Trials@uspto.gov
`Tel: 571-272-7822
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`
`
`Paper 9
`Entered: January 2, 2014
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`APOTEX CORP.,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner
`_______________
`
`Case IPR2013-00428
`U.S. Patent No. 8,268,299 B2
`_______________
`
`
`Before LORA M. GREEN, FRANCISCO C. PRATS, and RAMA G. ELLURU,
`Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`
`
`Tel: 571-272-7822
`
`
`
`Paper 9
`Entered: January 2, 2014
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`APOTEX CORP.,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner
`_______________
`
`Case IPR2013-00428
`U.S. Patent No. 8,268,299 B2
`_______________
`
`
`Before LORA M. GREEN, FRANCISCO C. PRATS, and RAMA G. ELLURU,
`Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`
`
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`Case IPR2013-00428
`Patent 8,268,299 B2
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`I. INTRODUCTION
`
`A. Statement of the Case
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`Petitioner, Apotex Corp. (“Apotex”), filed a petition (“Pet.”) to institute an
`
`inter partes review of claims 1-28 of U.S. Patent No. 8,268,299 B2 (Ex. 1001, “the
`
`’299 patent”). Paper 2. Patent Owner, Alcon Research Ltd. (“Alcon”), filed a
`
`Preliminary Response (“Prelim. Resp.”). Paper 8. We have jurisdiction under
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`35 U.S.C. §§ 6(b) and 314.
`
`The standard for instituting an inter partes review is set forth in 35 U.S.C.
`
`§ 314(a), which states:
`
`THRESHOLD. -- The Director may not authorize an inter partes
`review to be instituted unless the Director determines that the
`information presented in the petition filed under section 311 and any
`response filed under section 313 shows that there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of
`the claims challenged in the petition.
`
`Apotex has persuaded us that there is a reasonable likelihood that it will
`
`prevail with respect to claims 1-28 of the ’299 patent. Accordingly, for the reasons
`
`below, we grant an inter partes review of claims 1-28 of the’299 patent.
`
`B. Related Proceedings
`
`Concurrently with the petition under consideration herein, Apotex filed
`
`petitions seeking inter partes review of U.S. Patent No. 8,323,630 B2 and U.S.
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`Patent No. 8,388,941 B2, over references considered here. Pet. 3.
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`C. Proposed Grounds of Unpatentability
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`Apotex contends that the challenged claims are unpatentable under
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`35 U.S.C. § 103 on the following specific grounds (Pet. 8-60):1
`
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`1 Apotex supports its challenge with a declaration, executed July 5, 2013, by
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` 2
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`Reference[s]
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`Xia2 and Chowhan3
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`Basis
`
`§ 103
`
`Claims challenged
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`1, 2, 4, 8, 16, 17, and 20
`
`Xia, Chowhan, and Gadd4
`
`§ 103
`
`1-4, 8, 9, and 13-21
`
`§ 103
`
`5-7 and 28
`
`§ 103
`
`10-12 and 22-28
`
`§ 103
`
`13 and 14
`
`§ 103
`
`24 and 27
`
`§ 103
`
`28
`
`Xia, the Travatan Label,5
`and Chowhan
`Xia, the Travatan Label,
`Chowhan, and Gadd
`Xia, Kiyobayashi,6
`Chowhan, and Gadd
`Xia, Kiyobayashi, the
`Travatan Label, Chowhan,
`and Gadd
`Xia, Kiyobayashi, the
`Travatan Label, and
`Chowhan
`
`
`D. The ’299 patent
`
`The ’299 patent describes “multi-dose, self-preserved ophthalmic
`
`compositions.” Ex. 1001, Abstract. The ’299 patent explains that pharmaceutical
`
`compositions, such as irrigating solutions for the eye, “are typically utilized
`
`multiple times by the patient, and are therefore frequently referred to as being of a
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`‘multi-dose’ nature.” Id. at 1:44-46. The ’299 patent also explains that, while such
`
`
`Michael J. Miller, Ph.D. (“Miller Declaration”) (Ex. 1002).
`2 Xia, WO 2005/097067 A1 (published Oct. 20, 2005) (Ex. 1003).
`3 Chowhan, U.S. Patent No. 6,143,799 (issued Nov. 7, 2000) (Ex. 1004).
