activity to allow the composition to satisfy USP 27 preservative
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`efficacy requirements” is already present in each of the challenged claims, e.g.,
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`APO 1001 col. 25, ll. 43–46, Apotex’s definition has the effect of writing the “self-
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`preserved” limitation out of the claims.
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`The only purported support that Apotex provides for its definition is the
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`declaration of its expert, Dr. Michael Miller, that it submitted with its Petition.
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`APO 1002, ¶ 25; Pet. at 5. But Dr. Miller’s declaration adds nothing to the
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`11
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`conclusory statements in Apotex’s Petition. Dr. Miller reiterates the incorrect
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`statement that “[t]he specification of the ’299 patent does not specifically define
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`the term ‘self-preserved,’” and opines that the term refers to a composition that
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`“inhibits microbial growth and protects against microorganisms because of the
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`solution’s antimicrobial, preservative properties”—without any reference to
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`whether those properties come from a conventional preservative ingredient. APO
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`1002, ¶ 25. While he does claim to base his opinion “on the disclosure of the ’299
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`patent,” he does not cite the portion of the specification that defines “self-
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`preserved.” Id.
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`The only portion of the specification that Dr. Miller cites in interpreting
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`“self-preserved” is the beginning of the background of the invention, in which the
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`specification sets forth the general goal of satisfying preservative efficacy
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`requirements. Id. (citing APO 1001, col. 1, ll. 13–24). But this passage does not
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`support Dr. Miller’s opinion; it specifically states that the compositions of the
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`invention can meet preservative efficacy requirements “without requiring a
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`conventional antimicrobial preservative.” APO 1001, col. 1 ll. 13–24. That is, the
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`invention makes it possible to dispense with conventional preservatives entirely.
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`Thus, far from suggesting that the term “self-preserved” encompasses
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`compositions that contain a conventional preservative, the cited passage is entirely
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`consistent with the definition of “self-preserved” later in the patent. Compositions
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`12
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`having the ability to meet preservative efficacy requirements even though they “do
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`not contain a conventional antimicrobial preservative” are what the patent “refer[s]
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`to . . . as being ‘self-preserved.’” APO 1001, col. 3, ll. 27–29.
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`Dr. Miller ignores this intrinsic evidence, and therefore fails to define the
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`term “self-preserved” “in a way that comports with the [patent] as a whole.”
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`Markman v. Westview Instruments, Inc., 517 U.S. 370, 389 (1996). His failure to
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`even attempt to address the use of the term throughout the whole of the
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`specification means that his statement is precisely the type of “conclusory,
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`unsupported assertion[] by [an] expert[] as to the definition of a claim term” that
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`the Federal Circuit has deemed “not useful” to the claim construction process.
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`Phillips, 415 F.3d at 1318. And because his definition is “clearly at odds with the
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`claim construction mandated by . . . the written description,” the Board “should
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`discount” it. Id. (internal quotation marks omitted).
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`
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`In short, without even acknowledging that the ’299 patent defines the term
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`“self-preserved,” Apotex has effectively interpreted the term out of existence. Its
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`proffered “broadest reasonable interpretation” is inconsistent with the specification
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`and should be rejected.
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`II. Apotex Has Failed To Show a Substantial Likelihood that Any Claim Is
`Unpatentable.
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`Apotex’s unreasonable interpretation of “self-preserved” fatally undermines
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`every one of its Grounds for unpatentability. Before the Board initiates an IPR as
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`13
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`
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`to any claim, Apotex must show that there is a substantial likelihood that the claim
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`is invalid under one of Apotex’s proffered grounds. Illumina, Inc. v. Trs. of
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`Columbia Univ., IPR2012-00007, Paper No. 38, at 6 (P.T.A.B. Mar. 12, 2013); see
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`also 35 U.S.C. §§ 311, 314; 37 C.F.R. §§ 42.20(c), 42.108(c). Here, where all of
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`the invalidity arguments are allegations of obviousness, Apotex must show that the
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`claimed invention as a whole, including every limitation of the claim, would have
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`been obvious to a person of ordinary skill in the art. 35 U.S.C. § 103(a); Graham
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`v. John Deere Co., 383 U.S. 1, 3 (1966). To do so, it must show “where each
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`element of the claim is found” in the references on which it relies, and it must
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`show that the person of ordinary skill would have had a reason to combine those
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`elements in the way the claim requires. 37 C.F.R. § 42.104(b)(4); Wowza,
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`IPR2013-00054, Paper No. 12, at 15; Veeam, IPR2013-00144, Paper No. 11, at
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`11–12.
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`Apotex has failed to meet this burden. Apotex acknowledges that “self-
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`preserved” is a limitation of the challenged claims. Pet. at 10, 24, 37, 44. Despite
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`this, it fails to show that any of the references it cites, alone or in combination,
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`suggest making a composition that is “self-preserved” as that term is defined in the
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`patent, nor does it explain how the person of ordinary skill in the art would have a
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`reasonable expectation of success in doing so. Its Petition must therefore be
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`denied.
