Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 8
`Entered: July 18, 2016
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner.
`
`Case IPR2016-00544
`Patent 8,791,154 B2
`
`Before JENNIFER MEYER CHAGNON, CHRISTOPHER M. KAISER,
`and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`KAISER, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`IPR2016-00544
`Patent 8,791,154 B2
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`INTRODUCTION
`
`A. Background
`Argentum Pharmaceuticals LLC (“Petitioner”) filed a Petition (Paper
`1, “Pet.”) requesting inter partes review of claims 1–4, 8, 12, 13, 21, and 22
`of U.S. Patent No. 8,791,154 B2 (Ex. 1001, “the ’154 patent”). Alcon
`Research, Ltd. (“Patent Owner”) did not file a Preliminary Response.
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). The standard for
`instituting an inter partes review is set forth in 35 U.S.C. § 314(a), which
`provides that an inter partes review may not be instituted unless “there is a
`reasonable likelihood that the petitioner would prevail with respect to at least
`1 of the claims challenged in the petition.”
`After considering the Petition and the evidence currently of record, we
`determine that Petitioner has demonstrated that there is a reasonable
`likelihood that it would prevail with respect to at least one of the claims
`challenged in the Petition. Accordingly, we institute inter partes review.
`
`B. Related Matters
`The parties note that the ’154 patent is the subject of Alcon Research,
`Ltd. v. Watson Laboratories, Inc., Case No. 1-15-cv-01159-SLR (D. Del.).
`Pet. 1; Paper 6, 2.
`
`C. The Asserted Grounds of Unpatentability
`Petitioner contends that claims 1–4, 8, 12, 13, 21, and 22 of the ’154
`patent are unpatentable based on the following grounds (Pet. 17–60):1
`
`
`1 Petitioner also relies on declarations from Erning Xia, Ph.D., and Leonard
`Bielory, M.D. Ex. 1002 (“the Xia Declaration” or “Xia Decl.”); Ex. 1003
`(“the Bielory Declaration” or “Bielory Decl.”).
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`Statutory
`Ground
`§ 103
`
`§ 103
`
`Basis
`
`Challenged Claims
`
`Bhowmick,2 Yanni,3 and
`Castillo4
`Schneider,5 Hayakawa,6
`Bhowmick, and Castillo
`
`1–4, 8, 12, 13, 21, and 22
`
`1–4, 8, 12, 13, 21, and 22
`
`D. The ’154 Patent
`The ’154 patent relates to “an ophthalmic composition containing a
`relatively high concentration of olopatadine.” Ex. 1001, at [57]. This
`“invention is directed to an ophthalmic composition for treatment of allergic
`conjunctivitis.” Id. at 2:41–42. The ’154 patent describes the claimed
`compositions as including “at least 0.67 w/v % olopatadine, preferably
`dissolved in solution.” Id. at 2:42–45. The claimed compositions also are
`described as “typically includ[ing] a cyclodextrin, and more particularly, a
`γ-cyclodextrin derivative and/or a β-cyclodextrin derivative to aid in
`solubilizing the olopatadine.” Id. at 2:45–48. In addition, the ’154 patent
`describes other ingredients to assist in solubilization of the olopatadine,
`including “a lactam polymer (e.g., polyvinylpyrrolidone (PVP))” and “a
`
`2 Bhowmick et al., WO 2008/015695 A2, published Feb. 7, 2008 (Ex. 1004,
`“Bhowmick”).
`3 J.M. Yanni et al., The In Vitro and In Vivo Ocular Pharmacology of
`Olopatadine (AL-4943A), an Effective Anti-Allergic/Antihistaminic Agent,
`12 J. OCULAR PHARMACOLOGY & THERAPEUTICS 389, 389–400 (1996)
`(Ex. 1005, “Yanni”).
`4 Castillo et al., U.S. Patent No. 6,995,186 B2, issued Feb. 7, 2006
`(Ex. 1006, “Castillo”).
`5 Schneider et al., US 2011/0082145 A1, published Apr. 7, 2011 (Ex. 1007,
`“Schneider”).
`6 Hayakawa et al., U.S. Patent No. 5,641,805, issued June 24, 1997
`(Ex. 1008, “Hayakawa”).