`4 Geoffrey M. Gadd and Alan J. Griffiths, Microorganisms and Heavy Metal
`Toxicity, 4 MICROBIAL ECOLOGY 303-317 (1978) (Ex. 1005).
`5 FDA Approved Drug Label “TRAVATAN
`® (travoprost ophthalmic solution)
`0.004% Sterile” (Ex. 1006).
`6 Kiyobayashi, JP Appl. No. 2003-104870 (published Apr. 9, 2003) (Ex. 1007).
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`compositions can be prepared under sterile conditions, see id. at 1:26-39, “[d]ue to
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`the frequent, repeated exposure of multi-dose products to the risk of microbial
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`contamination, it is necessary to employ a means for preventing such
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`contamination from occurring.” Id. at 1:47-50.
`
`The ’299 patent discloses that the compositions of the invention “are multi-
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`dose products that do not require a conventional antimicrobial preservative (e.g.
`
`benzalkonium chloride), and yet are preserved from microbial contamination.” Id.
`
`at 3:10-13. More specifically, the ’299 patent explains that aqueous ophthalmic
`
`compositions can be preserved from microbial contamination, despite the absence
`
`of conventional preservatives, by including low concentrations of zinc ions and a
`
`borate polyol complex in the compositions, and by limiting the concentration of
`
`buffering anions and metal cations other than zinc in the compositions. See id. at
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`3:33-62.
`
`Claim 1, reproduced below, illustrates the claimed subject matter at issue:
`
`1. A multi-dose, self-preserved ophthalmic composition,
`comprising:
`zinc ions at a concentration of 0.04 to 0.4 mM; and
`borate and polyol, the borate being present in the composition
`at a concentration of 0.1 to 2.0% w/v and the polyol
`being present in the composition at a concentration of
`0.25 to 2.5% w/v, the polyol comprising propylene glycol
`in the composition at a concentration of 0.25 to 1.25%
`w/v and sorbitol in the composition at a concentration of
`0.05 to 0.5% w/v;
`wherein: (i) the composition has a concentration of anionic
`species less than 15 mM; and (ii) the composition
`exhibits sufficient antimicrobial activity to allow the
`composition to satisfy USP 27 preservative efficacy
`requirements.
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`E. Claim Interpretation
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`Consistent with the statute and legislative history of the Leahy-Smith
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`America Invents Act, Pub. L. No. 112-29, 125 Stat. 284 (2011) (AIA), the Board
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`interprets claims using the “broadest reasonable construction in light of the
`
`specification of the patent in which [they] appear[].” 37 C.F.R.
`
`§ 42.100(b); see also Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756,
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`48,766 (Aug. 14, 2012). Under that standard, terms in a claim of an unexpired
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`patent are given “the broadest reasonable meaning of the words in their ordinary
`
`usage as they would be understood by one of ordinary skill in the art, taking into
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`account whatever enlightenment by way of definitions or otherwise that may be
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`afforded by the written description contained in the . . . specification.” In re
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`Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997).
`
`Apotex submits proposed constructions for several claim terms. Pet. 4-6;
`
`see also Ex. 1002 ¶¶ 20-33. With one notable exception, we agree that, on the
`
`current record, Apotex’s proffered claim constructions are consistent with the
`
`broadest reasonable meaning an ordinary artisan would have given to the cited
`
`terms, when viewing the claims in light of the ’299 patent Specification.
`
`Alcon’s preliminary response is limited to the single issue of the
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`interpretation of “self-preserved.” See Prelim. Resp. 7-8.
`
`Specifically, the preambles of each of the independent claims of the ’299
`
`patent requires the claimed compositions to be “self-preserved.” Ex. 1001, 25:31
`
`(claim 1); 27:13 (claim 22); 27:49 (claim 26); 28:14 (claim 27); 28:36 (claim 28).
`
`As evidenced by the discussion below, when reasonably interpreted in light of the
`
`Specification of the ’299 patent, the term “self-preserved” breathes life and
`
`meaning into the claims, and we, therefore, conclude that it is construed properly
`
`as being a limitation of the claims, despite appearing in the preamble. See Pitney
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`Bowes Inc. v. Hewlett Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999).
