Page 1
`
`ALCON RESEARCH, LTD. (FORMERLY KNOWN AS ALCON
`MANUFACTURING, LTD.), ALCON LABORATORIES, INC., AND KYOWA
`HAKKO KIRIN CO. LTD., Plaintiffs-Appellees, v. APOTEX INC. AND APOTEX
`CORP., Defendants-Appellants.
`
`2011-1455
`
`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
`
`August 8, 2012, Decided
`
`SUBSEQUENT HISTORY: US Supreme Court
`certiorari denied by Alcon Research, Ltd. v. Apotex, Inc.,
`133 S. Ct. 1736, 185 L. Ed. 2d 787, 2013 U.S. LEXIS
`2613 (U.S., 2013)
`Related proceeding at Alcon Research, Ltd. v. Apotex,
`Inc., 2013 U.S. Dist. LEXIS 71432 (S.D. Ind., May 21,
`2013)
`
`PRIOR HISTORY: [**1]
`Appeal from the United States District Court for the
`Southern District of Indiana in case no.06-CV-1642,
`Judge Richard L. Young.
`Alcon Research, Ltd. v. Apotex Inc., 2012 U.S. App.
`LEXIS 1521 (Fed. Cir., Jan. 25, 2012)
`
`DISPOSITION:
`AFFIRMED-IN-PART.
`
`REVERSED-IN-PART,
`
`COUNSEL: KANNON KUMAR SHAMUGAM,
`Williams & Connolly, LLP, of Washington, DC, argued
`for plaintiffs-appellees. With him on the brief were
`ADAM L. PERLMAN, THOMAS H. L. SELBY and
`SHELLEY J. WEBB.
`
`ROBERT B. BREISBLATT, Katten Muchin Rosenman,
`LLP,
`of
`Chicago,
`Illinois,
`argued
`for
`defendants-appellants. With him on the brief were
`CRAIG M. KUCHII, BRIAN J. SODIKOFF and
`
`THOMAS J. MAAS. Of counsel on the brief was
`SHASHANK UPADHYE, Apotex,
`Inc., of Toronto,
`Ontario, Canada.
`
`JUDGES: Before PROST, MOORE, and O'MALLEY,
`Circuit Judges.
`
`OPINION BY: MOORE
`
`OPINION
`
`[***1738] [*1363] MOORE, Circuit Judge.
`
`Apotex Inc. and Apotex Corp. (collectively, Apotex)
`[***1739]
`submitted
`an Abbreviated New Drug
`Application
`(ANDA)
`to
`the
`Food
`and Drug
`Administration seeking approval
`to market a generic
`version of the anti-allergy eye drop Patanol®. Alcon
`Research, Ltd. et al. (collectively, Alcon), who market
`Patanol®, sued Apotex for patent infringement under 35
`U.S.C. § 271(e)(2)(A). Alcon asserted claims 1-8 of U.S.
`Patent No. 5,641,805 ('805 patent), which is listed in the
`[**2] Therapeutic
`Approved Drug Products with
`Equivalence Evaluations
`(Orange Book)
`entry for
`Patanol®. For the reasons set forth below, we reverse the
`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
`holding that claims 4 and 8 are not invalid.
`
`APOTEX EX1030
`
`Page 1
`
`

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

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

`
`687 F.3d 1362, *1366; 2012 U.S. App. LEXIS 16503, **10;
`103 U.S.P.Q.2D (BNA) 1737, ***1741
`
`Page 4
`
`Apotex argues that the district court erred by finding
`that the '805 patent claims would not have been obvious
`over the prior art. Apotex asserts that claims 1-3 and 5-7
`would have been obvious over Kamei, which discloses
`eye drops with olopatadine concentrations that overlap
`with the claimed concentration ranges. Apotex argues
`that even though Kamei tested olopatadine formulations
`only in guinea pig eyes, a person of ordinary skill in the
`art could use routine methods to adapt these formulations
`for human use with a reasonable expectation of success.