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`polyether (e.g., polyethylene glycol (PEG)).” Id. at 2:52–57. The claimed
`compositions also are described as including “a preservative” such as
`“benzalkonium chloride,” as well as “borate and/or polyol to aid in
`achieving desired preservation.” Id. at 2:60–67. In addition to the claimed
`compositions, the ’154 patent also describes “a method of treating ocular
`allergy symptoms” by “topically applying [the claimed compositions] to an
`eye of a human,” preferably by “dispensing an eyedrop from an
`eyedropper.” Id. at 3:1–6.
`
`E. Illustrative Claims
`Of the challenged claims in the ’154 patent, claims 1, 4, 8, and 21 are
`independent. Ex. 1001, 26:28–28:13. Independent claims 1 and 4 and
`dependent claim 12 are illustrative. They recite:
`
`1. An aqueous ophthalmic solution for treatment of ocular allergic
`conjunctivitis, the solution comprising:
`at least 0.67 w/v % olopatadine dissolved in the solution;
`PEG having a molecular weight of 300 to 500;
`polyvinylpyrrolidone;
`hydroxypropyl-γ-cyclodextrin;
`benzalkonium chloride; and
`water.
`Ex. 1001, 26:28–35.
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`4. An aqueous ophthalmic solution for treatment of ocular allergic
`conjunctivitis, the solution comprising:
`at least 0.67 w/v % but no greater than 1.0 w/v %
`olopatadine dissolved in the solution;
`2.0 w/v % to 6.0 w/v % PEG having a molecular weight
`of 300 to 500;
`2.0 w/v % to 6.0 w/v % polyvinylpyrrolidone;
`at least 0.5 w/v % but no greater than 2.0 w/v %
`cyclodextrin derivative selected from the group
`consisting of SAE-β-cyclodextrin, HP-γ-cyclodextrin,
`HP-β-cyclodextrin and combinations thereof; and
`water.
`Ex. 1001, 26:39–50.
`
`12. A method of treating at least one ocular allergy symptom in
`humans, the method comprising:
`topically applying to an eye of a human an amount of the
`solution of claim 4 sufficient to treat the at least one
`ocular allergy symptom.
`Ex. 1001, 27:7–11.
`
`ANALYSIS
`
`A. Claim Construction
`In an inter partes review, we construe claim terms in an unexpired
`patent according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b); see
`Cuozzo Speed Techs. LLC v. Lee, No. 15–446, 2016 WL 3369425, at *12
`(U.S. June 20, 2016) (upholding the use of the broadest reasonable
`interpretation standard). Claim terms also are given their ordinary and
`customary meaning, as would be understood by one of ordinary skill in the
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`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`F.3d 1249, 1257 (Fed. Cir. 2007).
`
`1. Preambles
`Petitioner argues that the preambles of claims 1, 4, 8, and 21 should
`be interpreted as non-limiting. Pet. 13–14. But Petitioner also provides
`argument and identifies evidence sufficient on the present record to show
`that these preambles are taught or suggested by the prior art on which
`Petitioner relies. Id. at 32–37, 39, 50, 52, 54, 56. Accordingly, we need not
`decide whether the preambles are limiting in order to determine whether to
`institute trial. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
`803 (Fed. Cir. 1999) (“only those terms need be construed that are in
`controversy, and only to the extent necessary to resolve the controversy”).
`
`2. “Solution comprising . . . at least 0.67 w/v % olopatadine . . .
`dissolved in the solution”
`Petitioner proposes that the phrase “solution comprising . . . at least
`0.67 w/v % olopatadine . . . dissolved in the solution” be interpreted to
`include solutions in which at least 0.67 w/v % olopatadine is dissolved in the
`solution and additional olopatadine may be present in an undissolved form.
`Pet. 14–15. This phrase does not need construction at this time. First, there
`is at this time no evidence of record that the prior art on which Petitioner
`relies is limited to solutions in which some amount of olopatadine is present
`in an undissolved form. Second, Petitioner’s proposed construction does not
`attribute any new meaning to the phrase beyond that granted by the use of
`the term “comprising,” which permits the presence of items not recited in the
`language of the claim. Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501
`(Fed. Cir. 1997) (holding that “comprising” is a term of art meaning that the
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`named elements are essential, but other elements may be added and still
`form a construct within the scope of the claim).