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`We do not agree with Apotex’s assertion that the “[S]pecification of the ’299
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`patent does not define the term ‘self-preserved.’” Pet. 5; see also Ex 1002 ¶ 25.
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`As Alcon discusses, see Prelim. Resp. 1-2, the ’299 patent Specification
`
`states expressly that “[t]he multi-dose compositions of the present invention, which
`
`do not contain a conventional antimicrobial preservative, are referred to herein as
`
`being ‘self-preserved’.” Ex 1001, 3:27-29. The ’299 patent Specification explains
`
`that benzalkonium chloride, polyquaternium-1, chlorite, and hydrogen peroxide are
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`among conventional antimicrobial preservatives which are excluded from
`
`self-preserved compositions. Id. at 4:23-25. Accordingly, we interpret “self-
`
`preserved” compositions as compositions that do not contain a conventional
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`antimicrobial preservative, such as benzalkonium chloride, polyquaternium-1,
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`chlorite, or hydrogen peroxide.
`
`We, thus, decline to adopt Apotex’s proffered claim construction of “self-
`
`preserved.” As explained below, however, we are persuaded, based on the record
`
`before us, that there is a reasonable likelihood that Apotex will prevail with respect
`
`to its challenge of claims 1-28 of the ’299 patent.
`
`II. ANALYSIS
`
`A. Obviousness of claims 1, 2, 4, 8, 16, 17, and 20 over Xia and Chowhan
`
`Having reviewed Apotex’s contentions and supporting evidence regarding
`
`the proposed ground of obviousness of claims 1, 2, 4, 8, 16, 17, and 20 of the ’299
`
`patent over Xia and Chowhan, we are persuaded that Apotex has shown a
`
`reasonable likelihood of prevailing in accordance with 35 U.S.C. §§ 312 and 314.
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`Patent 8,268,299 B2
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`Claim 1
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`“self-preserved ophthalmic composition”
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`As Apotex contends, and as claim 1 requires, both Xia and Chowhan
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`describe ophthalmic compositions. See Pet. 10, see also Ex. 1003, 3 (“According
`
`to one embodiment, the composition is an ophthalmic solution . . . .”); Ex. 1004,
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`2:4 (“This invention provides . . . ophthalmic compositions.”).
`
`As to the requirement in claim 1 that the composition must be self-
`
`preserved, Xia discloses that its compositions preferably do not contain
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`conventional antimicrobial preservatives. See Pet. 9, see also Ex. 1003, 3-4 (“The
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`present invention relates to a composition that includes a preservative-effective
`
`amount of a soluble zinc compound and has less than a preservative-effective
`
`amount of a primary preservative agent, preferably no primary preservative
`
`agent.”) (emphasis added).
`
`zinc ions at a concentration of 0.04 to 0.4 mM
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`As to the zinc concentration “of 0.04 to 0.4 mM” recited in claim 1, Xia
`
`discloses that zinc citrate and zinc chloride are preferred zinc compounds, Ex.
`
`1003, 5. Xia discloses:
`
`[T]he composition has a minimum of about 0.001 wt.%, about 0.005
`wt.%, about 0.01 wt.% or about 0.05 wt.% of a zinc compound per
`total weight of the composition and/or a maximum of about 1 wt.%,
`about 0.5 wt.%, about 0.1 wt.% or about 0.05 wt.% of the zinc
`compound per total weight of the composition.
`
`
`Id.
`
`Apotex contends that the ranges of concentrations of zinc compounds
`
`described in Xia overlap with the zinc concentration range in claim 1. In support,
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`Apotex provides the Declaration of Dr. Miller to explain the calculations involved
`
`in converting from the percentages disclosed in Xia to the molarity concentrations
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`recited in claim 1. See Pet. 11, see also Ex. 1002 § 51. We are persuaded of Dr.
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`Miller’s status as an expert in this art, see Ex. 1002 ¶¶ 4-13, and detect no material
`
`defect in the evidence underlying Apotex’s assertion in this regard. We determine,
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`therefore, that Apotex has advanced evidence adequate to show, on this record, that
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`an ordinary artisan would have considered it obvious to include, in an ophthalmic
`
`composition, zinc ions at a concentration encompassed by claim 1.