`Apotex also argues that
`the district court erred by
`focusing on Kamei's lack of disclosure that olopatadine is
`safe for human use because the '805 claims do not recite a
`"safety" limitation.
`
`the district court erred by
`Apotex contends that
`requiring that the prior art provide a motivation to use
`olopatadine specifically as a mast cell stabilizer. Apotex
`argues that the prior art's disclosure that olopatadine is an
`effective antihistamine that can be formulated for
`ophthalmic use provides sufficient motivation to develop
`an olopatadine eye drop for [**11] humans. Apotex also
`argues that claiming olopatadine's mechanism of action
`(stabilizing conjunctival mast
`cells)
`cannot
`impart
`patentability to the '805 patent claims because it is an
`inherent property of olopatadine. Apotex also asserts that
`even if this limitation restricts the claims to certain
`concentrations of olopatadine,
`the claims nonetheless
`would have been obvious because the prior art teaches
`using olopatadine at those concentrations.
`
`Apotex also argues that the district court erred by
`finding that objective evidence supported its holding of
`nonobviousness. Specifically, Apotex contends
`that
`olopatadine's superior clinical efficacy is due at least in
`part to its antihistaminic activity, which is not a novel
`aspect of the '805 patent. Apotex thus argues that the
`district court's findings regarding commercial success,
`industry praise, and unexpected results lack sufficient
`nexus to the '805 patent claims.
`
`Alcon contends that the court correctly found that a
`skilled artisan would not be motivated to formulate an
`olopatadine eye drop solely based on its antihistaminic
`activity because the prior art does not supply a reason to
`focus on olopatadine instead of many other promising
`[**12] antihistamines. Alcon also argues that the court
`correctly found that
`there would not have been a
`reasonable expectation of success in formulating an
`olopatadine eye drop because, at the time of invention,
`
`there were barriers to adapting an oral antihistamine for
`ophthalmic use.
`
`Alcon does not dispute that Kamei teaches using
`olopatadine eye drops at concentrations that overlap with
`those in claims 1-3 and 5-7 of the '805 patent. Instead,
`Alcon argues that Kamei does not teach that olopatadine
`would be a mast cell stabilizer at those concentrations or
`that it would be safe for use in the human eye. Alcon
`argues that the district court correctly found that the prior
`art as a whole teaches away from using olopatadine as a
`mast cell stabilizer. Alcon also asserts [*1367] that the
`district court correctly found that mast cell stabilization is
`not an inherent property of olopatadine because only
`some concentrations stabilize mast cells to a clinically
`relevant extent, as
`required by the court's claim
`construction. Finally, Alcon argues that the district court
`correctly found that objective evidence supports a finding
`of nonobviousness.
`
`As an initial matter, we believe the district court
`erred in [**13] its comparison of the '805 patent claims
`and the disclosure of the prior art. Claim 1 recites a
`method of treating allergic eye disease comprising using
`a "therapeutically effective amount" of olopatadine to
`stabilize conjunctival mast cells. The court construed the
`term "stabilizing conjunctival mast cells" to limit the
`claims only to concentrations of olopatadine that stabilize
`conjunctival mast cells "to an extent clinically relevant in
`the treatment of allergic eye disease." J.A. 176. This
`construction is not appealed. Because [***1742] it is not
`appealed, we do not decide whether this construction is
`correct.
`
`On appeal, however, we must determine what
`olopatadine concentrations constitute a "therapeutically
`effective amount." The dependent claims are a starting
`point for ascertaining the concentration of olopatadine
`covered by claim 1. Claim 2, for example, is directed to
`the method of claim 1 wherein "the amount of
`[olopatadine] is from about 0.0001 w/v. % to about 5%
`(w/v)." Claim 3 further narrows the range to "about 0.001
`to about 0.2% (w/v)." Claim 4 further narrows the range
`to "about 0.1% (w/v)." As far as the concentrations of
`olopatadine, claims 5-8 mirror the ranges disclosed in
`[**14] 1-4, respectively.