`
`3. “w/v %”
`Petitioner argues that “w/v %” should be interpreted as “the mass of
`the component in grams per 100 milliliters of solution multiplied by 100,”
`which Petitioner describes as “the standard used in the formulations and
`topical eye pharmaceutical industries.” Pet. 15 (citing Ex. 1002 ¶ 21).
`Based on the evidence currently of record, we agree with Petitioner that this
`is the appropriate interpretation of “w/v %.” Accordingly, we construe
`“w/v %” of a component as “the mass of the component in grams per 100
`milliliters of solution multiplied by 100.”
`
`B. Asserted Obviousness over Bhowmick, Yanni, and Castillo
`Petitioner argues that claims 1–4, 8, 12, 13, 21, and 22 would have
`been obvious over the combination of Bhowmick, Yanni, and Castillo.
`
`1. Bhowmick
`Bhowmick relates to “an aqueous topical solution comprising a
`therapeutically effective amount of olopatadine.” Ex. 1004, at [57]. It
`teaches that such solutions are “indicated for the treatment of signs and
`symptoms of allergic conjunctivitis.” Id. at 1:18–19. Bhowmick also
`teaches various means of “enhanc[ing] the physical stability of” its
`olopatadine solutions, including cyclodextrin derivatives, such as “the
`hydroxypropyl derivatives of alpha-, beta-, and gamma-cyclodextrin” and
`“sulfoalkyl ether cyclodextrin.” Id. at 4:16–5:12. When discussing the use
`of hydroxypropyl-β-cyclodextrin to stabilize olopatadine solutions “for
`ophthalmic administration,” Bhowmick teaches using “about 1.0% to about
`5%” of the cyclodextrin derivative. Id. at 6:5–6. More broadly, Bhowmick
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`teaches including between about 1.65 and about 50 times as much
`hydroxypropyl-β-cyclodextrin as olopatadine by weight. Id. at 6:18–20.
`Bhowmick teaches the use of other stabilizers, including hydroxypropyl
`methylcellulose in “concentrations ranging from about 0.001% to about
`5%.” Id. at 7:10–13. In addition, Bhowmick teaches adding other
`compounds, such as benzalkonium chloride as a preservative “in an amount
`ranging from about 0.005% to about 1%w/v,” and sodium borate as a
`buffering agent. Id. at 7:20–22, 8:14–21. Bhowmick teaches that its
`solution “is intended to be administered as . . . eye drops,” that its solution
`has an osmolality “between 150 [and] 450 mOsm,” and that its solution has
`a pH of “4 to 8, preferably pH of 6.5 to 7.5.” Id. at 8:10–12, 8:22–24.
`
`2. Yanni
`Yanni teaches that olopatadine “is an anti-allergic agent” and reports
`results of in vitro and in vivo studies of olopatadine using “human
`conjunctival mast cell preparations” as well as “guinea pigs.” Ex. 1005,
`389. Yanni teaches using solutions containing 0.001 to 1.0 w/v %
`olopatadine. Id. at 395.
`
`3. Castillo
`Castillo relates to “[t]opical formulations of olopatadine for treatment
`of allergic or inflammatory disorders of the eye.” Ex. 1006, at [57]; see id.
`at 2:13–15. Castillo teaches aqueous solutions with 0.17 to 0.62 w/v % of
`olopatadine and “an amount of polyvinylpyrrolidone . . . sufficient to
`enhance the physical stability of the formulations.” Id. at [57]; see id. at
`2:17–27, 2:66–3:2. The polyvinylpyrrolidone concentration in Castillo is
`taught as 0.1 to 3%. Id. at 3:22–25. Castillo also teaches the presence of
`other substances in the solutions, including polyols as tonicity-adjusting
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`agents, benzalkonium chloride as a preservative, borates as buffering agents,
`and 400-molecular-weight polyethylene glycol at a concentration of
`2 w/v %. Id. at 3:64–67, 4:2–3, Table 5.