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`0.1 to 2.0% borate, 0.25 to 1.25% propylene glycol,
`and 0.05 to 0.5% w/v sorbitol
`
`As to the borate, propylene glycol, and sorbitol required by claim 1,
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`Chowhan discloses that including borate-polyol complexes in ophthalmic solutions
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`potentiates the antimicrobial effect of other preservatives in the solutions:
`
`The ophthalmic compositions of the present invention comprise
`borate-polyol complexes which have surprisingly been found to have
`increased antimicrobial activity as compared to boric acid or its salts,
`particularly with respect to organisms such as A. niger. Moreover,
`these complexes unexpectedly increase the antimicrobial efficacy of
`other antimicrobial agents when used in combination.
`
`Ex. 1004, 2:5-12. Chowhan further explains that “[p]referred polyols are sugars,
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`sugar alcohols and sugar acids, including, but not limited to: mannitol, glycerin,
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`propylene glycol and sorbitol.” Id. at 3:4-6.
`
`As to the concentrations of borate and polyol suitable in ophthalmic
`
`compositions, Chowhan explains that its borate-polyol complexes “can be used in
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`conjunction with other known preservatives and disinfectants to meet preservative
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`efficacy and disinfection standards. In such compositions, the molar ratio of borate
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`to polyol is generally between about 1:0.1 and about 1:10, and is preferably
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`between about 1:0.25 and about 1:2.5.” Id. at 3:12-34. Chowhan discloses further:
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`The borate-polyol complexes are utilized in the compositions of
`the present invention in an amount between about 0.5 to about 6.0
`percent by weight (wt %), preferably between about 1.0 to about 2.5
`wt %. The optimum amount, however, will depend upon the
`complexity of the product, since potential interactions may occur with
`the other components of a composition. Such optimum amount can be
`readily determined by one skilled in the formulatory arts.
`
`Id. at 3:44-51.
`
`We detect no defect in Apotex’s assertion that, when the upper and lower
`
`concentration limits of borate, propylene glycol, and sorbitol recited in claim 1 are
`
`added together, the range of total concentrations for these ingredients overlaps the
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`0.5 to 6.0 percent range of borate-polyol complex disclosed in Chowhan as being
`
`suitable in its compositions. See Pet. 13 (explaining that claim 1’s lower limit of
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`0.1% borate, 0.25% propylene glycol, 0.05% sorbitol sums to 0.4% total combined
`
`borate-polyol, and that claim 1’s upper limit of 2.0% borate and 2.5% total polyol
`
`sums to 4.5% total combined borate-polyol).
`
`We also detect no defect in Apotex’s assertion that Chowhan suggests using
`
`the various polyols, including propylene glycol and sorbitol, in combination. See
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`Pet. 14; see also Ex. 1004, 3:10-12 (“The water soluble borate-polyol complexes of
`
`the present invention may be formed by mixing borate with the polyol(s) of choice
`
`in an aqueous solution.”). Moreover, given Chowhan’s express suggestion to
`
`optimize the concentration of its complexes, see Ex. 1004, 3:50-51, we detect no
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`defect in Apotex’s assertion that an ordinary artisan would have been prompted to
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`determine, through optimization, suitable concentrations of propylene glycol and
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`sorbitol for use ophthalmic compositions. Accordingly, we determine that, on the
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`current record, Apotex has advanced evidence sufficient to show that an ordinary
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`artisan would have considered an ophthalmic composition, having the
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`concentrations of borate, propylene glycol, and sorbitol recited in claim 1, obvious.
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`“anionic species less than 15 mM”
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`We also are persuaded that Apotex has advanced evidence sufficient to show
`
`that an ordinary artisan would have been prompted to maintain the concentration of
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`anionic species in ophthalmic solutions below 15 mM, as claim 1 requires. As
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`Apotex discusses, both Xia and Chowhan disclose that ophthalmic compositions
`
`need not be prepared as isotonic solutions, and suggest, therefore, that anionic
`
`species required to obtain isotonicity can be omitted from the compositions. See
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`Pet. 15-16; see also Ex. 1003, 10 (“The aqueous solutions of the present invention
`
`are typically adjusted with tonicity agents . . . .” (emphasis added)); also Ex. 1004,
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`4:51 (“It is not always necessary to have an isotonic solution . . . .”). Chowhan
`
`discloses also that phosphate ions can interfere with the activity of antimicrobial
`
`agents in the compositions, as Apotex describes. See Pet. 16; see also Ex. 1004,
`
`1:45-48 (“[P]hosphate is a good buffer but, when used in concentrations generally
`
`found in ophthalmic formulations, it reduces the antimicrobial activity of
`
`preservatives.”). Given these teachings, we determine that, on the current record,
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`Apotex has advanced evidence sufficient to show that an ordinary artisan would
`
`have considered it obvious to maintain the concentration of anionic species in
`
`ophthalmic solutions below 15 mM, as claim 1 requires.
