Trials@uspto.gov Paper 52
`571-272-7822 Date: September 20, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner.
`_______________
`
`Case IPR2017-01053
`Patent 8,268,299 B2
`_______________
`
`
`
`Before GRACE KARAFFA OBERMANN, SUSAN L. C. MITCHELL,
`and CHRISTOPHER M. KAISER, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Determining That Claims 1–28 Have Not Been Proven Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`I. INTRODUCTION
`
`The Petition requests inter partes review of claims 1–28 of U.S.
`
`Patent No. 8,268,299 B2 (Ex. 1001, “the ’299 patent”). Paper 2 (“Pet.”).
`
`Patent Owner filed no preliminary response. After trial institution, Patent
`
`Owner filed a Response (Paper 22, “Resp.”) and Petitioner filed a Reply
`
`(Paper 35). We held a final hearing on April 17, 2018. Paper 51 (“Tr.”).
`
`
`571-272-7822 Date: September 20, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner.
`_______________
`
`Case IPR2017-01053
`Patent 8,268,299 B2
`_______________
`
`
`
`Before GRACE KARAFFA OBERMANN, SUSAN L. C. MITCHELL,
`and CHRISTOPHER M. KAISER, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Determining That Claims 1–28 Have Not Been Proven Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`I. INTRODUCTION
`
`The Petition requests inter partes review of claims 1–28 of U.S.
`
`Patent No. 8,268,299 B2 (Ex. 1001, “the ’299 patent”). Paper 2 (“Pet.”).
`
`Patent Owner filed no preliminary response. After trial institution, Patent
`
`Owner filed a Response (Paper 22, “Resp.”) and Petitioner filed a Reply
`
`(Paper 35). We held a final hearing on April 17, 2018. Paper 51 (“Tr.”).
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`The Board has jurisdiction under 35 U.S.C. § 6. Petitioner bears the
`
`burden of demonstrating unpatentability by a preponderance of the evidence,
`
`a burden that never shifts to Patent Owner. 35 U.S.C. § 316(e); 37 C.F.R.
`
`§ 42.1(d); Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375,
`
`1378 (Fed. Cir. 2015). We issue this decision pursuant to 35 U.S.C.
`
`§ 318(a) and 37 C.F.R. § 42.73.
`
`A. Related Matters
`
`
`
`The ’299 patent was the subject of seven district court actions and a
`
`prior inter partes review. See Apotex Corp. v. Alcon Research, Ltd.,
`
`IPR2013-00428 (“the Apotex IPR”). Pet. 1; Paper 3, 2–3. The Apotex IPR
`
`was terminated by settlement after trial institution. Apotex IPR, Papers 9,
`
`58, 60. “Petitioner was not a party to any of these cases.” Pet. 1.
`
`B. Illustrative Claim
`
`Claim 1, reproduced below, illustrates the claimed subject matter:
`
`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.
`
`
`Ex. 1001, 25:31–47.
`
`
`
`
`2
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`
`C. Grounds of Unpatentability
`
`We instituted trial on the following grounds of unpatentability:
`
`(1) Whether claims 1, 2, 4–8, 16, 17, and 20 of the ’299 patent are
`
`unpatentable under 35 U.S.C. § 103 over Xia1, Schneider2, and Chowhan3;
`
`(2) Whether claim 28 is unpatentable under 35 U.S.C. § 103 over
`
`Xia, Schneider, the Travatan® Label4, and Chowhan;
`
`(3) Whether claims 1–23, 25, and 26 are unpatentable under 35
`
`U.S.C. § 103 over Xia, Schneider, Chowhan, and Gadd5; and
`
`(4) Whether claims 24, 27, and 28 are unpatentable under 35 U.S.C.
`
`§ 103 over Xia, Schneider, the Travatan® Label, Chowhan, and Gadd.
`
`Dec. 17–18; see Pet. 2–3 (statement of grounds).
`
`The Petition is supported by Declarations of Dr. Erning Xia
`
`(Ex. 1002) and Dr. Yvonne M. Buys (Ex. 1021). The Petition also is
`
`accompanied by Declarations of Dr. Richard P. Parrish (Ex. 1022) and Dr.
