United States Court of Appeals
for the Federal Circuit
__________________________
IN RE BRIMONIDINE PATENT LITIGATION
-------------------------------------------------
ALLERGAN, INC.,
Plaintiff-Appellee,
v.
EXELA PHARMSCI INC. AND EXELA PHARMSCI
PVT., LTD.,
Defendants-Appellants,
and
APOTEX INC. AND APOTEX CORP.,
Defendants-Appellants.
__________________________
2010-1102,-1103
__________________________
Appeal from the United States District Court for the
District of Delaware in Case No. 07-MD-1866, Chief Judge
Gregory M. Sleet.
___________________________
Decided: May 19, 2011
___________________________
JONATHAN E. SINGER, Fish & Richardson, P.C. of Min-
neapolis, Minnesota, argued for plaintiff-appellee. With him
on the brief were DEANNA J. REICHEL and JUANITA R.
ALLERGAN INC v. EXELA PHARMSCI 2
BROOKS, of San Diego, California, and W. CHAD SHEAR, of
Dallas, Texas.
HAROLD C. WEGNER, Foley & Lardner, LLP, of Washing-
ton, DC, argued for defendants-appellants Exela Pharmsci
Inc., et al. With him on the brief were C. EDWARD POLK, JR.
and STEPHEN B. MAEBIUS. Of counsel was DOUGLAS H.
CARSTEN, of San Diego, California.
ROBERT B. BREISBLATT, Katten Muchin & Rosenman,
LLP, of Chicago, Illinois, argued for plaintiffs-appellants
Apotex Inc. et al. With him on the brief were RACHEL M.
VORBECK, BRIAN J. SODIKOFF and STEPHEN P. BENSON. Of
counsel was CHARLES PARADIS.
__________________________
Before BRYSON, DYK, and PROST, Circuit Judges.
Opinion for the court filed by Circuit Judge BRYSON.
Opinion concurring-in-part and dissenting-in-part filed by
Circuit Judge DYK.
BRYSON, Circuit Judge.
This patent case involves a dispute over an eyedrop for-
mulation used to treat glaucoma. The appellee, Allergan,
Inc., has various patents that protect its glaucoma drug
Alphagan® P. The appellants, Apotex, Inc., and Exela
Pharmsci, Inc., each filed an Abbreviated New Drug Appli-
cation (“ANDA”) seeking permission from the Food and
Drug Administration (“FDA”) to market a generic version of
Alphagan® P. Allergan sued both Apotex and Exela for
infringement. After an eight-day bench trial, the district
court found that Allergan’s asserted patents were not inva-
lid and that Apotex and Exela infringed those patents. The
court enjoined both Apotex and Exela from making or
selling the products described in each defendant’s ANDA.
3 ALLERGAN INC v. EXELA PHARMSCI
Apotex appeals only the validity portion of the judgment
against it; Exela appeals only the finding of infringement.
On Apotex’s appeal, we affirm-in-part, reverse-in-part, and
affirm the entry of the injunction, as explained below. On
Exela’s appeal, we reverse.
I
Brimonidine tartrate is an α-2-adrenergic agonist that
reduces the elevated intraocular pressure (IOP) of the eye
that is associated with glaucoma. In 1996, Allergan intro-
duced Alphagan®, an aqueous eyedrop solution containing
0.2% brimonidine. Alphagan® is adjusted to a pH between
6.3 and 6.5. It includes a detergent preservative, benzalk-
onium chloride. Alphagan® was commercially successful.
However, a sizeable percentage of Alphagan® users devel-
oped an allergic reaction to brimonidine known as allergic
conjunctivitis.
Allergan’s efforts to address this allergic response led to
the introduction of Alphagan® P in 2001. Allergan sells
Alphagan® P at two brimonidine concentrations, 0.15% and
0.1%, each of which is lower than the 0.2% brimonidine
concentration in Alphagan®. Alphagan® P has a pH be-
tween 7.15 and 7.8, a range that is higher than that of
Alphagan®. The lower concentration Alphagan® P formula-
tion is sold at a pH of 7.6 to 7.8; the higher concentration is
sold at a pH of 7.15 to 7.3.
Two therapeutic benefits accompany the elevated pH.
First, the pH of Alphagan® P is closer to that of the human
eye than is the pH of Alphagan®. Therefore, Alphagan® P
does not produce a stinging sensation when administered.
Second, because brimonidine is an ionizable drug, a lower
concentration of brimonidine at the elevated pH of Al-
phagan® P will provide therapeutic benefits similar to the
ALLERGAN INC v. EXELA PHARMSCI 4
benefits provided by a higher concentration at a lower pH.
At an elevated pH, a higher fraction of brimonidine is un-
ionized as compared to the fraction that is un-ionized at the
slightly acidic pH of Alphagan®. The un-ionized species is
more lipid soluble and thus more readily crosses the corneal
membrane than does the ionized species. Because the
brimonidine-induced allergic reaction is dose-dependent,
Alphagan® P—with its lower concentration of bri-
monidine—does not pose the same risk of allergic response
as the original Alphagan®. Yet because a higher percentage
of the brimonidine passes into the eye at the higher pH,
Alphagan® P remains as therapeutically effective as Al-
phagan®.