`
`It is axiomatic that a dependent claim cannot be
`broader than the claim from which it depends. See 35
`U.S.C. § 112 ¶4 ("[A] claim in dependent form shall
`contain a reference to a claim previously set forth and
`
`Page 4
`
`

`
`687 F.3d 1362, *1367; 2012 U.S. App. LEXIS 16503, **14;
`103 U.S.P.Q.2D (BNA) 1737, ***1742
`
`Page 5
`
`then specify a further limitation of the subject matter
`claimed."); see also Intamin Ltd. v. Magnetar Techs.,
`Corp., 483 F.3d 1328, 1335 (Fed. Cir. 2007) ("An
`independent claim impliedly embraces more subject
`matter than its narrower dependent claim."); AK Steel
`Corp. v. Sollac & Ugine, 344 F.3d 1234, 1242 (Fed. Cir.
`("Under
`the doctrine of claim differentiation,
`2003)
`dependent claims are presumed to be of narrower scope
`than the independent claims from which they depend.").
`Therefore if claim 2 covers the range from 0.0001%
`w/v-5% w/v, claim 1 must cover at least that range.
`Furthermore, because a dependent claim narrows the
`claim from which it depends, it must "incorporate . . . all
`the limitations of the claim to which it refers." 35 U.S.C.
`§ 112 ¶4. As a result, the concentrations recited in the
`'805 patent's dependent claims must necessarily meet
`claim 1's limitations of being therapeutically effective for
`treating allergic eye disease by stabilizing conjunctival
`[**15] mast cells. This is clear from the express claim
`language. It is also supported by the specification: "The
`concentration of Compound A is 0.0001 to 5 w/v %,
`preferably 0.001 to 0.2 w/v %, and most preferably about
`0.1 w/v % . . . ." '805 patent col.6 ll.43-46.
`
`Despite the clear language of the '805 patent claims,
`Alcon argues
`that
`some olopatadine concentrations
`covered by claims 1-3 and 5-7 do not stabilize human
`conjunctival mast cells to a clinically relevant extent and
`should therefore be excluded from the claims' scope. The
`district court found that "[n]ot every concentration of
`olopatadine applied to the human eye will stabilize the
`mast cells in the human eye." Alcon v. Apotex, 790 F.
`Supp. 2d at 909. The court cited testimony by Alcon's
`expert, Dr. Kaliner,
`that olopatadine at 0.001% w/v
`(which is covered by claims 1-3 and 5-7) would not
`[*1368] mast cells to a
`stabilize human conjunctival
`clinically relevant extent. Id. at 909, 935.
`
`Alcon's counsel argued that, "to the extent that the
`dependent claims cover a broader range than the range
`that would be operative to stabilize mast cells," the
`inoperative portion of the range "wouldn't be covered by
`the claim by virtue of the limitation [**16] in claim 1"
`that mast cell stabilization must occur to a clinically
`relevant
`extent. Argument
`at
`14:56-15:22, Alcon
`Research v. Apotex, No. 2011-1455,
`available
`at
`http://oralarguments.cafc.uscourts.gov/d
`thus
`efault.aspx?fl=20 11-1455.mp3. Alcon's counsel
`contended that the claims "would be operative, just at a
`narrower concentration" than the claimed range. Id. at
`
`15:24-15:27. This is not how patent law works. When
`you claim a concentration range of 0.0001-5% w/v (as
`claim 2), you can't simply disavow the invalid portion
`and keep the valid portion of the claim. If everything up
`to 0.001% w/v is admittedly not enabled, then the entire
`claim is invalid. Similarly, if prior art discloses a portion
`of the claimed range, the entire claim is invalid. Courts
`do not rewrite the claims to narrow them for the patentee
`to cover only the valid portion. Alcon cannot have it both
`ways. Because claim 2 sets forth a concentration range,
`that range at a minimum must be included in claim 1,
`whatever its limitations. When analyzing the validity of
`claim 1 or claim 2, by the express claim language, the
`clinically relevant
`therapeutic amount must
`include
`0.0001-5% w/v olopatadine. That is the claimed [**17]
`concentration range which should be compared to the
`disclosure of the prior art.
