Page 1
`Page 1
`
`
`
`ALCON RESEARCH, LTD. (FORMERLY KNOWN AS ALCON
`ALCON RESEARCH, LTD. (FORMERLY KNOWN AS ALCON
`MANUFACTURING, LTD.), ALCON LABORATORIES, INC., AND KYOWA
`MANUFACTURING, LTD.), ALCON LABORATORIES, INC., AND KYOWA
`HAKKO KIRIN CO. LTD., Plaintiffs-Appellees, v. APOTEX INC. AND APOTEX
`HAKKO KIRIN CO. LTD., Plaintiffs-Appellees, v. APOTEX INC. AND APOTEX
`CORP., Defendants-Appellants.
`CORP., Defendants-Appellants.
`
`2011-1455
`2011-1455
`
`UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
`UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
`
`687 F.3d 1362; 2012 U.S. App. LEXIS 16503; 103 U.S.P.Q.2D (BNA) 1737
`687 F.3d 1362; 2012 U.S. App. LEXIS 16503; 103 U.S.P.Q.2D (BNA) 1737
`
`August 8, 2012, Decided
`August 8, 2012, Decided
`
`SUBSEQUENT HISTORY: US Supreme Court
`SUBSEQUENT HISTORY: US
`Supreme Court
`certiorari denied by Alcon Research, Ltd. v. Apotex, Inc.,
`certiorari denied by Alcon Research, Ltd. v. Apotex, Inc.,
`133 S. Ct. 1736, 185 L. Ed. 2d 787, 2013 U.S. LEXIS
`133 S. Ct. 1736, 185 L. Ed. 2d 787, 2013 U.S. LEXIS
`2613 (U.S., 2013)
`2613 (U.S., 2013)
`Related proceeding at Alcon Research, Ltd. v. Apotex,
`Related proceeding at Alcon Research, Ltd. v. Apotex,
`Inc., 2013 U.S. Dist. LEXIS 71432 (S.D. Ind., May 21,
`Inc., 2013 U.S. Dist. LEXIS 71432 (S.D. 1nd, May 21,
`2013)
`2013)
`
`PRIOR HISTORY: [**1]
`PRIOR HISTORY: [**1]
`Appeal from the United States District Court for the
`Appeal from the United States District Court for the
`Southern District of Indiana in case no.06—CV—l642,
`Southern District of Indiana in case no.06-CV-1642,
`Judge Richard L. Young.
`Judge Richard L. Young.
`Alcon Research, Ltd. v. Apotex Inc., 2012 U.S. App.
`Alcon Research, Ltd. v. Apotex Inc., 2012 U.S. App.
`LEXIS 1521 (Fed. Cir., Jan. 25, 2012)
`LEXIS 1521 (Fed. Cir., Jan. 25, 2012)
`
`DISPOSITION:
`DISPOSITION:
`AFFIRMED-IN-PART.
`AFFIRMED-IN-PART.
`
`REVERSED-IN-PART,
`REVERSED-IN-PART,
`
`COUNSEL: KANNON KUMAR SHAMUGAM,
`COUNSEL: KANNON KUMAR SHAMUGAM,
`Williams & Connolly, LLP, of Washington, DC, argued
`Williams & Connolly, LLP, of Washington, DC, argued
`for plaintiffs-appellees. With him on the brief were
`for plaintiffs—appellees. With him on the brief were
`ADAM L. PERLMAN, THOMAS H. L. SELBY and
`ADAM L. PERLMAN, THOMAS H. L. SELBY and
`SHELLEY J. WEBB.
`SHELLEY J. WEBB.
`
`ROBERT B. BREISBLATT, Katten Muchin Rosenman,
`ROBERT B. BREISBLATT, Katten Muchin Rosenman,
`LLP,
`of
`Chicago,
`Illinois,
`argued
`for
`LLP,
`of
`Chicago,
`Illinois,
`argued
`for
`defendants-appellants. With him on the brief were
`defendants—appellants. With him on the brief were
`CRAIG M. KUCHII, BRIAN J. SODIKOFF and
`CRAIG M. KUCHII, BRIAN J. SODIKOFF and
`
`THOMAS J. MAAS. Of counsel on the brief was
`THOMAS J. MAAS. Of counsel on the brief was
`SHASHANK UPADHYE, Apotex,
`Inc., of Toronto,
`SHASHANK UPADHYE, Apotex,
`Inc., of Toronto,
`Ontario, Canada.