`
`Henry Grabowski (Ex. 1037), which previously were submitted by Patent
`
`
`
`1 Xia et al., WO 2005/097067, “Zinc Preservative Composition and Method
`of Use” (filed March 24, 2005; published October 20, 2005) (“Xia”)
`(Ex. 1003).
`2 Schneider et al., U.S. Patent No. 6,011, 062, “Storage-Stable
`Prostaglandin Compositions” (Filed February 9, 1999; issued January 4,
`2000) (“Schneider”) (Ex. 1007).
`3 Chowhan et al., U.S. Patent No. 6,143,799, “Use of Borate-Polyol
`Complexes in Ophthalmic Compositions” (filed July 2, 1998; issued
`November 7, 2000) (“Chowhan”) (Ex. 1004).
`4 FDA Approved Drug Label “TRAVATAN® (travoprost
`ophthalmic solution) 0.004% Sterile” (2001) (“TRAVATAN® Label”)
`(Ex. 1006).
`5 Gadd et al., “Microorganisms and Heavy Metal Toxicity,” Microbial
`Ecology, 4:303–317 (1978) (“Gadd”) (Ex. 1005).
`3
`
`
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`Owner in the Apotex IPR. The Response to the Petition is supported by
`
`Declarations of Dr. Bhagwati P. Kabra (Ex. 2006), Dr. Stephen Shannon
`
`(Ex. 2007), Dr. Soumyajit Majumdar (Ex. 2023), Dr. George Zhanel
`
`(Ex. 2025), as well as newly-prepared Declarations of Dr. Parrish
`
`(Ex. 2027), and Dr. Grabowski (Ex. 2029). The Reply is supported by a
`
`Second Declaration of Dr. Yvonne M. Buys (Ex. 1092), a Second
`
`Declaration of Dr. Erning Xia (Ex. 1093) and a Declaration of Mr. John C.
`
`Staines, Jr. (Ex. 1094). Patent Owner filed three motions for observations
`
`pertaining to depositions of Dr. Xia, Dr. Buys, and Mr. Staines. Papers 43,
`
`44, 45. Petitioner responded to each motion for observation. Papers 48, 49,
`
`50. In making our final determinations, we have considered Patent Owner’s
`
`observations concerning those depositions and Petitioner’s responses.
`
`II. ANALYSIS
`
`
`
`
`
`We organize our analysis into four parts. First, we provide an
`
`overview of the invention claimed in the ’299 patent. Second, we address
`
`the level of ordinary skill in the art. Third, we discuss claim construction.
`
`Fourth, we assess the merits of the patentability challenge asserted in the
`
`Petition, weighing the objective indicia of nonobviousness against the
`
`evidence of obviousness.
`
`
`
`A. The Invention of the ’299 Patent (Ex. 1001)
`
`The ’299 patent describes “multi-dose, self-preserved ophthalmic
`
`compositions.” Ex. 1001, Abstract. The specification states 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 ‘multi-dose’ nature.” Id. at 1:44–46. The
`
`
`
`4
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`specification states that such compositions can be prepared under sterile
`
`conditions, but due to “frequent, repeated exposure of multi-dose products to
`
`the risk of microbial contamination, it is necessary to employ a means for
`
`preventing such contamination from occurring.” Id. at 1:26–39, 47–50.
`
`The ’299 patent discloses “multi-dose products that do not require a
`
`conventional antimicrobial preservative” “yet are preserved from microbial
`
`contamination.” Id. at 3:10–13. Such compositions are known in the art as
`
`“preservative free” or “self-preserved.” Id. at 3:14, 19. According to
`
`the ’299 patent, aqueous ophthalmic compositions may be preserved from
`
`microbial contamination, despite the absence of conventional preservatives,
`
`by combining low concentrations of zinc ions with a borate-polyol complex
`
`and limiting the concentration of anionic species (such as buffering anions
`
`and metal cations) other than zinc in the compositions. Id. at 3:33–62. The
`
`claimed composition is “able to satisfy the USP preservative efficacy
`
`requirements” and do so “without employing any conventional antimicrobial
`
`preservatives.” Id. at 4:10–17. The specification identifies prostaglandin
`
`analogs (including “travoprost”) as therapeutic agents suitable for use with
`
`the zinc-based preservation system of the invention. Id. at 8:60–65.