`
`The Kamei reference discloses treating eye allergies
`in guinea pigs using eye drops with olopatadine
`concentrations ranging from 0.0001% w/v to 0.01% w/v.
`J.A.
`10160-63. This
`range
`overlaps with
`the
`concentrations covered by claims 1-3 and 5-7. Claims 4
`and 8 are directed only to a 0.1% olopatadine
`formulation, and Kamei does not disclose a concentration
`[***1743] of olopatadine greater than 0.01%. Kamei
`expressly
`discloses
`eye
`drops with
`olopatadine
`concentrations covered by claims 1-3 and 5-7 and thus
`overlaps with the ranges disclosed in the '805 patent.
`
`The only remaining dispute is whether there was a
`motivation to adapt the formulation disclosed in Kamei,
`which was tested in guinea pigs, for use in treating
`allergic eye disease in humans. The district court found,
`as a factual matter, that animal tests, including guinea pig
`models, are predictive of a compound's antihistaminic
`activity and its topical ocular availability in humans.
`Alcon v. Apotex, 790 F. Supp. 2d at 881. Given this fact
`finding, the district court clearly erred when it concluded
`that a person of skill in the art would not have been
`motivated [**18] to use the olopatadine concentration
`disclosed in Kamei in human eyes. The district court's
`error stemmed from its refusal to look at any motivation
`beyond that articulated by the patent. We have repeatedly
`held that the motivation to modify a prior art reference to
`arrive at the claimed invention need not be the same
`motivation that the patentee had. See KSR, 550 U.S. at
`420 (stating that it is error to look "only to the problem
`the patentee was trying to solve"); see also In re Kahn,
`441 F.3d 977, 990 (Fed. Cir. 2006) ("[T]he skilled artisan
`
`Page 5
`
`

`
`687 F.3d 1362, *1368; 2012 U.S. App. LEXIS 16503, **18;
`103 U.S.P.Q.2D (BNA) 1737, ***1743
`
`Page 6
`
`need not be motivated to combine [the prior art] for the
`same reason contemplated by [the inventor]." (citing In re
`Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992) ("[T]he
`law does not require that the references be combined for
`the reasons contemplated by the inventor."))); Dystar
`Textilfarben GmbH v. C.H. Patrick Co.., 464 F.3d 1356,
`1361 (Fed. Cir. 2006) (stating that the motivation to
`modify the prior art to arrive at the claimed invention
`"may be found in any number of sources,
`including
`common [*1369] knowledge, the prior art as a whole, or
`the nature of the problem itself."). Here, the motivation to
`adapt Kamei's formulation for human use is that [**19]
`it is an effective antihistamine in guinea pigs and that
`animals models are (as the district court expressly found)
`predictive of antihistaminic efficacy in humans.
`
`The district court's fact finding that the prior art did
`teach that olopatadine would stabilize human
`not
`conjunctival mast cells, and indeed taught away from
`using olopatadine for
`this purpose,
`is not clearly
`erroneous. It is, however, not the only motivation to
`arrive at the claimed invention. A person of ordinary skill
`in the art at the time of invention would have been
`motivated to use olopatadine to treat human eye allergies
`as claimed for its established antihistaminic efficacy.
`Given that
`the patent defines, and expressly claims,
`olopatadine
`concentrations
`that
`are
`"therapeutically
`effective" to stabilize conjunctival mast cells, Kamei's
`disclosure of overlapping concentrations, even if for a
`different purpose, meets these claim limitations.