`Ontario, Canada.
`
`JUDGES: Before PROST, MOORE, and O'MALLEY,
`JUDGES: Before PROST, MOORE, and O'MALLEY,
`Circuit Judges.
`Circuit Judges.
`
`OPINION BY: MOORE
`OPINION BY: MOORE
`
`OPINION
`OPINION
`
`[***1738] [*1363] MOORE, Circuit Judge.
`[***1738] [*1363] MOORE, Circuitludge.
`
`Apotex Inc. and Apotex Corp. (collectively, Apotex)
`Apotex Inc. and Apotex Corp. (collectively, Apotex)
`[***1739]
`submitted
`an Abbreviated New Drug
`submitted
`an Abbreviated New Drug
`[***1739]
`Application
`(ANDA)
`to
`the
`Food
`and Drug
`Application
`(ANDA)
`to
`the
`Food
`and Drug
`Administration seeking approval
`to market a generic
`Administration seeking approval
`to market a generic
`version of the anti-allergy eye drop Patanol®. Alcon
`version of the anti—allergy eye drop Patanol®. Alcon
`Research, Ltd. et al. (collectively, Alcon), who market
`Research, Ltd. et al. (collectively, Alcon), who market
`Patanol®, sued Apotex for patent infringement under 35
`Patanol®, sued Apotex for patent infringement under 35
`U.S.C. § 271(e)(2)(A). Alcon asserted claims 1-8 of U.S.
`U.S.C. § 27I(e)(2)(A). Alcon asserted claims 1-8 of U.S.
`Patent No. 5,641,805 ('805 patent), which is listed in the
`Patent No. 5,641,805 ( ’805 patent), which is listed in the
`[**2] Therapeutic
`Approved Drug Products with
`Approved Drug Products with
`[**2] Therapeutic
`Equivalence Evaluations
`(Orange Book)
`entry for
`Equivalence Evaluations
`(Orange Book)
`entry for
`Patanol®. For the reasons set forth below, we reverse the
`Patanol®. For the reasons set forth below, we reverse the
`district court's holding that claims 1-3 and 5-7 would not
`district court's holding that claims 1-3 and 5-7 would not
`have been obvious over the prior art but affirm the court's
`have been obvious over the prior art but afiirm the court's
`holding that claims 4 and 8 are not invalid.
`holding that claims 4 and 8 are not invalid.
`
`000001
`
`ARGENTUM PHARM. 1030
`
`ARGENTUM PHARM. 1030
`
`000001
`
`

`
`687 F.3d 1362, *1363; 2012 U.S. App. LEXIS 16503, **2;
`687 F.3d 1362, *1363; 2012 U.S. App. LEXIS 16503, **2;
`103 U.S.P.Q.2D (BNA) 1737, ***1739
`103 U.S.P.Q.2D (BNA) 1737, ***1739
`
`Page 2
`Page 2
`
`BACKGROUND
`BACKGROUND
`
`An allergic reaction is the body's mechanism for
`An allergic reaction is the body's mechanism for
`expelling antigens,
`such as pollen or pet dander.
`expelling antigens,
`such as pollen or pet dander.
`Exposure to an antigen causes the body to produce
`Exposure to an antigen causes the body to produce
`antibodies. These antibodies bind to the surface of mast
`antibodies. These antibodies bind to the surface of mast
`cells, which are specialized cells that exist in many places
`cells, which are specialized cells that exist in many places
`in the body and are the primary cells involved in allergic
`in the body and are the primary cells involved in allergic
`reactions. This binding sensitizes the mast cells to that
`reactions. This binding sensitizes the mast cells to that
`antigen. If the mast cells are subsequently exposed to the
`antigen. If the mast cells are subsequently exposed to the
`same antigen again, the antigen binds to the antibodies on
`same antigen again, the antigen binds to the antibodies on
`the surface of the mast cell. This causes the mast cells to
`the surface of the mast cell. This causes the mast cells to
`release chemicals called mediators, such as histamine and
`release chemicals called mediators, such as histamine and
`heparin. These mediators bind to receptors in surrounding
`heparin. These mediators bind to receptors in surrounding
`tissues, triggering the reactions commonly identified as
`tissues, triggering the reactions commonly identified as
`allergic symptoms, such as itching and redness. In the
`allergic symptoms, such as itching and redness. In the
`human eye, mast cells are located in the conjunctiva,
`human eye, mast cells are located in the conjunctiva,
`which is the membrane that covers the inner surface of
`which is the membrane that covers the inner surface of
`the eyelid [**3] and the white part of the eyeball.