`
`4. Analysis of Obviousness over Bhowmick, Yanni, and Castillo
`Petitioner argues that Bhowmick, Yanni, and Castillo teach or suggest
`all the limitations of each of claims 1–4, 8, 12, 13, 21, and 22 of the ’154
`patent and that a person of ordinary skill in the art would have had a reason
`to combine the teachings of the three references. Pet. 17–41. After
`reviewing the Petition and the evidence cited therein, we conclude that
`Petitioner has made a sufficient showing regarding each of these matters to
`establish a reasonable likelihood of prevailing on its assertion that the
`challenged claims are obvious over the combination of Bhowmick, Yanni,
`and Castillo.
`
`a. Claim 1
`Claim 1 recites “[polyethylene glycol] having a molecular weight of
`300 to 500,” “polyvinylpyrrolidone,” and “benzalkonium chloride” as
`components of its “aqueous ophthalmic solution.” Ex. 1001, 26:28–35.
`Petitioner has made a sufficient showing that each of these is taught or
`suggested by Castillo. Pet. 33–34 (citing Ex. 1006, 2:23–27, 3:66–67,
`Table 5). Claim 1 also recites “hydroxypropyl-γ-cyclodextrin” and “water.”
`Ex. 1001, 26:28–35. Petitioner has made a sufficient showing that each of
`these is taught or suggested by Bhowmick. Id. (citing Ex. 1004, at [57],
`4:16–17, 5:3–5, 5:12–18). Finally, claim 1 recites “at least 0.67 w/v %
`olopatadine dissolved in the solution.” Petitioner has made a sufficient
`showing that this limitation is taught or suggested by Yanni. Pet. 33 (citing
`Ex. 1005, 395). Yanni teaches olopatadine concentrations from 0.001 to
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`1.0 w/v %. Ex. 1005, 395. A prima facie case of obviousness exists in
`situations where, as here, the claimed ranges overlap the ranges disclosed by
`the prior art. See In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997); In re
`Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). There is as yet no
`evidence of record to overcome this prima facie case of obviousness.
`The fact that the prior art contains individual teachings of each of the
`limitations of claim 1 would not be sufficient to establish obviousness if a
`person of ordinary skill in the art would not have had a reason to combine
`the prior-art teachings in question. There must be “some articulated
`reasoning with some rational underpinning” to combine the known elements
`in the manner required in the claim at issue. KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 418 (2007). “[I]f a technique has been used to improve one
`device, and a person of ordinary skill in the art would recognize that it would
`improve similar devices in the same way, using the technique is obvious
`unless its actual application is beyond his or her skill.” Id. at 417. Here,
`Petitioner has identified evidence of record suggesting that the compounds
`added to the ophthalmic solutions of Bhowmick and Castillo to stabilize,
`preserve, buffer, and adjust the tonicity of those solutions would perform the
`same functions in ophthalmic solutions using the higher amount of
`olopatadine taught by Yanni. Pet. 23 (citing Ex. 1007 ¶ 7; Ex. 1003 ¶ 36;
`Ex. 1006, 2:19–22), 25 (citing Ex. 1004, at [57], 7:20–22).
`Because Petitioner has made a sufficient showing both that
`Bhowmick, Yanni, and Castillo teach or suggest all the limitations of claim
`1 and that a person of ordinary skill in the art would have had a reason to
`combine the teachings of Bhowmick, Yanni, and Castillo, we determine that
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`Petitioner has established a reasonable likelihood of prevailing in showing
`the obviousness of claim 1 over this combination of references.
`
`b. Claim 2
`Claim 2 depends from claim 1 and adds the requirement that the
`aqueous ophthalmic solution contain borate. Ex. 1001, 26:36. Petitioner
`argues that this new limitation is taught or suggested by both Bhowmick and
`Castillo. Pet. 34 (citing Ex. 1004, 8:14–21; Ex. 1006, 4:2–4). Bhowmick
`teaches the inclusion of “buffering agents includ[ing] . . . sodium borate,”
`while Castillo teaches “buffering agents includ[ing] . . . borates.” Ex. 1004,
`8:16–20; Ex. 1006, 4:2–3. Petitioner thus has established a reasonable
`likelihood of prevailing in showing the obviousness of claim 2 over
`Bhowmick, Yanni, and Castillo.