`
`Although Alcon argues that Kamei would not give a
`skilled artisan an expectation of success because it does
`not teach that olopatadine is safe for the human eye, we
`find this contention to be without merit. Id. While it is
`true that Kamei does not expressly disclose that
`olopatadine [**20] would be safe for use in human eyes,
`neither does the '805 patent. The patent is not based on
`testing in humans; instead it reports only in vitro tests of
`olopatadine in human conjunctival mast cells. '805 patent
`col.3 l.43 - col.4 l.24. We conclude that, just as a skilled
`artisan would be able to practice the invention claimed in
`the '805 patent despite its lack of explicit instruction that
`olopatadine is safe for human ophthalmic use, the artisan
`would have a reasonable expectation of success for
`adapting Kamei's formulation for the same use in a
`human eye.
`
`The parties dispute whether stabilizing conjunctival
`mast cells is an inherent property of olopatadine and
`
`inherency may be used in an obviousness
`whether
`analysis. We addressed a similar situation in In re Kubin,
`where we explained that, "[e]ven if no prior art of record
`explicitly
`discusses
`the
`[limitation],
`the
`[patent
`applicant's] application itself instructs that [the limitation]
`is not an additional requirement imposed by the claims on
`the [claimed invention], but rather a property necessarily
`present in the [claimed invention]." 561 F.3d 1351, 1357
`(Fed. Cir. 2009). The same is true here. The district
`court's construction [**21] of "stabilizing conjunctival
`mast cells" restricts the claims to certain olopatadine
`concentrations. As in In re Kubin, this claim language
`does not impose any additional requirement because the
`itself defines mast cell stabilization as a
`'805 patent
`property
`that
`is
`necessarily
`present
`at
`those
`concentrations.
`
`Kamei expressly discloses using olopatadine eye
`drops to treat eye allergies at concentrations [***1744]
`that overlap with those in claims 1-3 and 5-7 of the '805
`patent and thus meets the "stabilizing conjunctival mast
`cells" limitation. Moreover, Kamei would give a person
`of ordinary skill in the art an expectation of success for
`using olopatadine to treat human eye allergies. We
`therefore conclude that
`the district court erred in its
`determination that
`there was no prima facie case of
`obviousness based on Kamei.
`
`objective
`that
`argues
`appeal, Alcon
`On
`considerations support the district court's conclusion of
`nonobviousness. We weigh these objective considerations
`along with the other parts of the obviousness analysis to
`determine de novo whether the claims would have been
`obvious to one of skill in [*1370]
`the art. We see no
`clear error
`in the district court's fact
`findings, but
`[**22] balancing the objective evidence
`conclude after
`against
`the strong evidence of obviousness discussed
`above,
`that Apotex has established by clear and
`convincing evidence that claims 1-3 and 5-7 would have
`been obvious to one of ordinary skill in the art over
`Kamei, which discloses every limitation of these claims
`except
`that
`the formulation can be used to treat eye
`allergies in humans. We have considered all of Alcon's
`arguments regarding these claims and find them to be
`without merit.
`
`II. Claims 4 and 8
`
`While Kamei renders claims 1-3 and 5-7 obvious
`because it discloses olopatadine concentrations
`that
`overlap with the ranges in those claims, it does not teach
`
`Page 6
`
`

`
`687 F.3d 1362, *1370; 2012 U.S. App. LEXIS 16503, **22;
`103 U.S.P.Q.2D (BNA) 1737, ***1744
`
`Page 7
`
`the 0.1% w/v composition recited in claims 4 and 8 of the
`'805 patent. Apotex argues that even though Kamei does
`not disclose the claimed 0.1% w/v concentration, routine
`experimentation would have led a skilled artisan to try
`this formulation. Apotex contends that because Kamei's
`testing showed that antihistaminic efficacy increased as
`olopatadine concentration increased from 0.0001% w/v to
`0.01% w/v, it would be logical to try a 0.1% formulation.
`Apotex also argues that a skilled artisan would rely on
`U.S. Patent No. 4,923,892 (Lever) as guidance [**23]
`for formulating a 0.1% w/v eye drop. Lever claims a class
`of chemical compounds that includes olopatadine and a
`method of treating allergies in animals by using this class
`of compounds. See, e.g., '892 patent cl.1, 7. One example
`in Lever teaches an ophthalmic solution containing 0.1%
`w/v of a different active compound (i.e., not olopatadine).