`the eyelid [**3] and the white part of the eyeball.
`
`Anti-allergy drugs can treat allergic symptoms by
`Anti—allergy drugs can treat allergic symptoms by
`interfering at one of several points in this process.
`interfering at one of several points in this process.
`Antihistamines, for example, prevent the histamine that is
`Antihistamines, for example, prevent the histamine that is
`released from mast cells from binding to receptors in
`released from mast cells from binding to receptors in
`surrounding tissues and also displace the histamine that is
`surrounding tissues and also displace the histamine that is
`already bound to receptors. By contrast, drugs known as
`already bound to receptors. By contrast, drugs known as
`mast cell stabilizers prevent mast cells from releasing
`mast cell stabilizers prevent mast cells from releasing
`mediators, and thus counteract the effects of histamine
`mediators, and thus counteract the effects of histamine
`and other mediators that cause allergic symptoms.
`and other mediators that cause allergic symptoms.
`
`The '805 patent is directed to a method for treating
`The ’805 patent is directed to a method for treating
`allergic eye disease in humans comprising stabilizing
`allergic eye disease in humans comprising stabilizing
`conjunctival mast cells by topically administering an
`conjunctival mast cells by topically administering an
`1 composition.
`olopatadine [*1364]
`'805 patent col.1
`olopatadine [*1364]
`1 composition.
`’805 patent col.1
`ll.7-15, col.2 l.64 - col.3 l.3. The specification explains
`11.7-15, col.2 1.64 - col.3 1.3. The specification explains
`that the discovery that olopatadine can treat human eye
`that the discovery that olopatadine can treat human eye
`allergies through this mechanism of action -- stabilizing
`allergies through this mechanism of action -- stabilizing
`mast cells in the human eye -- is the novel aspect of the
`mast cells in the human eye —— is the novel aspect of the
`'805 patent. See, e.g., id. col.2 ll.56-61 ("What is needed
`’805 patent. See, e.g., id. col.2 ll.56—61 ("What is needed
`are topically administrable drug compounds which have
`are topically administrable drug compounds which have
`demonstrated stabilizing activity on mast cells obtained
`demonstrated stabilizing activity on mast cells obtained
`from human conjunctiva,
`the target cells for treating
`from human conjunctiva,
`the target cells for treating
`allergic eye [**4] diseases."); see also id. col.3 ll.18-23
`allergic eye [**4] diseases."); see also id. col.3 ll.18—23
`("[Olopatadine] has human conjunctival mast
`cell
`("[O1opatadine]
`has human conjunctival mast
`cell
`stabilizing activity, and may be applied as infrequently as
`stabilizing activity, and may be applied as infrequently as
`once or twice a day in some cases.").
`once or twice a day in some cases.").
`
`1 The method claimed in the '805 patent uses the
`1 The method claimed in the ’805 patent uses the
`compound
`compound
`11-(3-dimethylaminopropylidene)-6,11-dih
`1 1—(3—dimethylaminopropylidene)—6,1 1—dih
`ydrodibenz(b,e) oxepin-2-acetic
`acid or
`ydrodibenz(b,e)
`oxepin—2—acetic
`acid or
`
`a
`a
`
`thereof.
`salt
`acceptable
`pharmaceutically
`thereof.
`salt
`acceptable
`pharmaceutically
`two geometric
`Although this compound has
`two geometric
`Although this compound has
`isomers (a cis and a trans form), we refer to these
`isomers (a cis and a trans form), we refer to these
`compounds throughout
`this opinion simply as
`compounds throughout
`this opinion simply as
`olopatadine (the cis form).
`olopatadine (the cis form).
`
`The specification states that at the time of invention,
`The specification states that at the time of invention,
`it was already known in the art that olopatadine was an
`it was already known in the art that olopatadine was an
`effective antihistamine and that
`some chemicals
`in
`effective antihistamine and that some chemicals in
`olopatadine's genus may have mast cell stabilizing
`olopatadine's genus may have mast cell
`stabilizing
`activity. Id. col.1 l.16 - col.2 l.61. Indeed, both the
`activity.