The Allergan researchers who developed Alphagan® P
were concerned that brimonidine would not be soluble at a
pH as high as 7.15 or above; accordingly, they included a
solubility-enhancing component, carboxymethylcellulose
(“CMC”). The original Alphagan® included a detergent
preservative, benzalkonium chloride, which was known to
be somewhat irritating to the eye. The preservative in
Alphagan® P is stabilized chlorine dioxide (“SCD”), an
oxidative preservative that was known to be compatible
with the eye. Although the formulators expressed concern
that SCD would oxidize brimonidine, they found that the
two were compatible. Both the preservative, SCD, and the
solubility-enhancing component, CMC, are components of
Refresh Tears®, an Allergan artificial tears solution with a
pH between 7.2 and 7.9.
Allergan submitted five patents associated with Al-
phagan® P to the FDA for publication in the FDA’s list of
patents on branded drugs, known as the Orange Book. The
first patent, U.S. Patent No. 5,424,078 (“the ’078 patent”), is
directed to a sterilized ophthalmic solution at physiologic
pH and osmolality. The other four patents, which the
5 ALLERGAN INC v. EXELA PHARMSCI
parties refer to as the “related patents,” are directed to
medicated ophthalmic solutions.
In 2007, Apotex submitted two ANDAs to the FDA seek-
ing approval to manufacture and sell a generic version of
Alphagan® P in the 0.1% and 0.15% brimonidine concentra-
tions. Exela filed a single ANDA targeting the 0.15% bri-
monidine product. Allergan sued Exela in the United States
District Court for the Central District of California for
patent infringement under 35 U.S.C. § 271(e)(2). Allergan
filed a similar suit against Apotex in the United States
District Court for the District of Delaware.
The multidistrict litigation panel consolidated both
cases in the District of Delaware. Following a bench trial,
the district court upheld the validity of all the asserted
claims of the ’078 and related patents against an obvious-
ness challenge. Apotex stipulated to infringement. The
district court held a bench trial on the infringement action
against Exela and found that the product proposed in Ex-
ela’s ANDA would infringe the asserted claims. Accord-
ingly, the court enjoined both Apotex and Exela from
making or selling the products described in their respective
ANDAs.
II
Apotex challenges the district court’s determination that
the asserted patents are not invalid. With respect to the
’078 patent, we hold that the asserted claims would have
been obvious. With respect to the four “related patents,”
however, we uphold the district court’s determination that
the claims would not have been obvious. The injunction
against Apotex stands unless Apotex overcomes the pre-
sumption of validity for every claim of the ’078 patent and
the “related patents.” Because Apotex failed to meet this
ALLERGAN INC v. EXELA PHARMSCI 6
burden with respect to the “related patents,” we affirm the
court’s award of injunctive relief in favor of Allergan.
A
The ’078 patent describes and claims a buffered, aque-
ous ophthalmic solution at a pH of about 6.8 to 8, which
roughly corresponds to the pH of the human eye. Claim 1
recites a method for preserving an aqueous ophthalmic
formulation. The claimed method employs a solution having
three active components: an amount of stabilized chlorine
dioxide sufficient to serve as the sole preservative, an oph-
thalmically acceptable buffer component effective to main-
tain a pH range of about 6.8 to 8, and an ophthalmically
acceptable tonicity component effective to maintain an
osmolality of at least 200 mOsmol/kg. Stabilized chlorine
dioxide is a salt-balanced, aqueous solution of chlorite, ClO2-
. The addition of an acid (or an oxidant) to an SCD solution
“activates” the SCD by oxidizing chlorite to chlorine dioxide,
ClO2. Both SCD and chlorine dioxide are oxidants, although
chlorine dioxide is the stronger of the two.
Apotex’s invalidity argument focuses on two references,
U.S. Patent No. 4,499,077 (“Stockel”) and U.S. Patent No.
4,689,215 (“Ratcliff”). The district court determined that
those references were insufficient to rebut the presumption
of validity. According to the district court, Ratcliff discloses
“stabilized chlorine dioxide as a starting material, and the
use of chlorine dioxide as the active antimicrobial species for
ophthalmic applications.” The court found that Stockel
teaches away from the claimed invention. The court ex-
plained that the claims of the Stockel patent require enough
SCD to serve as the sole preservative, whereas Stockel’s
written description states that an antimicrobial solution
that relies only on SCD would require so much SCD that the
solution would irritate the eye. For that reason, Stockel
7 ALLERGAN INC v. EXELA PHARMSCI
suggests the use of a second preservative along with SCD if
the disclosed solution is used in an ophthalmic formulation.
Stockel, col. 10, ll. 1-6.
Apotex argues that the only difference between Ratcliff
and the asserted claims is that the claims specify a pH
range and include a buffer component and a tonicity compo-
nent. Apotex contends that those modifications would have
been obvious. Allergan acknowledges that Ratcliff discloses
an SCD solution, but responds that Ratcliff “only teaches
the use of stabilized chlorine dioxide as a starting material.”