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`14
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`
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`A. Apotex’s discussion of Ground 1 is illustrative. In its claim chart,
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`Apotex purports to show that the “self-preserved” limitation has been met by the
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`Xia reference, which, it alleges, discloses an “ophthalmic solution” in which there
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`is a “preservative-effective” amount of zinc. Pet. at 10. Those allegations relate to
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`whether the solution is “self-preserved” under Apotex’s definition—they suggest it
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`inhibits microbial growth “because of the solution’s antimicrobial properties.” See
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`Pet. at 5. But Apotex’s claim chart does not provide any suggestion that the
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`solutions of the Xia reference have adequate preservation without a conventional
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`antimicrobial preservative, as the ’299 patent’s definition of “self-preserved”
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`requires. Nor does Apotex’s discussion of Ground 1 contain any other discussion
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`of the “self-preserved” limitation that could possibly satisfy Apotex’s obligation to
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`show where that element is found in the prior art. See 37 C.F.R. § 42.104(b)(4).
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`To the contrary, Apotex’s own Petition demonstrates how Xia would lead a
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`person of ordinary skill to use a conventional antimicrobial preservative, and thus
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`away from making a “self-preserved” composition as the ’299 patent defines the
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`term. Apotex highlights the teaching of Xia that certain “polycationic materials
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`[antimicrobial agents], by themselves, do not have sufficient preservative efficacy
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`to adequately preserve an ophthalmic composition . . . but can enhance
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`preservative efficacy when used in conjunction with a soluble zinc compound.”
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`Pet. at 9 (quoting APO 1003, at 5; the alterations are Apotex’s). In other words, as
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`15
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`Apotex’s own Petition emphasizes, Xia encourages the use of “polycationic
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`materials.” The “polycationic materials” in Xia, however, include conventional
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`ophthalmic preservatives. As Xia explains, a preferred “polycationic material” is
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`“polyquaternium-1,” APO 1003, at 5, which the ’299 patent gives as an example of
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`the “conventional antimicrobial preservative[s]” that, by definition, are absent from
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`“self-preserved” compositions. APO 1001, col. 1, ll. 14–25. Accordingly, far
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`from suggesting “self-preserved” compositions as the ’299 patent defines the term,
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`Xia encourages the use of certain conventional antimicrobial preservatives.
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`Each of Apotex’s other Grounds suffers the same flaw. Ground 2 adds to
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`Ground 1 the Gadd reference, which is about microbes’ responses to heavy metals
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`and has nothing to do with making self-preserved compositions (even assuming
`
`arguendo that it is relevant art). When it comes to the “self-preserved” limitation,
`
`however, Apotex’s discussion of Ground 2 simply refers back to Ground 1;
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`Ground 2 is therefore deficient for the same reason as Ground 1. Pet. at 24.
`
`Grounds 3 and 4 add to Grounds 1 and 2 the label for TRAVATAN®, an
`
`earlier Alcon product containing a conventional antimicrobial preservative—
`
`benzalkonium chloride. Pet. at 34, 42; APO 1006, at 1. As in Grounds 1 and 2,
`
`Apotex’s only allegation regarding how the “self-preserved” limitation is met is
`
`that Xia teaches a “preservative-effective” amount of zinc, without any discussion
`
`
`
`16
`
`
`
`
`
`of whether it would teach doing so without a conventional antimicrobial
`
`preservative. Thus, like Grounds 1 and 2, Grounds 3 and 4 fail.
`
`Grounds 5, 6, and 7 add the Kobayashi reference to the references of
`
`Grounds 1–4, purportedly to show that zinc has some antimicrobial activity at the
`
`concentrations claimed in the ’299 patent. Pet. at 53–59. Apotex does not contend
`
`that Kobayashi has anything to do with whether the proffered combinations of
`
`references teach “self-preserved” compositions. Indeed, Grounds 5–7 are
`
`sufficiently duplicative of Grounds 1–4 that Apotex does not even provide new
`
`claim charts for Grounds 5–7, but merely argues how the combination of
`
`references suggests the particular concentration ranges of zinc chloride in certain
`
`claims of the ’299 patent. There is no further discussion of whether any
`
`composition is “self-preserved.” Thus, for the same reasons that the previously
`
`discussed Grounds fail to meet Apotex’s burden, these Grounds fail as well.
`
`B.
`
`Separately from any discussion of the term “self-preserved,” Apotex’s
`
`Petition does argue that a person of ordinary skill “would have had a reason to
`
`combine the teachings of Xia and Chowhan [the two principal references that are
`
`the basis for each of Apotex’s Grounds] to gain the benefits of the antimicrobial
`
`agents taught in each reference without using traditional preservative agents.” Pet.