`Id. col.1 1.16 — col.2 1.61. Indeed, both the
`olopatadine compound itself and a method of treating
`olopatadine compound itself and a method of treating
`allergies using the class of chemicals that encompasses
`allergies using the class of chemicals that encompasses
`olopatadine were both already patented. See U.S. Patent
`olopatadine were both already patented. See U.S. Patent
`No. 5,116,863; U.S. Patent No. 4,923,892. The '805
`No. 5,1 I 6,863; U.S. Patent No. 4,923,892. The ’805
`patent specification states, however,
`that
`it was not
`patent specification states, however,
`that
`it was not
`known whether olopatadine would stabilize mast cells in
`known whether olopatadine would stabilize mast cells in
`human eyes. Id. col.1 ll.43-58. The specification explains
`human eyes. Id. col.1 ll.43—58. The specification explains
`[**5] because mast cells in different
`that
`this was
`that
`this was
`[**5] because mast cells in different
`species, and in different tissues within the same species,
`species, and in different tissues within the same species,
`exhibit different biological responses -- a concept called
`exhibit different biological responses —— a concept called
`mast cell heterogeneity. Id. col.1 ll.43-58. As a result, a
`mast cell heterogeneity. Id. col.1 11.43-58. As a result, a
`compound's activity in a rodent's conjunctival mast cells
`compound's activity in a rodent's conjunctival mast cells
`or in mast cells located elsewhere in the human body
`or in mast cells located elsewhere in the human body
`cannot predict its ability to stabilize mast cells in the
`carmot predict its ability to stabilize mast cells in the
`human eye. Id. col.1 l.43 - col.2 l.19. The '805 patent's
`human eye. Id. col.1 1.43 — col.2 1.19. The ’805 patent's
`inventors conducted in vitro testing showing that
`inventors
`conducted in vitro testing showing that
`olopatadine stabilizes conjunctival mast cells in humans.
`olopatadine stabilizes conjunctival mast cells in humans.
`'805 patent col.3 ll.18-23, col.3 l.43 - col.5 l.55.
`’805 patent col.3 ll.18—23, col.3 1.43 - col.5 1.55.
`
`The '805 patent claims are limited to a method of
`The ’805 patent claims are limited to a method of
`treating human eye allergies that [***1740] comprises
`treating human eye allergies that
`[***1740] comprises
`stabilizing conjunctival mast cells. Claim 1 reads:
`stabilizing conjunctival mast cells. Claim 1 reads:
`
`A method for treating allergic eye
`A method for treating allergic eye
`diseases in humans comprising stabilizing
`diseases in humans comprising stabilizing
`by
`topically
`conjunctival mast
`cells
`conjunctival mast
`cells
`by
`topically
`administering to the eye a composition
`administering to the eye a composition
`comprising a
`therapeutically
`effective
`comprising
`a
`therapeutically eflective
`amount
`of
`of
`amount
`11-(3-dimethylaminopropylidene)-6,11-dih
`1 1—(3—dimethyla1ninopropylidene)—6,1 1—dih
`ydrodibenz(b,e) oxepin-2-acetic acid or a
`ydrodibenz(b,e) oxepin—2—acetic acid or a
`pharmaceutically acceptable salt thereof.
`pharmaceutically acceptable salt thereof.
`
`'805 patent cl.1 (emphases added). The parties do not
`’805 patent c1.1 (emphases added). The parties do not
`dispute the district court's construction of "stabilizing
`dispute the district court's construction of "stabilizing
`conjunctival mast cells" [**6] as "preventing or reducing
`conjunctival mast cells" [**6] as "preventing or reducing
`release of mediators including histamine from mast cells
`release of mediators including histamine from mast cells
`in the conjunctiva to an extent clinically relevant in the
`in the conjunctiva to an extent clinically relevant in the
`treatment of allergic eye disease." J.A. 176. Although
`treatment of allergic eye disease." J.A. 176. Although
`
`000002
`
`000002
`
`

`
`687 F.3d 1362, *1364; 2012 U.S. App. LEXIS 16503, **6;
`687 F.3d 1362, *1364; 2012 U.S. App. LEXIS 16503, **6;
`103 U.S.P.Q.2D (BNA) 1737, ***1740
`103 U.S.P.Q.2D (BNA) 1737, ***1740
`
`Page 3
`Page 3
`
`independent claim 1 does not specify the "therapeutically
`independent claim 1 does not specify the "therapeutically
`effective amount" of olopatadine required to stabilize
`effective amount" of olopatadine required to stabilize
`conjunctival mast cells, dependent claims limit
`the
`conjunctival mast cells, dependent claims
`limit
`the
`method of claim 1 to specific concentration ranges.