`
`B. Level of Ordinary Skill in the Art
`
`We consider each ground of unpatentability in view of the
`
`understanding of a person of ordinary skill in the art at the time of the
`
`invention. Petitioner submits that such a person would have had a Doctorate
`
`in microbiology or chemistry (or a related field) with at least a few years of
`
`experience in the development of ophthalmic formulations. Pet. 7.
`
`Alternatively, in Petitioner’s view, that person would have had a Bachelor’s
`
`
`
`5
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`or Master’s Degree combined with significant (5 years or more) practical
`
`experience developing ophthalmic formulations. Id. Patent Owner, for its
`
`part, advances a definition that “does not differ materially” from that
`
`proposed by Petitioner. Resp. 5.
`
`Petitioner’s definition is comparable to the level of skill reflected in
`
`the asserted prior art. The prior art itself is sufficient to demonstrate the
`
`level of ordinary skill in the art. See Okajima v. Bourdeau, 261 F.3d 1350,
`
`1355 (Fed. Cir. 2001) (prior art itself can reflect appropriate level of
`
`ordinary skill in the art). To the extent more specified findings are required,
`
`we adopt the definition proposed by Petitioner. Pet. 7. We observe,
`
`however, that there is no appreciable difference between the parties’
`
`respective definitions that would “materially” alter the outcome of this
`
`decision based on our acceptance of one definition over the other. Resp. 5.
`
`C. Claim Interpretation
`
`
`
`The Board interprets claims in an unexpired patent using the “broadest
`
`reasonable construction in light of the specification of the patent.” 37 C.F.R.
`
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`
`(2016). Under that standard, we assign terms their ordinary and customary
`
`meaning in view of the specification, as understood by one of ordinary skill
`
`in the art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d
`
`1249, 1257 (Fed. Cir. 2007). In this section, we adopt the preliminary claim
`
`construction set forth in our decision to institute review. Dec. 7–8. Neither
`
`party advances evidence supporting a different final claim construction.
`
`
`
`Petitioner argues that we should adopt the claim construction resolved
`
`in the Apotex IPR, as we did in the decision on institution in this case.
`
`
`
`6
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`Pet. 5–7; Dec. 7–8. Patent Owner tacitly agrees. See Resp. 1 (stating that a
`
`“self-preserved” composition is “one that has sufficient antimicrobial
`
`activity to pass standard tests for ‘preservative efficacy’ without needing a
`
`conventional preservative”). Accordingly, for reasons set forth in our
`
`decision instituting review in the Apotex IPR, we determine that:
`
`
`
`(a) The preamble term “self-preserved” breathes life and meaning
`
`into the claims, and is construed as a limitation of claims 1–28; and
`
`
`
`(b) The broadest reasonable interpretation of “self-preserved”
`
`compositions is “compositions that do not contain a conventional
`
`antimicrobial preservative.” Apotex IPR, Paper 9, 5–6; Dec. 7–8.
`
`Schneider, which is asserted in each ground of unpatentability stated in the
`
`Petition, informs that edetate disodium (“EDTA”) and benzalkonium
`
`chloride (“BAC”) were conventional antimicrobial preservatives known and
`
`available at the time of the invention—an issue not meaningfully disputed by
`
`Petitioner. Ex. 1007, 7:14–21; Pet. 15.
`
`
`
`Our claim construction findings are supported by the specification of
`
`the ’299 patent, which states 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 specification identifies BAC as an example of a conventional
`
`antimicrobial preservative excluded from the self-preserved composition of
`
`the challenged claims. Id. at 4:23–25. No other claim term requires express
`
`construction for the purposes of this decision. See, e.g., Vivid Techs., Inc. v.
`
`Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (only claim terms
`
`in controversy need be construed, and then only to the extent necessary to
`
`resolve the controversy).
`
`7
`
`
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`D. Analysis of the Asserted Grounds of Unpatentability
`
`
`
`In this section, we first analyze the two grounds of unpatentability
`
`asserted in the Petition against claim 1. Pet. 2–3 (statement of grounds of
`
`unpatentability). We then turn to the remaining challenged claims.
