  United States Court of Appeals
      for the Federal Circuit
              __________________________

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
              __________________________

   Appeal from the United States District Court for the
Southern District of Indiana in case no.06-CV-1642,
Judge Richard L. Young.
             ___________________________

                Decided: August 8, 2012
             ___________________________

   BRUCE R. GENDERSON, Williams & Connolly, LLP, of
Washington, DC, argued for plaintiffs-appellees. With
him on the brief were ADAM L. PERLMAN, KANNON K.
SHANMUGAM, 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,
ALCON RESEARCH   v. APOTEX                                2


BRIAN J. SODIKOFF and THOMAS J. MAAS. Of counsel on
the brief was SHASHANK UPADHYE, Apotex, Inc., of To-
ronto, Ontario, Canada.
               __________________________

  Before PROST, MOORE, and O’MALLEY, Circuit Judges.
MOORE, Circuit Judge.
    Apotex Inc. and Apotex Corp. (collectively, Apotex)
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 infringe-
ment 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 Approved Drug Products with
Therapeutic 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.
                       BACKGROUND
    An allergic reaction is the body’s mechanism for expel-
ling 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 hepa-
rin. These mediators bind to receptors in surrounding
3                                 ALCON RESEARCH   v. APOTEX


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 and the white part of the eyeball.
    Anti-allergy drugs can treat allergic symptoms by in-
terfering at one of several points in this process. Antihis-
tamines, 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 al-
lergic eye disease in humans comprising stabilizing
conjunctival mast cells by topically administering an
olopatadine 1 composition. ’805 patent col.1 ll.7-15, col.2
l.64 - col.3 l.3. The specification explains that the discov-
ery 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
diseases.”); see also id. col.3 ll.18-23 (“[Olopatadine] has
human conjunctival mast cell stabilizing activity, and

    1   The method claimed in the ’805 patent uses the
compound            11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenz(b,e) oxepin-2-acetic acid or a pharmaceuti-
cally acceptable salt thereof. Although this compound has
two geometric isomers (a cis and a trans form), we refer to
these compounds throughout this opinion simply as
olopatadine (the cis form).
ALCON RESEARCH   v. APOTEX                                   4


may be applied as infrequently as once or twice a day in
some cases.”).
    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 olo-
patadine’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 olo-
patadine would stabilize mast cells in human eyes. Id.
col.1 ll.43-58. The specification explains that this was
because mast cells in different species, and in different
tissues within the same species, exhibit different biologi-
cal 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 test-
ing 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 comprises stabilizing
conjunctival mast cells. Claim 1 reads:
    A method for treating allergic eye diseases in hu-
    mans comprising stabilizing conjunctival mast
    cells by topically administering to the eye a com-
    position comprising a therapeutically effective
    amount of 11-(3-dimethylaminopropylidene)-6,11-
5                                ALCON RESEARCH   v. APOTEX


    dihydrodibenz(b,e) oxepin-2-acetic acid or a phar-
    maceutically acceptable salt thereof.
’805 patent cl.1 (emphases added). The parties do not
dispute the district court’s construction of “stabilizing
conjunctival mast cells” as “preventing or reducing release
of mediators including histamine from mast cells in the
conjunctiva to an extent clinically relevant in the treat-
ment of allergic eye disease.” J.A. 176. Although inde-
pendent 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 com-
position 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 com-
mercial embodiment of the ’805 patent. Apotex filed an
ANDA seeking permission to sell a generic version of
Patanol® and included a Paragraph IV certification that
the ’805 patent was invalid, 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 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
ALCON RESEARCH   v. APOTEX                                 6


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 formula-
tion 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 stabi-
lizer. 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 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 conclu-
sion, the court relied largely on testimony by Alcon’s
expert, Dr. Kaliner, that not every concentration of olo-
patadine 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 ex-
pected 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.
7                                  ALCON RESEARCH   v. APOTEX


    Apotex now appeals from the district court’s final
judgment that the ’805 patent would not have been obvi-
ous over the prior art and from the grant 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.” 35 U.S.C. § 103(a). “Obvi-
ousness is a question of law, which we review de novo,
with underlying factual questions, which we review 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 at issue; (3) the level of ordinary
skill in the field of the invention; and (4) objective consid-
erations such as commercial success, long felt need, and
the failure of others. KSR Int’l Co., v. Teleflex, Inc., 550
U.S. 398, 406 (2007) (citing Graham v. John Deere Co. of
Kan. City, 383 U.S. 1, 17-18 (1966)). Patent invalidity
must be established by clear and convincing evidence.
Microsoft Corp. v. i4i Ltd., 131 S. Ct. 2238, 2242 (2011).
                  I.   Claims 1-3 and 5-7
    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
ALCON RESEARCH   v. APOTEX                                8