`method of claim 1
`to specific concentration ranges.
`Claims 2 and 6, for example, are limited to using a
`Claims 2 and 6, for example, are limited to using a
`composition that contains from about 0.0001% w/v to
`composition that contains from about 0.0001% w/v to
`about 5% w/v of olopatadine. Claims 4 and 8 are limited
`about 5% w/v of olopatadine. Claims 4 and 8 are limited
`to a concentration of 0.1% w/v of olopatadine.
`to a concentration of 0.1% w/v of olopatadine.
`
`Alcon's Patanol® product, an anti-allergy eye drop
`Alcon's Patanol® product, an anti—allergy eye drop
`with a 0.1% w/v concentration of olopatadine,
`is a
`with a 0.1% w/v concentration of olopatadine,
`is a
`commercial embodiment of the '805 patent. Apotex filed
`commercial embodiment of the ’805 patent. Apotex filed
`an [*1365] ANDA seeking permission to sell a generic
`an [*1365] ANDA seeking permission to sell a generic
`version of Patanol® and included a Paragraph IV
`version of Patanol® and included a Paragraph IV
`certification
`that
`the
`patent was
`invalid,
`'805
`certification
`that
`the
`’805
`patent was
`invalid,
`unenforceable, and/or would not be infringed by Apotex's
`unenforceable, and/or would not be infringed by Apotex's
`generic
`product. Alcon
`sued Apotex
`for
`patent
`generic
`product. Alcon
`sued Apotex
`for
`patent
`infringement, asserting claims 1-8. In a bench trial, the
`infringement, asserting claims 1-8. In a bench trial, the
`district court held that the '805 patent was enforceable
`district court held that the ’805 patent was enforceable
`and not
`invalid, and that Apotex's generic product
`and not
`invalid, and that Apotex's generic product
`infringed the [**7] asserted claims. Alcon Research, Ltd.
`infringed the [**7] asserted claims. Alcon Research, Ltd.
`v. Apotex Inc., 790 F. Supp. 2d 868, 944-45 (S.D. Ind.
`v. Apotex Inc., 790 F. Supp. 2d 868, 944-45 (S.D. Ind.
`2011).
`2011).
`
`On the issue of validity, the district court held that
`On the issue of validity, the district court held that
`Apotex failed to establish that the claims would have
`Apotex failed to establish that the claims would have
`been obvious by clear and convincing evidence. The
`been obvious by clear and convincing evidence. The
`court recognized that olopatadine was known to be an
`court recognized that olopatadine was known to be an
`effective antihistamine, but found that at
`the time of
`effective antihistamine, but found that at the time of
`invention a skilled artisan "understood that there were
`invention a skilled artisan "understood that there were
`significant barriers
`to adapting a known systemic
`significant barriers
`to adapting a known systemic
`antihistamine for topical use in the eye." Id. at 877. The
`antihistamine for topical use in the eye." Id. at 877. The
`court also found that
`the prior art as a whole, and
`court also found that
`the prior art as a whole, and
`specifically an article by Kamei et al., taught away from
`specifically an article by Kamei et al., taught away from
`using olopatadine as a mast cell stabilizer. Kamei tested
`using olopatadine as a mast cell stabilizer. Kamei tested
`an ophthalmic formulation of olopatadine in guinea pig
`an ophthahnic formulation of olopatadine in guinea pig
`eyes at concentrations that overlap with those recited in
`eyes at concentrations that overlap with those recited in
`most of the '805 patent claims. Kamei discloses that,
`most of the ’805 patent claims. Kamei discloses that,
`although olopatadine is a good antihistamine, it is not an
`although olopatadine is a good antihistamine, it is not an
`effective mast cell stabilizer. J.A. 10162-63. The court
`effective mast cell stabilizer. J.A. 10162-63. The court
`further
`found
`that Ka-mei's
`disclosure
`of
`using
`further
`found that Ka—mei's
`disclosure of using
`olopatadine eye drops in guinea pigs would not give a
`olopatadine eye drops in guinea pigs would not give a
`skilled artisan an expectation of success because it does
`skilled artisan an expectation of success because it does
`not show whether olopatadine is safe to use in the human
`not show whether olopatadine is safe to use in the human
`[**8] eye. The district court rejected Apotex's argument
`[**8] eye. The district court rejected Apotex's argument
`that the prior art need not teach mast cell stabilization
`that the prior art need not teach mast cell stabilization
`because this mechanism of action is an inherent property
`because this mechanism of action is an inherent property
`of olopatadine. In reaching this conclusion, the court
`of olopatadine. In reaching this conclusion,
`the court
`relied largely on testimony by Alcon's expert, Dr.