`
`(a) The Grounds Asserted Against Claim 1
`
`The Petition asserts two grounds of unpatentability against claim 1,
`
`both of which are based on obviousness. Pet. 2, 3. The first ground is based
`
`on obviousness over Schneider, Xia, and Chowhan. Id. at 8–23. The second
`
`ground adds Gadd to the analysis. Id. at 33–35, 37–42. Because the two
`
`grounds raise substantially similar issues, we address them together in this
`
`section, discussing Gadd only as necessary to resolve the second ground.
`
`Petitioner argues that a person of ordinary skill in the art would have
`
`selected Schneider’s Formulation A as the starting point for modification.
`
`Pet. 9–10 (claim chart, identifying Schneider’s Formulation A), 14–15, 17,
`
`33–35; Tr. 8:7–11. According to Petitioner’s witness, Dr. Xia, one would
`
`have made that selection because Formulation A was “already in the
`
`marketplace” and had demonstrated “both safety and effectiveness.”
`
`Resp. 11 (citing Ex. 2121, 18:12–16); Pet. 15; see Ex. 1002 ¶¶ 46–47
`
`(Dr. Xia’s declaration). Significantly, Petitioner acknowledges that one
`
`undertaking to improve Formulation A “would have retained as much of”
`
`the original composition “as feasible.” Pet. 14–15 (bridging sentence). Yet
`
`the challenge to claim 1 depends on at least six modifications to
`
`Formulation A—which, in unmodified form, bears little resemblance to the
`
`composition specified in claim 1. Pet. 14–20; compare Ex. 1001, claim 1,
`
`with Ex. 1007, 9:25–42 (Table, Formulation A).
`
`
`
`8
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`Claim 1 requires a combination of zinc, borate, sorbitol, and
`
`propylene glycol, and of those four ingredients, Formulation A includes only
`
`borate. Compare Ex. 1001, claim 1 (requiring “borate”), with
`
`Ex. 1007, 9:25–42 (including “boric acid”); see Ex. 1001, 6:6 (“[a]s used
`
`herein, the term “borate” includes “boric acid”). Further, Formulation A
`
`includes two conventional preservatives (BAC and EDTA) that are excluded
`
`from the “self-preserving” composition of claim 1. Ex. 1001, claim 1; see
`
`Ex. 1007, 7:14–21 (Schneider, identifying BAC and EDTA as conventional
`
`preservatives), 9:25–42 (Table, Formulation A).
`
`Petitioner asserts that an ordinarily skilled artisan, notwithstanding a
`
`desire to retain as much of the original composition “as feasible” (Pet. 15),
`
`would have undertaken at least six modifications necessary to bring
`
`Formulation A within the scope of claim 1: (1) replacing BAC with zinc
`
`ions; (2) replacing mannitol with sorbitol; (3) adding propylene glycol;
`
`(4) adjusting the amounts of zinc ions, sorbitol, and propylene glycol to fall
`
`within specific concentration ranges required by claim 1; (5) removing
`
`EDTA; and (6) limiting anionic species present in the modified composition
`
`to a concentration that is less than 15 mM. Pet. 14–20.
`
`We address each of those proposed modifications in sections (1)
`
`through (6) below. In section (7), we discuss a further limitation of claim 1
`
`that requires a composition that meets USP 27 preservative efficacy
`
`requirements; in section (8), we consider Patent Owner’s evidence of
`
`secondary considerations of nonobviousness; and, in section (9), we provide
`
`our conclusions regarding the challenge to claim 1.
`
`
`
`
`
`
`
`9
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`(1) Replacing BAC with Zinc Ions
`
`First, Petitioner proposes that an ordinarily skilled artisan would have
`
`recognized the advantage of replacing BAC (a conventional preservative
`
`excluded in the “self-preserved” composition of claim 1) with a zinc
`
`compound disclosed in Xia. Pet. 14–16. Petitioner submits that this
`
`modification would have been undertaken to improve Formulation A “by
`
`removing BAC, a known source of toxicity, discomfort, and irritation to the
`
`eye.” Id. at 14; Ex. 1002 ¶¶ 36, 47.