`
`c. Claim 3
`Claim 3 depends from claim 2 and requires that the aqueous
`ophthalmic solution contain “a polyol.” Ex. 1001, 26:37. Petitioner argues
`that this limitation is taught or suggested by Castillo. Pet. 34 (citing Ex.
`1006, 3:64–65). The ’154 patent lists examples of polyols, including
`mannitol, glycerin, and sorbitol, among others. Ex. 1001, 7:65–8:1. Castillo
`teaches the inclusion of “tonicity-adjusting agents includ[ing] mannitol, . . .
`glycerin, [and] sorbitol.” Ex. 1006, 3:64–65. Petitioner thus has established
`a reasonable likelihood of prevailing in showing the obviousness of claim 3
`over Bhowmick, Yanni, and Castillo.
`
`d. Claim 4
`Claim 4 is similar to claim 1, but it narrows the scope of claim 1 by
`reciting limits on the concentration of the recited compounds in the
`ophthalmic solution. Petitioner argues that Yanni teaches or suggests the
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`recited “at least 0.67 w/v % but no greater than 1.0 w/v % olopatadine
`dissolved in the solution.” Pet. 35 (citing Ex. 1005, 391–392, 394–396,
`Tables 2, 3). As noted above, Yanni teaches olopatadine concentrations
`between 0.001 and 1.0 w/v %, which overlaps the claimed range. Ex. 1005,
`395. Accordingly, Petitioner has made a sufficient showing that this
`limitation is taught or suggested by the prior art.
`Petitioner argues that Castillo teaches or suggests the recited “2.0
`w/v % to 6.0 w/v % [polyethylene glycol] having a molecular weight of 300
`to 500.” Pet. 35 (citing Ex. 1006, Table 5). The cited portion of Castillo
`teaches 2 w/w % of “Polyethylene Glycol (400).” Ex. 1006, Table 5.
`Castillo does not explain how to convert its “w/w %” into the “w/v %” of the
`claims of the ’154 patent. There is evidence in the record that suggests that
`Castillo’s 2 w/w % equates to 2.06 to 2.10 w/v % when converted into the
`units used in the ’154 patent. Pet. 27 (citing Ex. 1003 ¶¶ 43–44). This
`evidence is, for the moment at least, not contradicted by any evidence of
`record. Accordingly, Petitioner has made a sufficient showing that this
`limitation is taught or suggested by the prior art.
`Petitioner argues that Castillo teaches or suggests the recited
`“2.0 w/v % to 6.0 w/v % polyvinylpyrrolidone.” Pet. 35 (citing Ex. 1006,
`2:66–3:2, 3:22–25). Castillo teaches polyvinylpyrrolidone concentrations
`between 0.1 and 3 percent. Ex. 1006, 3:22–25. Although the cited portion
`of Castillo does not say whether the type of percentage intended is w/v %,
`another portion of Castillo makes clear that “all component amounts are
`presented on a % (w/v) basis.” Id. at 2:32–34. Accordingly, Petitioner has
`made a sufficient showing that this limitation is taught or suggested by the
`prior art.
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`Claim 4 also broadens the scope of claim 1 by allowing a
`“cyclodextrin derivative selected from the group consisting of
`[sulfoalkyl ether]-β-cyclodextrin, [hydroxypropyl]-γ-cyclodextrin,
`[hydroxypropyl]-β-cyclodextrin and combinations thereof,” rather than
`restricting the choice to claim 1’s “hydroxypropyl-γ-cyclodextrin.”
`Ex. 1001, 26:39–50. As discussed above, Petitioner has made a sufficient
`showing that Bhowmick teaches or suggests hydroxypropyl-γ-cyclodextrin.
`Pet. 33 (citing Ex. 1004, 4:16–17, 5:3–5, 5:12–18). Petitioner also has made
`a sufficient showing that Bhowmick teaches or suggests the other
`compounds recited. Pet. 35–36 (citing Ex. 1004, 5:10–18, 6:1–8). As for
`the requirement that the cyclodextrin derivative be present at a concentration
`of “at least 0.5 w/v % but no greater than 2.0 w/v %,” Petitioner argues that
`Bhowmick teaches this. Pet. 35–36 (citing Ex. 1004, 6:5–6, 6:18–21).