`
`at 9. But this passing argument does not provide the required teaching of a “self-
`
`preserved” composition, for at least two reasons.
`
`
`
`17
`
`
`
`
`
`First, Xia and Chowhan do not support Apotex’s argument, as neither
`
`teaches towards a self-preserved composition, i.e., one that meets preservative
`
`efficacy requirements but lacks a conventional preservative—indeed, Apotex’s
`
`own discussion of these references provides no basis for concluding that either
`
`reference contains any such teaching. At most, the portions of those references to
`
`which Apotex points suggest that “it is generally advantageous to employ as low as
`
`possible concentration of preservative agent to avoid the risk of eye irritation.”
`
`APO 1003, at 1, quoted in APO 1002, ¶ 49; see Pet. at 9 (citing APO 1002, ¶ 49).
`
`But Apotex points to no suggestion that it is possible to use no conventional
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`preservative agent at all and yet still meet preservative efficacy requirements.
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`Moreover, as discussed above, Xia expressly advocates the use of
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`conventional “polyquaternium” preservatives. See supra p. 16; APO 1003, at 5.
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`Similarly, Chowhan encourages the use of polyquaternium-1 in ophthalmic
`
`compositions. E.g., APO 1004, at 2 (col 1, ll. 56–63, col. 2, ll. 26–35), 3–5
`
`(Examples 1–7 & 9, containing “Polyquad®,” i.e., polyquaternium-1). Solutions
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`containing such preservatives are not, by definition, “self-preserved.” APO 1001,
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`col. 1, ll. 20–25.
`
`Indeed, the very passage of Xia that Apotex cites in support of its argument
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`(Pet. at 9 (quoting APO 1003, at 4)) acknowledges that the solutions of Xia may
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`contain a conventional ophthalmic preservative. Xia states that the compositions it
`
`
`
`18
`
`
`
`
`
`discloses may contain “primary preservative agents.” i.e., any “non-zinc containing
`
`compounds that derive their preservative activity through a chemical or
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`physiochemical interaction with the microbial organisms.” APO 1003, at 5. That
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`broad definition includes “conventional antimicrobial preservatives,” so solutions
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`containing such agents are not “self-preserved.” Likewise, as Apotex’s own
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`expert, Dr. Miller, acknowledges, Xia states that it is “‘generally advantageous to
`
`employ as low as possible concentration of preservative agent.’” APO 1002, ¶ 49
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`(quoting APO 1003, at 1) (emphasis added). In his declaration, Dr. Miller does not
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`point to any solution in the Xia reference and argue that it would meet preservative
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`efficacy standards with no conventional preservative agent at all. APO 1002, ¶ 49.
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`Nor does he opine that the Xia reference suggests that it is even possible to make a
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`self-preserved solution that satisfies USP 27 preservative efficacy requirements
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`and otherwise meets the limitations of Alcon’s claims, much less that Xia would
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`teach a person of ordinary skill how to formulate such a solution. Id. Similarly,
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`Chowhan does not suggest that the compositions it discloses should be self-
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`preserved, only that “borate-polyol complexes” exhibit “increased antimicrobial
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`activity over boric acid or its salts, and “increase the antimicrobial efficacy of other
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`antimicrobial agents when used in combination.” APO 1004, at 2 (col. 2, ll. 4–12).
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`For these reasons, Apotex’s conclusory statement that the person of ordinary
`
`skill would have reason to “gain the benefits of the antimicrobial agents taught in
`
`
`
`19
`
`
`
`
`
`each reference without using traditional preservative agents,” Pet. at 9, fails to
`
`show that Xia or Chowhan, alone or in combination, teach “self-preserved”
`
`compositions.
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`Second, even assuming, contrary to the record, that the combination of Xia
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`and Chowhan somehow suggested making “self-preserved” compositions, they do
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`not provide a reasonable expectation of success in doing so. In order to show
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`obviousness, Apotex must show not only a reason to combine the teachings of Xia
`
`and Chowhan, but also “that the [ordinarily] skilled artisan would have had a
`
`reasonable expectation of success” in “achiev[ing] the claimed invention.” In re
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`Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d
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`1063, 1069 (Fed. Cir. 2012); see Leo Pharm. Prods., Ltd. v. Rea, ___ F.3d ___,
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`107 U.S.P.Q.2d (BNA) 1943, at 1952 (Fed. Cir. Aug. 12, 2013). Apotex does not
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`so much as attempt to argue that the person of ordinary skill in the art—based on
`
`any of the combinations of references it cites—would have reasonably expected to
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`succeed in making a composition that can meet preservative efficacy requirements
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`without the use of a conventional antimicrobial preservative, i.e., succeed in
`
`making a “self-preserved” composition.
`
`While Apotex does discuss reasonable expectation of success in the context
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`of USP 27 preservative efficac
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