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`USP 27 preservative efficacy
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`Claim 1 also requires the composition to exhibit sufficient antimicrobial
`
`activity to allow the composition to satisfy USP 27 preservative efficacy
`
`requirements. The ’299 patent Specification explains the criteria for satisfying
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`USP 27, see Ex. 1001, 7:30-38, and further notes that the “standards identified . . .
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`for the USP 27 are substantially identical to the requirements set forth in prior
`
`editions of the USP, particularly USP 24, USP 25 and USP 26.” Id. at 7:53-55.
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`As Apotex discusses, both Xia and Chowhan describe standards by which
`
`they judge the preservative efficacy of their compositions. See Pet. 12; see also
`
`Ex. 1003; Ex. 1004, 9:38-41. Apotex asserts that the tests described in Xia and
`
`Chowhan are more stringent than USP 27, and cites the Declaration of Dr. Miller
`
`as support. See Pet. 12-13; see also Ex. 1002 ¶¶ 38, 60, and 61. Apotex contends
`
`that, given the references’ disclosures of compositions meeting the described
`
`standards, an ordinary artisan would have had a reasonable expectation that an
`
`ophthalmic composition including zinc, borate, propylene glycol, and sorbitol also
`
`would meet USP 27, and again cites to the Miller Declaration for support. See Pet.
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`17-18; see also Ex. 1002 ¶61.
`
`Furthermore, Xia describes a number of compositions that meet the
`
`preservative efficacy standard applied in that reference. See Ex. 1003, 16-23. A
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`number of compositions passing the preservative efficacy test contained the
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`preservative-enhancing “Polymer JR.” See id. at 17-18 (Examples 2 and 3); see
`
`also id. at 2 (describing “Polymer JR (Polyquaternium 10)” as a “preservative-
`
`enhancing additive”). Xia also describes several formulations containing zinc,
`
`sodium borate, boric acid, and sodium chloride, which passed the preservative
`
`efficacy test despite the absence of Polymer JR in the composition. See id. at 23
`
`(Examples 16-18).
`
`Given these teachings, we determine, on the current record, that Apotex has
`
`advanced evidence sufficient to show that an ordinary artisan would have had a
`
`reasonable expectation that an ophthalmic composition containing zinc, borate,
`
`propylene glycol, and sorbitol would meet USP 27, even without a conventional
`
`antimicrobial preservative in the composition. Specifically, Xia discloses that
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`compositions containing zinc and borate meet a preservative efficacy standard
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`more stringent than USP 27 despite the absence of a conventional antimicrobial in
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`the composition, and Chowhan discloses, as discussed above, that its borate polyol
`
`complexes potentiate the antimicrobial activity of other preservatives.
`
`Thus, because we are persuaded, for the reasons discussed above, that Xia
`
`and Chowhan would have suggested to an ordinary artisan a composition having
`
`all of the features required by claim 1, we determine that Apotex has, on the
`
`current record, shown a reasonable likelihood that it will prevail in its obviousness
`
`challenge of claim 1 over those references. Having considered carefully Apotex’s
`
`arguments and evidence regarding the obviousness of dependent claims 2, 4, 8, 16,
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`17, and 20 over Xia and Chowhan, Apotex also persuades us that, on the current
`
`record, it has shown a reasonable likelihood that it will prevail in its challenge to
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`those claims as well.