`relied largely on testimony by Alcon's expert, Dr.
`Kaliner, that not every concentration of olopatadine will
`Kaliner, that not every concentration of olopatadine will
`
`stabilize human conjunctival mast cells to a "clinically
`stabilize human conjunctival mast cells to a "clinically
`relevant" extent, as
`required by the court's claim
`relevant"
`extent,
`as
`required by the court's claim
`construction.
`construction.
`
`The district court also held that objective evidence
`The district court also held that objective evidence
`supported its holding of nonobviousness. For example,
`supported its holding of nonobviousness. For example,
`the court found that Patanol® showed unexpected results
`the court found that Patanol® showed unexpected results
`because a person of ordinary skill would not have
`because a person of ordinary skill would not have
`expected it to be an effective mast cell stabilizer in the
`expected it to be an effective mast cell stabilizer in the
`human eye. Alcon v. Apotex, 790 F. Supp. 2d at 905. The
`human eye. Alcon v. Apotex, 790 F. Supp. 2d at 905. The
`court concluded that Patanol® satisfied a long-felt but
`court concluded that Patanol® satisfied a long—felt but
`unmet need for a human conjunctival mast cell stabilizer.
`unmet need for a human conjunctival mast cell stabilizer.
`The court further found that Patanol® has been "an
`The court further found that Patanol® has been "an
`outstanding commercial success," achieving nearly a 70%
`outstanding commercial success," achieving nearly a 70%
`market share within two years of its launch. Id. at 904.
`market share within two years of its launch. Id. at 904.
`
`Apotex now appeals from the district court's final
`Apotex now appeals from the district court's final
`judgment
`that
`the '805 patent would not have been
`judgment
`that
`the ’805 patent would not have been
`obvious over the prior art and from the grant [**9] of a
`obvious over the prior art and from the grant
`[**9] of a
`permanent
`injunction barring Apotex from selling its
`permanent
`injunction barring Apotex from selling its
`generic product. We have jurisdiction under 28 U.S.C. §
`generic product. We have jurisdiction under 28 U.S. C. §
`1295(a)(1).
`1295(a)(1).
`
`DISCUSSION
`DISCUSSION
`
`A patent is invalid for obviousness "if the differences
`A patent is invalid for obviousness "if the differences
`between the subject matter sought to be patented and the
`between the subject matter sought to be patented and the
`prior art are such that the subject matter as a whole would
`prior art are such that the subject matter as a whole would
`have been obvious at the time the invention was made to
`have been obvious at the time the invention was made to
`a person having ordinary skill in the art to which said
`a person having ordinary skill in the art to which said
`subject matter
`pertains."
`103(a).
`35 U.S.C.
`§
`subject matter
`pertains."
`35 U.S.C.
`§
`103(a).
`"Obviousness is a question of law, which we review de
`"Obviousness is a question of law, which we review de
`novo, with underlying factual questions, which we review
`novo, with underlying factual questions, which we review
`[***1741]
`for clear
`error following a bench trial."
`for clear
`[***1741]
`error following a bench trial."
`Honeywell Int'l, Inc. v. United States, 609 F.3d 1292,
`Honeywell Int’l, Inc. v. United States, 609 F.3d 1292,
`1297 (Fed. Cir. 2010). These underlying factual inquires
`1297 (Fed. Cir. 2010). These underlying factual inquires
`are: (1) the scope and content of the prior art; (2) the
`are: (1) the scope and content of the prior art; (2) the
`differences between the prior art and the claims [*1366]
`differences between the prior art and the claims [*1366]
`at issue; (3) the level of ordinary skill in the field of the
`at issue; (3) the level of ordinary skill in the field of the
`invention; and (4) objective considerations such as
`invention; and (4) objective considerations
`such as
`commercial success, long felt need, and the failure of
`commercial success,
`long felt need, and the failure of
`others. KSR Int'l Co., v. Teleflex, Inc., 550 U.S. 398, 406,
`others. KSR Int’l Co., v. Teleflex, Inc., 550 U.S. 398, 406,
`127 S. Ct. 1727, 167 L. Ed. 2d 705 (2007) (citing
`127 S. Ct. 1727, 167 L. Ed. 2d 705 (2007)
`(citing
`Graham v. John Deere Co. of Kan. City, 383 U.S. 1,
`Graham v. John Deere Co. of Kan. City, 383 U.S. 1,
`17-18, 86 S. Ct. 684, 15 L. Ed. 2d 545 (1966)). Patent
`17-18, 86 S. Ct. 684, 15 L. Ed. 2d 545 (1966)). Patent
`invalidity must be established by clear and convincing
`invalidity must be established by clear and convincing
`[**10] evidence. Microsoft Corp. v. i4i Ltd., 131 S. Ct.