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 focus-
ing on Kamei’s lack of disclosure that olopatadine is safe
for human use because the ’805 claims do not recite a
“safety” limitation.
    Apotex contends that the district court erred by re-
quiring 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 humans. Apotex also argues
that claiming olopatadine’s mechanism of action (stabiliz-
ing 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
9                                  ALCON RESEARCH   v. APOTEX


activity because the prior art does not supply a reason to
focus on olopatadine instead of many other promising
antihistamines. Alcon also argues that the court correctly
found that there would not have been a reasonable expec-
tation 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 olo-
patadine 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 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 construc-
tion. Finally, Alcon argues that the district court cor-
rectly found that objective evidence supports a finding of
nonobviousness.
    As an initial matter, we believe the district court
erred in 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 “thera-
peutically 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 con-
junctival mast cells “to an extent clinically relevant in the
treatment of allergic eye disease.” J.A. 176. This con-
struction is not appealed. Because it is not appealed, we
do not decide whether this construction is correct.
ALCON RESEARCH   v. APOTEX                                 10


    On appeal, however, we must determine what olo-
patadine 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 [olo-
patadine] 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 olo-
patadine, claims 5-8 mirror the ranges disclosed in 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 con-
tain a reference to a claim previously set forth and 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 inde-
pendent claim impliedly embraces more subject matter
than its narrower dependent claim.”); AK Steel Corp. v.
Sollac & Ugine, 344 F.3d 1234, 1242 (Fed. Cir. 2003)
(“Under the doctrine of claim differentiation, 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 limita-
tions of being therapeutically effective for treating allergic
eye disease by stabilizing conjunctival mast cells. This is
clear from the express claim language. It is also sup-
11                               ALCON RESEARCH   v. APOTEX


ported by the specification: “The concentration of Com-
pound 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 cov-
ered by claims 1-3 and 5-7 do not stabilize human con-
junctival 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 stabi-
lize human conjunctival mast cells to a 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 inop-
erative portion of the range “wouldn’t be covered by the
claim by virtue of the limitation 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/default.aspx?fl=20
11-1455.mp3. Alcon’s counsel thus contended that the
claims “would be operative, just at a narrower concentra-
tion” than the claimed range. Id. at 15:24-15:27. This is
not how patent law works. When you claim a concentra-
tion 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
ALCON RESEARCH   v. APOTEX                              12


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 mini-
mum must be included in claim 1, whatever its limita-
tions. 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 olo-
patadine. That is the claimed 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 concen-
trations ranging from 0.0001% w/v to 0.01% w/v.
J.A. 10160-63. This range overlaps with the concentra-
tions 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 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 aller-
gic 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 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
13                               ALCON RESEARCH   v. APOTEX


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 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 Textil-
farben 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 knowledge,
the prior art as a whole, or the nature of the problem
itself.”). Here, the motivation to adapt Kamei’s formula-
tion for human use is that it is an effective antihistamine
in guinea pigs and that animals models are (as the dis-
trict court expressly found) predictive of antihistaminic
efficacy in humans.
    The district court’s fact finding that the prior art did
not teach that olopatadine would stabilize human con-
junctival 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 conjuncti-
val mast cells, Kamei’s disclosure of overlapping concen-
trations, even if for a different purpose, meets these claim
limitations.
ALCON RESEARCH   v. APOTEX                                14


    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 olo-
patadine 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 olo-
patadine 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 adapt-
ing 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
whether inherency may be used in an obviousness analy-
sis. 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 appli-
cant’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 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 ’805 patent itself
defines mast cell stabilization as a property that is neces-
sarily present at those concentrations.
    Kamei expressly discloses using olopatadine eye drops
to treat eye allergies at concentrations that overlap with
those in claims 1-3 and 5-7 of the ’805 patent and thus
15                               ALCON RESEARCH   v. APOTEX


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.
    On appeal, Alcon argues that objective 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 the art. We see no clear error in the district
court’s fact findings, but conclude after balancing the
objective evidence against the strong evidence of obvious-
ness 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 be-
cause it discloses olopatadine concentrations that overlap
with the ranges in those claims, it does not teach 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.
ALCON RESEARCH   v. APOTEX                                16


Apotex also argues that a skilled artisan would rely on
U.S. Patent No. 4,923,892 (Lever) as guidance for formu-
lating a 0.1% w/v eye drop. Lever claims a class of chemi-
cal compounds that includes olopatadine and a method of
treating allergies in animals by using this class of com-
pounds. 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 cor-
rectly found that a skilled artisan could not simply substi-
tute 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
17                               ALCON RESEARCH   v. APOTEX


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 increas-
ing 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 be biphasic at this
increased concentration, and 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 olo-
patadine eye drop by substituting olopatadine for the
active compound 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 concen-
tration 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 commer-
cial 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. The 0.1% w/v olopatadine
concentration recited in claims 4 and 8 is the same as is
ALCON RESEARCH   v. APOTEX                                18


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 ’805 patent would
not have been obvious. We affirm its holding that claims
4 and 8 would not have been obvious.
      REVERSED-IN-PART, AFFIRMED-IN-PART
                             COSTS
    No costs.