`
`Patent Owner responds that the use of Xia’s zinc compound in place
`
`of BAC in Formulation A would have been a “more complicated and less
`
`obvious route” than selecting one of many conventional BAC alternatives
`
`known and available in the art at the time of the invention. Resp. 10;
`
`Ex. 2023 ¶ 45 (identifying known and available conventional preservatives
`
`that would have been recognized as less toxic than BAC). Patent Owner’s
`
`witness, Dr. Majumdar, identifies zinc as “an unconventional preservative”
`
`in a field rife with “conventional” BAC alternatives. Ex. 2023 ¶ 45. Patent
`
`Owner further observes that zinc “had never before been the sole
`
`preservative in a marketed ophthalmic drug.” Resp. 9; Ex. 2023 ¶ 46;
`
`Ex. 2025 ¶ 30. Already, with this first modification, a glimmer of doubt
`
`creeps in, regarding whether Petitioner’s selection of zinc is driven by
`
`disclosures in the prior art or impermissible hindsight reconstruction.
`
`(2) Replacing Mannitol with Sorbitol
`
`Second, Petitioner proposes that one would have replaced mannitol in
`
`Formulation A “with sorbitol.” Pet. 18; Ex. 1002 ¶ 54. The Petition does
`
`not articulate any particular reason why an ordinarily skilled artisan would
`
`
`
`10
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`have resolved on that substitution, except to argue that “mannitol and
`
`sorbitol are sugars . . . differing only in their stereochemistry at a single
`
`carbon and therefore share many similar physical properties.” Pet. 17 (citing
`
`Ex. 1017, 5767, 8797)6. Petitioner stops short of arguing, much less
`
`presenting evidence, that an ordinarily skilled artisan would have identified
`
`sorbitol and mannitol as interchangeable alternative ingredients that would
`
`serve a common function in the modified composition of Formulation A.
`
`Pet. 15–17. Nor does Petitioner identify an express suggestion in the art to
`
`substitute one polyol for the other in the modified composition. Id.
`
`Instead, the Petition raises a third reference (Chowhan) and advances
`
`conclusory opinion testimony that “[i]t would have been obvious to combine
`
`Chowhan and Xia and Schneider in order to optimize the borate-polyol
`
`portion of the self-preservation system and to arrive at the claimed
`
`invention.” Pet. 15 (citing Ex. 1002 ¶ 48) (repeating that conclusory
`
`assertion). That conclusory opinion is not persuasive to show how or why
`
`one would have resolved to replace mannitol with sorbitol in Formulation A.
`
`We discuss Chowhan in more detail below, in connection with the third
`
`proposed modification to Formulation A.
`
`(3) Adding Propylene Glycol in Combination with Sorbitol
`
`Third, Petitioner proposes adding propylene glycol, which is present
`
`in the composition of claim 1 but not in Formulation A. Pet. 17. For
`
`support, Petitioner directs us to Chowhan, which concerns the use of borate-
`
`polyol complexes in ophthalmic compositions that employ “small organic
`
`
`
`6 The cited pages do not exist in Exhibit 1017, which consists of three pages
`from the Merck Index that do not appear to relate to the proposition asserted.
`11
`
`
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`compounds” such as “BAC” as antimicrobial preservatives. Id.; Ex. 1004,
`
`Title, 1:49–63. Chowhan uses the borate-polyol complexes “as adjunctive
`
`disinfecting agents” to improve the antifungal activity of conventional
`
`preservatives. Ex. 1004, 1:49–63, 2:26–36; see Resp. 20–21; Ex. 2025
`
`¶¶ 41, 65; Ex. 2025 ¶¶ 48–49; Ex. 2021 86:19–87:7, 93:5–9. Chowhan does
`
`not mention zinc, much less suggest that a polyol-borate complex would
`
`boost the antimicrobial efficacy of zinc ions in an ophthalmic composition.
`
`See, e.g., Ex. 1004, Examples 1–12; Tr. 38:7–20.
`
`Petitioner submits that Chowhan would have supplied “a reason to
`
`optimize” the polyol selection in Formulation A and, in so doing, would
`
`have prompted an ordinarily skilled artisan to arrive at a polyol mixture of
`
`“propylene glycol and sorbitol” to improve the antimicrobial efficacy of zinc
`
`ions in the modified composition of Formulation A. Pet. 17. The Petition
`
`assumes, but does not establish, that polyol selection was a result-effective
`
`variable for that function, and that an ordinarily skilled artisan would have
`
`been equipped to “optimize” that variable by routine experimentation. Id. at
`
`15, 17; see Resp. 30–38 (for persuasive opposing argument and evidence on
`
`that point); Tr. 7:1–16.