`Bhowmick teaches a concentration of hydroxypropyl-β-cyclodextrin “in the
`range from about 1.0% to about 5%.” Ex. 1004, 6:5–6. The surrounding
`portions of Bhowmick make clear that these percentages are intended to be
`w/v %. See Ex. 1004, 6:1–4 (stating that preferable hydroxypropyl-β-
`cyclodextrin concentration ranges “from about 0.1% to about 20%w/v of the
`composition, and more preferably . . . from about 1.0% to about 10% w/v of
`the composition”). Accordingly, Petitioner has made a sufficient showing
`that this limitation is taught or suggested by the prior art.
`As discussed above with respect to claim 1, Petitioner has made a
`sufficient showing that a person of ordinary skill in the art would have had a
`reason to combine the teachings of Bhowmick, Yanni, and Castillo.
`Accordingly, we determine that Petitioner has established a reasonable
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`likelihood of prevailing in showing the obviousness of claim 4 over this
`combination of references.
`
`e. Claim 8
`Claim 8 is identical to claim 4, except that it limits the cyclodextrin
`derivative to hydroxypropyl-γ-cyclodextrin, rather than allowing other
`possible cyclodextrin derivatives as claim 4 does. Ex. 1001, 26:58–67. As
`discussed above with respect to claims 1 and 4, Petitioner has made a
`sufficient showing that Bhowmick teaches the use of hydroxypropyl-γ-
`cyclodextrin. Pet. 33 (citing Ex. 1004, 4:16–17, 5:3–5, 5:12–18). We note
`that, with respect to the limitation on the amount of hydroxypropyl-γ-
`cyclodextrin that may be present, Ex. 1001, 26:65–66 (“at least 0.5 w/v %
`but no greater than 2.0 w/v % hydroxypropyl-γ-cyclodextrin”), Bhowmick
`presents an overlapping range of compositions only for hydroxypropyl-β-
`cyclodextrin. Ex. 1004, 6:1–6. But Petitioner directs us to evidence of
`record suggesting that a person of ordinary skill in the art would have
`understood that hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-
`cyclodextrin were interchangeable in identical quantities. Pet. 27–28 (citing
`Ex. 1001, 5:30–47; Ex. 1002 ¶¶ 38–40, 60; Ex. 1045 ¶¶ 18, 163). There is
`as yet no evidence of record contradicting this evidence. Accordingly, we
`determine that Petitioner has established a reasonable likelihood of
`prevailing in showing the obviousness of claim 8 over Bhowmick, Yanni,
`and Castillo.
`
`f. Claim 12
`Claim 12 depends from claim 4 and recites a “method of treating at
`least one ocular allergy symptom in humans, the method comprising:
`topically applying to an eye of a human an amount of the solution of claim 4
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`sufficient to treat the at least one ocular allergy symptom.” Ex. 1001, 27:7–
`11. Petitioner directs us to evidence of record that Bhowmick teaches
`treating “symptoms of allergic conjunctivitis.” Pet. 38 (citing Ex. 1004,
`1:16–19). Petitioner also directs us to evidence of record that Castillo
`teaches using a topical olopatadine solution to treat “allergic . . . disorders of
`the eye.” Id. at 38–39 (citing Ex. 1006, 2:13–19). Although Petitioner does
`not explicitly argue that the combination of Bhowmick, Yanni, and Castillo
`teaches or suggests that the eyes whose allergic disorders would be treated
`were human eyes, Petitioner does implicitly argue that this limitation is
`satisfied by citing to Alcon Research, Ltd. v. Apotex Inc. Pet. 32 (citing 687
`F.3d 1362, 1369 (Fed. Cir. 2012)). In Alcon, the Federal Circuit held that,
`even though the prior-art references relied upon “d[id] not expressly disclose
`that olopatadine would be safe for use in human eyes,” a person of ordinary
`skill in the art “would have [had] a reasonable expectation of success for
`adapting [the prior-art olopatadine] formulation for the same use in a human
`eye.” 687 F.3d at 1369. Accordingly, we determine that Petitioner has
`established a reasonable likelihood of prevailing in showing the obviousness
`of claim 12 over Bhowmick, Yanni, and Castillo.