`
`We have considered carefully the arguments Alcon presents in its
`
`Preliminary Response regarding the cited references’ teaching or suggestion to
`
`prepare a composition that is self-preserved, when that term is given its broadest
`
`reasonable construction in light of the ’299 patent Specification. See Prel. Resp. 7-
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`23. Given the teachings in the cited references discussed above, however, we are
`
`not persuaded that Apotex has failed to show a reasonable likelihood of prevailing
`
`in accordance with 35 U.S.C. §§ 312 and 314.
`
`Accordingly, for the reasons discussed, we institute inter partes review of
`
`claims 1, 2, 4, 8, 16, 17, and 20 for obviousness over Xia and Chowhan.
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`B. Obviousness of claims 1-4, 8, 9, and 13-21 in view of Xia, Chowhan,
`and Gadd
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`Having reviewed Apotex’s contentions and supporting evidence regarding
`
`the proposed ground of obviousness of claims 1-4, 8, 9, and 13-21 of the ’299
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`patent over Xia, Chowhan, and Gadd, we are persuaded that Apotex shown a
`
`reasonable likelihood of prevailing in accordance with 35 U.S.C. §§ 312 and 314.
`
`Claims 1, 2, 4, 8, 16, 17, and 20
`
`As discussed above, we are persuaded that Apotex has, on the current
`
`record, shown a reasonable likelihood that it will prevail in its obviousness
`
`challenge of claims 1, 2, 4, 8, 16, 17, and 20 over Xia and Chowhan. In addition to
`
`the claims challenged in the first ground of unpatentability discussed above, this
`
`second ground challenges the patentability of claims 3, 9, 13-15, 18, 19, and 21, all
`
`of which depend directly or ultimately from claim 1.
`
`Claims 3, 9, 15, 18, and 19
`
`Claims 3, 9, and 15 place limits on the permissible concentration of
`
`multivalent buffering anions in the claimed composition, as well as limiting the
`
`concentration of multivalent metal cations, other than zinc, in the composition. See
`
`Ex. 1001, 25:51-26:61. Specifically, claim 3 recites “[a] composition according to
`
`claim 1, wherein: (i) the composition has a concentration of multivalent buffering
`
`anions that is less than 5 mM; and (ii) the composition has a concentration of
`
`multivalent metal cations other than zinc that is less than 5 mM.” Id. at 25:51-55.
`
`Claim 9, which also depends from claim 1, is similar to claim 3, and adds
`
`the further limitation that “the borate is present in the composition at a
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`concentration of 0.5 to 1.2% w/v.” Id. at 26:38-39.
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`Claim 15 recites “[a] composition according to claim 1 or claim 9 wherein
`
`the composition does not contain multivalent buffering anions and does not contain
`
`multivalent cations other than zinc.” Id. at 26:58-61.
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`Claims 18 and 19 depend from claim 9 and limit the concentration of anionic
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`species in the composition to less than 10 mM, and less than 5 mM, respectively.
`
`See id. at 27:1-6.
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`Apotex cites Gadd as evidence that an ordinary artisan would have been
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`prompted to minimize the concentration of multivalent anions and cations in
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`compositions using zinc as an antimicrobial preservative agent. See Pet. 25-26, 28,
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`29, 31-32.
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`Gadd is a review article describing various factors that can influence the
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`toxicity of heavy metals to microorganisms. See Ex. 1005, 303.
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`Gadd states:
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`Zinc precipitates as zinc hydroxide, Zn(OH)2, above pH 5, and
`above pH 8.5 it forms zincate ion which can be precipitated by
`calcium ions . . . .
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`. . . Cations such as magnesium and calcium can often reduce heavy
`metal inhibition. Toxic effects of nickel, cobalt, cadmium, zinc, and
`manganese to Escherichia coli were decreased in media with a high
`magnesium content.
`
`Id. at 306 (citation omitted). Gadd states:
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`Anions are able to reduce metal toxicity by precipitation. The
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`hydroxyl ion has already been mentioned with regard to pH. Besides
`this, phosphate, thiosulfate, carbonate, and bicarbonate ions can form
`precipitates with heavy metals depending on their concentrations and
`the pH of the solution. The addition of such anions to growth media
`often reduces metal toxicity . . . .
`
`Id. at 307 (citation omitted).
`
`Moreover, as Apotex shows, and as discussed above, Chowhan describes
`
`using borate polyol complexes in ophthalmic compositions. Ex. 1004, Abstract.