`
`Petitioner does not establish how or why one would have resolved to
`
`include propylene glycol and sorbitol together in Formulation A. None of
`
`Chowhan’s examples uses sorbitol, only one uses propylene glycol; and,
`
`where Chowhan selects a mixture of polyols, propylene glycol is used in
`
`combination with mannitol. Ex. 1004, Example 5; Ex. 2023 ¶ 88; Resp. 34;
`
`see Resp. 30–38 (Patent Owner’s position that the selection of sorbitol and
`
`propylene glycol, in combination with the other specified ingredients and the
`
`express limitation on anionic species, is based on impermissible hindsight).
`
`
`
`12
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`It is not clear on this record why an ordinarily skilled artisan, seeking
`
`to improve the preservative efficacy of zinc, would have turned to Chowhan,
`
`which does not mention zinc. Resp. 21; see Ex. 1004 (Chowhan). In a
`
`nutshell, the Petition directs us to no rational reason why the combined
`
`disclosures of the prior art would have suggested including a polyol mixture
`
`of sorbitol and propylene glycol in the composition of Formulation A as
`
`modified to include zinc ions in place of BAC. Pet. 13–17. Having
`
`considered the second and third modifications proposed in the Petition, that
`
`glimmer of doubt, regarding impermissible hindsight, glows brighter.
`
`(4) Removing EDTA
`
`Formulation A also includes EDTA, a conventional preservative that
`
`is excluded from the “self-preserved” composition of claim 1. Ex. 1001,
`
`claim 1; Ex. 1007, 7:14–21, 9:25–42. And as Petitioner acknowledges,
`
`EDTA is an anionic species. Pet. 19; see Ex. 1001, claim 1 (limiting the
`
`concentration of anionic species). Petitioner proposes that an ordinarily
`
`skilled artisan would have been prompted to remove EDTA from the
`
`modified composition of Formulation A, led by a desire “to avoid chelation
`
`of the zinc and interference with its antimicrobial properties.” Pet. 19 (citing
`
`Ex. 1007, 9:21–42, claims 8, 11; Ex. 1002 ¶ 55).
`
`That position runs counter to the disclosure of Xia––the very
`
`reference upon which Petitioner relies for a suggestion to include zinc in
`
`Formulation A in the first modification. Pet. 10, 14–15. Xia itself identifies
`
`EDTA as a “preferred” chelating or sequestering agent suitable for use in a
`
`zinc-preserved ophthalmic composition. Resp. 12–13; Ex. 2023 ¶ 49;
`
`Ex. 1003, 11. Although EDTA is not a required ingredient of Xia’s
`
`
`
`13
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`composition, the fact that Xia contemplates the use of EDTA as a
`
`“preferred” optional ingredient undercuts Petitioner’s view that EDTA
`
`would have been understood to interfere with zinc ions in an ophthalmic
`
`formulation. Ex. 1003, 11; Pet. 19. With this fourth modification, we
`
`discern that Petitioner is picking and choosing ingredients in Xia’s
`
`formulation to include those required, and remove those precluded, by the
`
`terms of claim 1. Petitioner’s rationale appears to be “entirely hindsight-
`
`driven.” Resp. 13, see id. at 30–41 (and evidence cited therein).
`
`(5) Employing Zinc Ions, Sorbitol, and
`Propylene Glycol in the Specified Concentration Ranges
`
`Even if we accept that an ordinarily skilled artisan would have
`
`replaced BAC with zinc, substituted sorbitol for mannitol, added propylene
`
`glycol, and removed EDTA from Formulation A, we are not persuaded that
`
`the artisan also would have recognized the necessity of maintaining the zinc
`
`ions, sorbitol, and propylene glycol within the specific concentration ranges
`
`required for each component in claim 1. Ex. 1001, claim 1.