`[**10] evidence. Microsoft Corp. v.
`i4i Ltd., 131 S. Ct.
`2238, 2242, 180 L. Ed. 2d 131 (2011).
`2238, 2242, 180 L. Ed. 2d 131 (2011).
`
`I. Claims 1-3 and 5-7
`I. Claims 1-3 and 5-7
`
`000003
`
`000003
`
`

`
`687 F.3d 1362, *1366; 2012 U.S. App. LEXIS 16503, **10;
`687 F.3d 1362, *1366; 2012 U.S. App. LEXIS 16503, **1o;
`103 U.S.P.Q.2D (BNA) 1737, ***1741
`103 U.S.P.Q.2D (BNA) 1737, ***1741
`
`Page 4
`Page 4
`
`Apotex argues that the district court erred by finding
`Apotex argues that the district court erred by finding
`that the '805 patent claims would not have been obvious
`that the ’805 patent claims would not have been obvious
`over the prior art. Apotex asserts that claims 1-3 and 5-7
`over the prior art. Apotex asserts that claims 1-3 and 5-7
`would have been obvious over Kamei, which discloses
`would have been obvious over Kamei, which discloses
`eye drops with olopatadine concentrations that overlap
`eye drops with olopatadine concentrations that overlap
`with the claimed concentration ranges. Apotex argues
`with the claimed concentration ranges. Apotex argues
`that even though Kamei tested olopatadine formulations
`that even though Kamei tested olopatadine formulations
`only in guinea pig eyes, a person of ordinary skill in the
`only in guinea pig eyes, a person of ordinary skill in the
`art could use routine methods to adapt these formulations
`art could use routine methods to adapt these formulations
`for human use with a reasonable expectation of success.
`for human use with a reasonable expectation of success.
`Apotex also argues that
`the district court erred by
`Apotex also argues that
`the district court erred by
`focusing on Kamei's lack of disclosure that olopatadine is
`focusing on Ka1nei's lack of disclosure that olopatadine is
`safe for human use because the '805 claims do not recite a
`safe for human use because the '805 claims do not recite a
`"safety" limitation.
`"safety" limitation.
`
`the district court erred by
`Apotex contends that
`the district court erred by
`Apotex contends that
`requiring that the prior art provide a motivation to use
`requiring that the prior art provide a motivation to use
`olopatadine specifically as a mast cell stabilizer. Apotex
`olopatadine specifically as a mast cell stabilizer. Apotex
`argues that the prior art's disclosure that olopatadine is an
`argues that the prior art's disclosure that olopatadine is an
`effective antihistamine that can be formulated for
`effective antihistamine that can be formulated for
`ophthalmic use provides sufficient motivation to develop
`ophthalmic use provides sufficient motivation to develop
`an olopatadine eye drop for [**11] humans. Apotex also
`an olopatadine eye drop for [**11] humans. Apotex also
`argues that claiming olopatadine's mechanism of action
`argues that claiming olopatadine's mechanism of action
`(stabilizing conjunctival mast
`cells)
`cannot
`impart
`(stabilizing conjunctival mast
`cells)
`carmot
`impart
`patentability to the '805 patent claims because it is an
`patentability to the ’805 patent claims because it is an
`inherent property of olopatadine. Apotex also asserts that
`inherent property of olopatadine. Apotex also asserts that
`even if this limitation restricts the claims to certain
`even if this limitation restricts the claims to certain
`concentrations of olopatadine,
`the claims nonetheless
`concentrations of olopatadine,
`the claims nonetheless
`would have been obvious because the prior art teaches
`would have been obvious because the prior art teaches
`using olopatadine at those concentrations.
`using olopatadine at those concentrations.