`Id. col.17 ll.20-25, col.19 ll.5-13. Apotex argues that a
`skilled artisan would simply modify this 0.1% w/v
`formulation by substituting olopatadine for the other
`active compound at the same concentration.
`
`Alcon contends that neither Kamei nor Lever would
`have motivated a person of ordinary skill in the art to try
`a 0.1% w/v olopatadine formulation. Alcon cites the
`district court's finding that a skilled artisan would have
`expected olopatadine to be "biphasic," or to stabilize mast
`cells below a certain concentration but destabilize them
`above that concentration. Alcon argues that the court
`correctly determined that the potential to destabilize mast
`cells would have led a skilled artisan not to try higher
`concentrations of olopatadine than those disclosed in
`Kamei. Alcon also argues that the district court correctly
`found that a skilled artisan [**24] could not simply
`substitute olopatadine into the ophthalmic solution
`disclosed in Lever at the same concentration, and thus
`that Lever does not teach using olopatadine at 0.1% w/v.
`
`We have considered all of Apotex's arguments and
`conclude that the district court correctly held that claims
`4 and 8 of the '805 patent would not have been obvious.
`These claims are limited to using formulations with an
`olopatadine concentration of about 0.1% w/v. Kamei,
`however, only tested formulations with olopatadine
`concentrations up to 0.01% w/v and thus does not
`disclose this limitation. We cannot say the district court
`clearly erred by finding that Kamei does not teach or
`suggest using olopatadine at a concentration of 0.1% w/v.
`As the court noted, the concentrations tested in Kamei
`were substantially lower than 0.1%. The court relied on
`expert testimony that a person of ordinary skill in the art
`
`would not have a reasonable expectation of success for
`increasing the highest dosage used in Kamei by an order
`of magnitude. Alcon v. Apotex, 790 F. Supp. 2d at 894
`(citing J.A. 21759-60). We also agree with the court that
`a person of ordinary skill in the art would have been
`concerned that olopatadine might [**25] be biphasic at
`this increased concentration, and [*1371] thus would not
`have tried a formulation with ten times more olopatadine
`than the highest dosage used in Kamei. Id.
`
`Moreover, the court did not clearly err by finding
`that a skilled artisan would not arrive at a 0.1% w/v
`olopatadine eye drop by substituting olopatadine for the
`active compound [***1745] used in the ophthalmic
`formulation disclosed in Lever. As the district court
`explained, a person of ordinary skill in the art would have
`known that one could not simply substitute one active
`ingredient
`for
`another without
`adjusting
`the
`concentration. Id. at 900. The court thus correctly found
`that Lever does not teach an ophthalmic formulation with
`an olopatadine concentration of 0.1% w/v.
`
`Objective evidence further supports the district
`court's holding that claims 4 and 8 would not have been
`obvious. The district court's fact findings regarding the
`objective considerations are not clearly erroneous. The
`court
`found that Patanol® was
`"an outstanding
`commercial success," achieving nearly 70% market share
`within two years of its launch, accounting for nearly $2
`billion in sales within ten years,
`and garnering
`wide-spread praise within the industry. Id. at 904. [**26]
`The 0.1% w/v olopatadine concentration recited in claims
`4 and 8 is the same as is used in Patanol®. As a result,
`with respect to claims 4 and 8, Alcon's objective evidence
`demonstrates that "the commercial success was caused by
`the merits of the invention as distinct from the prior art."
`In re Kao, 639 F.3d 1057, 1069 (Fed. Cir. 2011).
`Because Alcon failed to prove by clear and convincing
`evidence that a 0.1% w/v olopatadine formulation would
`have been obvious over the prior art, we conclude the
`district court correctly held that claims 4 and 8 would not
`have been obvious.
`
`CONCLUSION
`
`In view of the foregoing, we reverse the district
`court's holding that claims 1-3 and 5-7 of the '