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`Chowhan discloses that it can be undesirable to use phosphate as a buffer in
`
`ophthalmic compositions due to its capacity to reduce the activity of antimicrobial
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`compounds. See Pet. 31-32; see also Ex. 1004, 1:45-48 (“[P]hosphate is a good
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`14
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`buffer but, when used in concentrations generally found in ophthalmic
`
`formulations, it reduces the antimicrobial activity of preservatives.”).
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`In view of these teachings, we are persuaded that Apotex has advanced
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`evidence sufficient to show that an ordinary artisan would have considered it
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`obvious to minimize the content of multivalent buffering anions and multivalent
`
`metal cations, other than zinc, in ophthalmic compositions such as those suggested
`
`by Xia and Chowhan. Accordingly, we determine that, based on the current
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`record, Apotex has shown a reasonable likelihood of prevailing in its obviousness
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`challenge of claims 3, 9, 15, 18, and 19 over Xia, Chowhan, and Gadd.
`
`Claims 13, 14, and 21
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`
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`Claim 13 recites “[a] composition according to claim 9 wherein the zinc ions
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`are provided by zinc chloride at a concentration of 0.001 to 0.005 w/v%.” Ex.
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`1001, 26:48-50.
`
`Claim 14 reads as follows:
`
`14. A composition according to claim 9 wherein the propylene glycol
`is present in the composition at a concentration of 0.75 w/v%, the
`borate is boric acid and is present in the composition at a
`concentration of 1.0 w/v% and the zinc ions are provided by zinc
`chloride at a concentration of 0.0025 w/v%.
`
`Id. at 26:52-57.
`
`Claim 21 recites “[a] composition according to claim 9 wherein the
`
`composition comprises zinc ions at a concentration of 0.1 to 0.4 mM.” Id. at
`
`27:10-12.
`
`As noted above, Xia discloses zinc chloride as a suitable zinc compound,
`
`and we detect no error in Apotex’s assertion that the suitable concentration range
`
`of zinc compounds described in Xia overlaps the concentrations ranges of zinc
`
`required in claims 13, 14, and 21. See Ex. 1003, 5; Pet. 29-31, 33-34. Moreover,
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`15
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`given Chowhan’s disclosure of determining suitable concentrations of its borate-
`
`polyol complexes through optimization, we are persuaded that Apotex has
`
`advanced evidence sufficient to show that an ordinary artisan would have
`
`considered the boric acid concentration recited in claim 14 obvious in view of
`
`Chowhan. See Ex. 1004, 3:50-51; Pet. 30-31.
`
`
`
`Accordingly, we determine also that, based on the current record, Apotex
`
`has shown a reasonable likelihood of prevailing in its obviousness challenge of
`
`claims 13, 14, and 21 over Xia, Chowhan, and Gadd.
`
`In sum, for the reasons discussed, we institute inter partes review of claims
`
`1-4, 8, 9, and 13-21 for obviousness over Xia, Chowhan, and Gadd.
`
`C. Obviousness of claims 5-7 and 28 over Xia, the Travatan Label,
`
`and Chowhan.
`
`Having reviewed Apotex’s contentions and supporting evidence regarding
`
`the proposed ground of obviousness of claims 5-7 and 28 of the ’299 patent in
`
`view of Xia, the Travatan Label, and Chowhan, we are persuaded that Apotex
`
`shown a reasonable likelihood of prevailing in accordance with 35 U.S.C. §§ 312
`
`and 314.
`
`Claims 5 and 6
`
`Claim 5 recites “[a] composition according to claim 1 further comprising a
`
`therapeutic agent selected from the group consisting of bimatoprost, latanoprost,
`
`travoprost and unoprostone.” Ex. 1001, 25:58-60. Claim 6 recites “[a]
`
`composition according to claim 5 wherein the therapeutic agent comprises
`
`travoprost.” Id. at 25:61-62.