`
`Apotex also argues that the district court erred by
`Apotex also argues that the district court erred by
`finding that objective evidence supported its holding of
`finding that objective evidence supported its holding of
`nonobviousness. Specifically, Apotex contends
`that
`nonobviousness. Specifically, Apotex contends
`that
`olopatadine's superior clinical efficacy is due at least in
`olopatadine's superior clinical efficacy is due at least in
`part to its antihistaminic activity, which is not a novel
`part to its antihistaminic activity, which is not a novel
`aspect of the '805 patent. Apotex thus argues that the
`aspect of the ’805 patent. Apotex thus argues that the
`district court's findings regarding commercial success,
`district court's findings regarding commercial success,
`industry praise, and unexpected results lack sufficient
`industry praise, and unexpected results lack sufficient
`nexus to the '805 patent claims.
`nexus to the ’805 patent claims.
`
`Alcon contends that the court correctly found that a
`Alcon contends that the court correctly found that a
`skilled artisan would not be motivated to formulate an
`skilled artisan would not be motivated to formulate an
`olopatadine eye drop solely based on its antihistaminic
`olopatadine eye drop solely based on its antihistaminic
`activity because the prior art does not supply a reason to
`activity because the prior art does not supply a reason to
`focus on olopatadine instead of many other promising
`focus on olopatadine instead of many other promising
`[**12] antihistamines. Alcon also argues that the court
`[**12] antihistamines. Alcon also argues that the court
`correctly found that
`there would not have been a
`correctly found that
`there would not have been a
`reasonable expectation of success in formulating an
`reasonable expectation of success in formulating an
`olopatadine eye drop because, at the time of invention,
`olopatadine eye drop because, at the time of invention,
`
`there were barriers to adapting an oral antihistamine for
`there were barriers to adapting an oral antihistamine for
`ophthalmic use.
`ophthahnic use.
`
`Alcon does not dispute that Kamei teaches using
`Alcon does not dispute that Kamei
`teaches using
`olopatadine eye drops at concentrations that overlap with
`olopatadine eye drops at concentrations that overlap with
`those in claims 1-3 and 5-7 of the '805 patent. Instead,
`those in claims 1-3 and 5-7 of the ’805 patent. Instead,
`Alcon argues that Kamei does not teach that olopatadine
`Alcon argues that Kamei does not teach that olopatadine
`would be a mast cell stabilizer at those concentrations or
`would be a mast cell stabilizer at those concentrations or
`that it would be safe for use in the human eye. Alcon
`that it would be safe for use in the human eye. Alcon
`argues that the district court correctly found that the prior
`argues that the district court correctly found that the prior
`art as a whole teaches away from using olopatadine as a
`art as a whole teaches away from using olopatadine as a
`mast cell stabilizer. Alcon also asserts [*1367] that the
`mast cell stabilizer. Alcon also asserts [*1367]
`that the
`district court correctly found that mast cell stabilization is
`district court correctly found that mast cell stabilization is
`not an inherent property of olopatadine because only
`not an inherent property of olopatadine because only
`some concentrations stabilize mast cells to a clinically
`some concentrations stabilize mast cells to a clinically
`relevant extent, as
`required by the court's claim
`relevant
`extent,
`as
`required by the
`court's
`claim
`construction. Finally, Alcon argues that the district court
`construction. Finally, Alcon argues that the district court
`correctly found that objective evidence supports a finding
`correctly found that objective evidence supports a finding
`of nonobviousness.
`of nonobviousness.
`
`As an initial matter, we believe the district court
`As an initial matter, we believe the district court
`erred in [**13] its comparison of the '805 patent claims
`erred in [**13] its comparison of the ’805 patent claims
`and the disclosure of the prior art. Claim 1 recites a
`and the disclosure of the prior art. Claim 1 recites a
`method of treating allergic eye disease comprising using
`method of treating allergic eye disease comprising using
`a "therapeutically effective amount" of olopatadine to
`a "therapeutically effective amount" of olopatadine to
`stabilize conjunctival mast cells. The court construed the
`stabilize conjunctival mast cells. The court construed the
`term "stabilizing conjunctival mast cells" to limit the
`term "stabilizing conjunctival mast cells" to limit the
`claims only to concentrations of olopatadine that stabilize
`claims only to concentrations of olopatadine that stabilize
`conjunctival mast cells "to an extent clinically relevant in
`conjunctival mast cells "to an extent clinically relevant in
`the treatment of allergic eye disease." J.A. 176. This
`the treatment of allergic eye disease." J.A. 176. This
`construction is not appealed