`
`g. Claim 13
`Claim 13 depends from claim 12 and recites a “method as in claim 12
`wherein the step of topically applying the solution includes dispensing at
`least one drop of the solution to the eye.” Ex. 1001, 27:12–14. Petitioner
`has made a sufficient showing that Bhowmick and Castillo each teach
`administering olopatadine solutions as eye drops. Pet. 39 (citing Ex. 1004,
`8:10–11; Ex. 1006, 4:16–19). Petitioner thus has established a reasonable
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`likelihood of prevailing in showing the obviousness of claim 13 over
`Bhowmick, Yanni, and Castillo.
`
`h. Claim 21
`Claim 21 is similar to claim 8, discussed above, but it includes two
`additional limitations not present in claim 8. Ex. 1001, 27:32–28:10. First,
`claim 21 requires “greater than 0.003 w/v % but less than 0.03 w/v %
`benzalkonium chloride.” Id. at 28:6–7. Petitioner has made a sufficient
`showing that this limitation is taught or suggested by Bhowmick. Pet. 40
`(citing Ex. 1004, 7:20–22). Bhowmick discloses the use of benzalkonium
`chloride “in an amount ranging from about 0.005% to about 1 %w/v.”
`Ex. 1004, 7:20–22. This range overlaps with the claimed range.
`Second, claim 21 requires that “the pH of the solution [be] 6.0 to 7.8
`and the osmolality of the solution [be] 200 to 400 mOsm/kg.” Ex. 1001,
`28:9–10. Petitioner argues that the pH portion of this limitation is taught or
`suggested by Bhowmick, while the osmolality portion is taught or suggested
`by both Bhowmick and Castillo. Pet. 41 (citing Ex. 1004, 8:11–12, 8:22–24;
`Ex. 1006, 4:16–19). With respect to pH, Bhowmick discloses a solution
`with “a pH 4 to 8, preferably . . . 6.5 to 7.5, and most preferably . . . 6.8 to
`7.2.” Ex. 1004, 8:22–24. With respect to osmolality, Bhowmick discloses a
`solution with an osmolality of “150 to 450 mOsm, and more preferably
`between 250 [and] 350 mOsm,” and Castillo discloses an osmolality of
`“150–450 mOsm, preferably 250–350 mOsm.” Ex. 1004, 8:11–12;
`Ex. 1006, 4:17–19. We note that claim 21 recites its osmolality requirement
`in units of mOsm/kg, while Bhowmick and Castillo disclose osmolality in
`units of mOsm. Ex. 1001, 28:9–10; Ex. 1004, 8:11–12; Ex. 1006, 4:17–19.
`Petitioner directs us to evidence of record that a person of ordinary skill in
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`the art would interpret Bhowmick’s and Castillo’s osmolality values as
`being reported in mOsm/kg rather than in mOsm, making them comparable
`to those of claim 21. Pet. 28–29 (citing Ex. 1002 ¶ 51). There is as yet no
`evidence of record contradicting this evidence. Accordingly, Petitioner has
`established a reasonable likelihood of prevailing in showing the obviousness
`of claim 21 over Bhowmick, Yanni, and Castillo.
`
`i. Claim 22
`Claim 22 depends from claim 21 and adds a limitation requiring “at
`least 0.15 w/v % but no greater than 1.0 w/v % hydroxypropylmethyl
`cellulose.” Ex. 1001, 28:11–13. Petitioner argues that this limitation is
`taught or suggested by Bhowmick. Pet. 41 (citing Ex. 1004, 7:10–13).
`Bhowmick discloses the use of “hydroxypropyl methylcellulose” in
`“concentrations ranging from about 0.001% to about 5%, and more
`preferably in concentrations ranging from about 0.01% to about 1% w/v.”
`Ex. 1004, 7:10–13. Given that these disclosed ranges overlap the range
`recited in claim 22, Petitioner has established a reasonable likelihood of
`prevailing in showing the obviousness of claim 22 over Bhowmick, Yanni,
`and Castillo.