`
`In that regard, Claim 1 requires a composition that includes zinc ions,
`
`sorbitol, and propylene glycol in these concentration ranges: (1) zinc ions
`
`must be present “at a concentration of 0.04 to 0.4 mM”; (2) propylene glycol
`
`“at a concentration of 0.25 to 1.25% w/v”; and (4) sorbitol “at a
`
`concentration of 0.05 to 0.5% w/v.” Ex. 1001, claim 1. In addition, polyols
`
`must be present in a concentration range “of 0.25% to 2.5% w/v.” Id.
`
`Xia discloses “minimum” and “maximum” concentration ranges for
`
`the zinc employed in its composition, and there is no dispute that the
`
`“minimum” concentration falls within the range of claim 1. Ex. 1003, 5;
`
`Pet. 9, 15–16; Ex. 1002 ¶ 50; Resp. 16. But Xia discloses two preservation
`
`
`
`14
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`methods; one using zinc alone, and another using zinc in combination with a
`
`“primary preservative agent” such as Polymer JR, “which provides the
`
`preservative efficacy” when zinc is employed at the disclosed “minimum”
`
`concentrations. Ex. 1003, 3–5; Resp. 16–17; Ex. 1002 ¶ 50; Ex. 2023 ¶ 59;
`
`Ex. 2166, 72:17–73:5. Xia makes plain that when the “minimum”
`
`concentrations for zinc are employed in an ophthalmic composition, the zinc
`
`is not an effective preservative on its own, and a “primary preservative
`
`agent” must be included to attain a useful preservation system. Ex. 1003, 4.
`
`Accordingly, we agree with Patent Owner that Xia does not suggest using
`
`zinc ions, at the concentrations required by claim 1, as a useful alternative
`
`to BAC in Formulation A. Resp. 16–17; Ex. 2023 ¶¶ 42–44; Ex. 1003, 5.
`
`Further, as Petitioner’s counsel confirmed during the final hearing,
`
`“the polyol in” Formulation A “isn’t within the claimed range and it’s not
`
`even the same polyol.” Tr. 17:15–17; see Ex. 1007, 9:25–42 (Table,
`
`Formulation A, incorporating mannitol in a concentration of 4.6% w/v). The
`
`Petition includes no coherent explanation of why or how a person of
`
`ordinary skill in the art would have been led to incorporate sorbitol or
`
`propylene glycol in concentrations that fall within the ranges required for
`
`each of those ingredients or maintain the specified limit on total polyol
`
`concentration. See Pet. 11 (claim chart).
`
`This fifth proposed modification rests on conclusory argument that the
`
`concentrations of zinc, sorbitol, and propylene glycol were result-effective
`
`variables and, further, that an ordinarily skilled artisan would have
`
`recognized a need, and understood how, to optimize those concentrations by
`
`routine experimentation to improve the efficacy of zinc ions in the modified
`
`composition of Formulation A. Pet. 17–18. Patent owner persuasively
`
`
`
`15
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`argues that an ordinarily skilled artisan would not “have recognized a
`
`connection between the concentrations of sorbitol or propylene glycol (let
`
`alone both) and zinc’s preservative efficacy, much less” would have known
`
`“how to modify those concentrations to enhance preservative efficacy” of
`
`zinc ions in a formulation that lacks a conventional preservative. Resp. 39;
`
`see id. at 30–41 (and evidence cited therein).
`
`We agree that the asserted prior art does not suggest a “relationship
`
`between polyol concentrations and the preservative efficacy of zinc ions.”
`
`Resp. 40; Ex. 2023 ¶¶ 89, 92–93, 95. Chowhan’s disclosure says nothing
`
`about optimizing the concentrations of individual polyols in a mixed-polyol
`
`composition. See Ex. 1004 (Chowhan). And Petitioner identifies no prior-
`
`art driven suggestion that the concentrations of sorbitol and propylene glycol
`
`(selected to form a mixed-polyol complex with borate) would have been
`
`understood to affect the preservative efficacy of zinc ions in an ophthalmic
`
`composition. Pet. 17–18; see Resp. 30–41 (and evidence cited therein).
`
`(6) Limiting Anionic Species to Less Than 15 mM
`
`Petitioner advances a sixth modification, which pertains to a limitation
`
`on anionic species. According to claim 1, anionic species, to the extent
`
`present, must be limited to a concentration that is “less than 15 mM.”