`
`As Apotex discusses, the Travatan Label describes an ophthalmic solution,
`
`having a pH of “approximately 6.0,” which contains 0.004% of the prostaglandin
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`analogue travoprost as an anti-glaucoma therapeutic agent, and which also contains
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`16
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`polyoxyl 40 hydrogenated castor oil. See Pet. 34-37; Ex. 1006, 1. Given Xia’s
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`disclosure that prostaglandin therapeutic agents are suitable in its zinc-preserved
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`compositions, see Ex. 1003, 12, we are persuaded that Apotex has advanced a
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`sufficient evidentiary basis to show that an ordinary artisan would have considered
`
`it obvious to include the prostaglandin analogue travoprost in such solutions, as
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`recited in claims 5 and 6 of the ’299 patent.
`
`Claim 7
`
`Claim 7 recites “[a] composition according to claim 1 further comprising
`
`polyoxyl 40 hydrogenated castor oil wherein the composition has a pH from 5.5 to
`
`5.” Ex. 1001, 25:63-659.
`
`Given Xia’s disclosure of the suitability of surfactants in its compositions,
`
`see Ex. 1003, 13, as well as the knowledge that polyoxyl 40 hydrogenated castor
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`oil was a common surfactant known to be suitable in ophthalmic solutions, see Ex.
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`1006, 1; Ex. 1002 ¶ 125, we are persuaded also that Apotex has advanced a
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`sufficient evidentiary basis to show that an ordinary artisan would have been
`
`prompted to include polyoxyl 40 hydrogenated castor oil in an ophthalmic
`
`solution, as recited in claim 7 of the ’299 patent.
`
`Further, given the closeness of the pH of 6.0 of the solution described in the
`
`Travatan label to the range of 5.5 to 5.9 recited in claim 7 of the ’299 patent, as
`
`well as Xia’s disclosure that a suitable pH range for ophthalmic solutions is “a
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`minimum of about 5, about 6, about 6.5 or about 7,” Ex. 1003, 12, we are
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`persuaded that Apotex has advanced a sufficient evidentiary basis to show that the
`
`pH range recited in claim 7 would have been considered obvious by an ordinary
`
`artisan.
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`Claim 28
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`As to claim 28, Apotex relies on the disclosures in Xia, Chowhan, and the
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`Travatan Label, essentially as discussed above, to show that an ordinary artisan
`
`would have considered the claimed ingredients, at the concentrations recited in
`
`claim 28, to be obvious in an ophthalmic solution. See Pet. 37-42. For the reasons
`
`similar to those discussed above, we are persuaded that Apotex has advanced a
`
`sufficient evidentiary basis to show that compositions containing the ingredients
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`recited in claim 28, at the concentrations recited in the claim, would have been
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`obvious to an ordinary artisan.
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`Accordingly, we determine that, based on the current record, Apotex has
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`shown a reasonable likelihood of prevailing in its obviousness challenge of claims
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`5-7 and 28 over Xia, the Travatan Label, and Chowhan. We, therefore, institute
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`inter partes review of claims 5-7 and 28 for obviousness over Xia, the Travatan
`
`label, and Gadd.
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`D. Obviousness of claims 10-12 and 22-28 over Xia, the Travatan Label,
`
`Chowhan, and Gadd
`
`Having reviewed Apotex’s contentions and supporting evidence regarding
`
`the proposed ground of obviousness of claims 10-12 and 22-28 over Xia, the
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`Travatan Label, Chowhan, and Gadd, we are persuaded that Apotex has shown a
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`reasonable likelihood of prevailing in accordance with 35 U.S.C. §§ 312 and 314.
`
`Claims 10, 11, and 12
`
`As discussed above, we are persuaded that Apotex has shown a reasonable
`
`likelihood, on the current record, of prevailing in its obviousness challenge to
`
`claim 9 over Xia, Chowhan, and Gadd. Claims 10 and 11 depend from claim 9 and
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`limit the composition, ultimately, to one that contains travoprost in addition to the
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`preservative ingredients. See Ex. 1001, 26:40-44. Claim 12 depends from claim
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`18
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`11, and limits the composition to one that also contains “polyoxyl 40 hydrogenated
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`castor oil and has a pH from 5.5 to 5.9.” See id. at 26:45-47.
`
`In view of the disclosure of the Travatan Label discussed above, we agree
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`with Apotex that, in addition to the zinc, borate, polyol, and ion concentrations
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`suggested by Xia, Chowhan, and Gadd, an ordinary artisan woul
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