`
`C. Asserted Obviousness over Schneider, Hayakawa, Bhowmick, and
`Castillo
`Petitioner argues that claims 1–4, 8, 12, 13, 21, and 22 would have
`been obvious over the combination of Schneider, Hayakawa, Bhowmick,
`and Castillo.
`
`1. Schneider
`Schneider relates to “solution compositions comprising olopatadine.”
`Ex. 1007, at [57]. In particular, Schneider “relates to formulations of
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`olopatadine and their use for treating and/or preventing allergic or
`inflammatory disorders of the eye, nose, skin, and ear.” Id. It teaches that,
`“[i]n general, it is more desirable for active ingredients to be in solution
`rather than suspension in a pharmaceutical composition.” Id. ¶ 7.
`Schneider’s products are “pharmaceutical aqueous solution compositions,”
`id. ¶ 9, that “are used to treat . . . allergic conjunctivitis,” id. ¶ 48. The
`amount of olopatadine in Schneider is taught as “about . . . 0.60% w/v, or
`higher.” Id. ¶ 45. In addition to olopatadine, Schneider teaches adding
`several other compounds to its ophthalmic solutions, including sodium
`borate as a buffer, id. ¶ 44, water, id. ¶ 49, benzalkonium chloride as a
`preservative, id. ¶ 51, polyethylene glycol and polyvinylpyrrolidone “as
`lubricants or as viscosity agents,” id. ¶ 52, and dextrose, mannitol, sorbitol,
`propylene glycol, or glycerol as tonicity agents, id. ¶ 53. Schneider teaches
`a composition pH between 6.0 and 7.5. Id. ¶ 44. It also teaches osmolality
`“about 150–450 mOsm, preferably 250–350 mOsm.” Id. ¶ 53.
`
`2. Hayakawa
`Hayakawa relates to “[t]opical ophthalmic formulations” containing
`olopatadine.7 Ex. 1008, at [57]. Olopatadine is disclosed as having “human
`
`7 Hayakawa uses “Compound A” or “11-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid” to refer to either individual
`isomer or to a mixture of both isomers of 11-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. Ex. 1008, 3:10–15. This
`compound, in the hydrochloride salt of its Z isomer, is identified as
`olopatadine in Yanni. Ex. 1005, 389. Schneider identifies this compound,
`not in its hydrochloride salt, but still in its Z isomer, as olopatadine.
`Ex. 1007 ¶ 3. There is as yet no evidence in the record contradicting the
`identification of the compound disclosed in Hayakawa as olopatadine.
`Accordingly, we use the term “olopatadine” when referring to the compound
`that Hayakawa discloses.
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`conjunctival mast cell stabilizing activity” and “significant antihistaminic
`activity.” Id. at 3:18–22. Accordingly, Hayakawa notes that olopatadine has
`both “a prophylactic effect” and “a therapeutic effect.” Id. at 3:22–23.
`Hayakawa discloses using olopatadine in concentrations ranging from
`“0.0001 to 5 w/v %,” id. at 6:43–44, with histamine inhibition increasing as
`the dose of olopatadine increases, id. at Table 1.
`
`3. Analysis of Obviousness over Schneider, Hayakawa, Bhowmick,
`and Castillo
`Petitioner argues that Schneider, Hayakawa, Bhowmick, and Castillo
`teach or suggest all the limitations of each of claims 1–4, 8, 12, 13, 21, and
`22 of the ’154 patent and that a person of ordinary skill in the art would have
`had a reason to combine the teachings of the four references. Pet. 42–58.
`After reviewing the Petition and the evidence cited therein, we conclude that
`Petitioner has made a sufficient showing regarding each of these matters to
`establish a reasonable likelihood of prevailing on its assertion that the
`challenged claims are obvious over the combination of Schneider,
`Hayakawa, Bhowmick, and Castillo.
`
`a. Claim 1
`Claim 1 recites “[polyethylene glycol] having a molecular weight of
`300 to 500,” “polyvinylpyrrolidone,” “benzalkonium chloride,” and “water”
`as components of its “aqueous ophthalmic solution.” Ex. 1001, 26:28–35.
`Petitioner has made a sufficient show