`
`Ex. 1001, claim 1. In Petitioner’s view, Xia and Chowhan would have led
`
`an ordinarily skilled artisan to limit the amount of anionic species in the
`
`modified composition of Formulation A to fall below a concentration
`
`of 15 mM as required by claim 1. Pet. 12 (claim chart). On that point,
`
`Petitioner argues that compositions disclosed in Xia and Chowhan
`
`“encompass formulations” that include anionic species in “concentrations of
`
`
`
`16
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`zero or at least less than 15 mM.” Id. at 19 (citing Ex. 1002 ¶ 56); see id.
`
`at 12 (claim chart). That observation, however, does not speak to whether
`
`one would have recognized a desire or need to maintain anionic species in
`
`the modified composition of Formulation A at less than 15 mM.
`
`Petitioner directs us to Chowhan’s disclosure “that phosphate anions
`
`can interfere with antimicrobial activity.” Id. at 19–20 (Ex. 1004, 1:45–48).
`
`From there, Petitioner asserts that Chowhan “would have guided a [person
`
`of ordinary skill in the art] to keep the concentration of anionic species as
`
`low as possible” when added to any “ophthalmic compositions”—including
`
`the modified composition of Formulation A. Id. at 20 (citing Ex. 1002 ¶ 57).
`
`For support, Petitioner directs us to opinion testimony that is not tethered
`
`adequately to disclosures in the prior art or other objective proof. Id.
`
`At this point in the analysis, faced with a challenge that depends on at
`
`least six modifications to Formulation A, our steadily brightening glimmer
`
`of doubt catches fire. The challenge appears to be based on impermissible
`
`hindsight rather than a course recommended by the combined disclosures of
`
`the prior art or the understanding of an ordinarily skilled artisan. Patent
`
`Owner observes, and we agree, that “[t]here is no suggestion anywhere in
`
`Xia, Schneider, or Chowhan that anionic species interfere with zinc ions, or
`
`that anionic species are to be avoided.” Resp. 25. On the contrary, Xia—the
`
`very reference asserted to provide an impetus for introducing zinc ions into
`
`Formulation A—identifies “anionic surfactants” and “anionic” counterions
`
`as “suitable for use” in a composition that includes zinc ions. Ex. 1003, 5,
`
`13; Resp. 25. Petitioner does not explain adequately how or why Chowhan
`
`would have prompted an ordinarily skilled artisan to avoid using anions,
`
`given that anions are freely employed in Xia’s own formulation.
`
`
`
`17
`
`
`
`IPR2017-01053
`Patent 8,268,299 B2
`
`
`Here, the Petition pulls in yet another reference—Gadd—to show that
`
`a person of ordinary skill in the art would have undertaken this sixth
`
`modification to Formulation A. Pet. 34. In Petitioner’s view, Gadd would
`
`have provided a reason to avoid “anions and multivalent metal cations other
`
`than zinc” as ingredients in the modified composition. Pet. 33. Petitioner
`
`argues that Gadd discloses that “ions can interfere with the activity of
`
`antimicrobial agents” but directs us to no mention in Gadd of the use of zinc
`
`in an ophthalmic formulation. Id. at 34. In fact, Gadd relates to the
`
`bioavailability of organic materials that bind to heavy metals, such as zinc,
`
`when present in soil or clay. Ex. 1005, 304.
`
`Patent Owner responds that, “[a]bsent hindsight knowledge” of the
`
`claimed invention, one “would have had no reason to go looking for
`
`information about whether anions or multivalent cations could interfere with
`
`the preservative efficacy of zinc” in an ophthalmic formulation. Resp. 48.
`
`That argument has merit, given that Petitioner identifies nothing in the
`
`combined disclosures of Xia, Schneider, or Chowhan that suggests “any
`
`concern with the concentrations of anions or cations in a formulation
`
`containing zinc, borate, and polyol.” Id. Here again, we find significant that
`
`“Xia affirmatively suggests using certain anionic components” in an
`
`ophthalmic formulation that contains zinc. Resp. 48; see Ex. 1003, 5, 13
`
`(Xia, disclosing numerous anions, including “anionic organic or inorganic
`
`counterion[s]” (id. at 5) as well as “anionic surfactants” (id. at 13) that are
`
`use
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