According to Allergan, Ratcliff teaches the use of chlorine
dioxide as a preservative, not the use of stabilized chlorine
dioxide, i.e., the chlorite ion. Allergan maintains that the
solution disclosed in Ratcliff is distinct from the claims
because Ratcliff requires “activation” of the disclosed SCD
solution, such as by adding an acid to convert the SCD to
chlorine dioxide.
Contrary to Allergan’s contention, nothing in the
Ratcliff patent provides that its SCD must be “activated.”
Instead, it simply discloses and claims the use of an SCD
solution as an antimicrobial agent. For instance, with
respect to the first example, a deodorizing mouthwash, the
specification states: “The chlorine dioxide mouthwash or
rinse solution serves to attack production and origin of
malodor from the mouth [by breaking sulfide bonds]. There-
fore, delivery of stabilized chlorine dioxide will reduce the
number of [oral] microorganisms.” Ratcliff, col. 3, ll. 25-34.
Nowhere in the first example—or in any other example—
does the protocol disclosed by Ratcliff require “activation” of
the SCD solution. Moreover, even if Ratcliff did disclose an
“activation” step, the distinction would not be relevant to
Allergan’s patentability arguments, as the claims of the ’078
patent are directed to an SCD solution irrespective of its
“activation.”
ALLERGAN INC v. EXELA PHARMSCI 8
Example 8 of Ratcliff is a contact lens soak with a pre-
ferred concentration of 0.005% to 2.0% SCD in water. Id.,
col. 11, ll. 20-27. That example clearly discloses an oph-
thalmic SCD solution. The only distinction between that
solution and the claimed invention is the presence of tonic-
ity and buffering components and an explicit pH limitation.
Based on the evidence presented at trial, we are con-
vinced that it would have been obvious to one skilled in the
art to adjust the SCD solution disclosed in Ratcliff to ap-
proximate physiologic pH, to include a buffer component to
maintain that pH, and to include a tonicity component to
approximate physiologic osmolality. Stockel explicitly
discloses the modifications that Allergan argues impart
patentability. That reference discloses the use of SCD as a
preservative in an ophthalmic solution and teaches that “[i]t
is desirable to make the solution isotonic and for this pur-
pose any of the well-known agents may be used.” Stockel,
col. 10, ll. 57-58. The Stockel patent continues: “Other
materials commonly used in contact lens solutions may also
be employed such as buffering, chelating and thickening
agents.” Id., col. 10, ll. 62-64. Allergan points out that
Stockel also discloses that the amount of SCD necessary to
serve as the sole preservative would irritate the eye, and
accordingly recommends a combination of two preservative
agents. But Stockel’s teachings with respect to the required
quantity of SCD do not undercut the force of its disclosure
that maintenance of a physiologic pH and osmolality by use
of buffer and tonicity components would have been simple
and well-known modifications. See, e.g., Beckman Instru-
ments, Inc. v. LKB Produkter AB, 892 F.2d 1547, 1551 (Fed.
Cir. 1989) (“Even if a reference discloses an inoperative
device, it is prior art for all that it teaches.”). And Ratcliff,
which postdates Stockel by nearly two years, discloses that
SCD can be used as an effective sole preservative for an
ophthalmic solution. Although the burden to negate pat-
9 ALLERGAN INC v. EXELA PHARMSCI
entability remains firmly with Apotex, we note that there is
no evidence in the record that the tonicity or buffer compo-
nents are incompatible with SCD. We therefore hold that
the district court committed legal error in concluding that it
would not have been obvious to one skilled in the art to
create an ophthalmic solution that was adjusted to ocular
pH and tonicity and that relied on SCD as the sole preserva-
tive agent.
B
With respect to the four “related patents,” we reach a
different conclusion. Neither party argued its validity case
to the district court on a claim-by-claim basis and neither
presents a claim-by-claim argument to this court. Apotex
stipulated to infringement of all asserted claims of the
related patents, so the injunction stands unless Apotex can
demonstrate that all of the 69 asserted claims are invalid.
For purposes of Apotex’s appeal, we therefore focus on the
narrowest claims, as they are the least vulnerable to Apo-
tex’s validity challenge. Based on our careful review of the
proceedings at trial, we reject Apotex’s argument that as to
each of the asserted claims of those patents, the district
court erred in concluding that Apotex failed to overcome the
presumption of validity by clear and convincing evidence.
The first of those patents is U.S. Patent No. 6,562,873
(“the ’873 patent”). Claim 33, the narrowest of the asserted
claims, recites an aqueous solution including brimonidine in
an amount effective to provide a therapeutic benefit, along
with CMC as a solubility-enhancing component and chlorite
(i.e., SCD) as a preservative. That claim does not specify a
pH level for the solution. The second patent, U.S. Patent
No. 6,627,210 (“the ’210 patent”), claims brimonidine, as
well as the general class of α-2-adrenergic agonists, along
with various anionic solubility enhancers. Many of the
ALLERGAN INC v. EXELA PHARMSCI 10
asserted claims are silent as to the preservative to be used,
but claims 26, 30, and 34 require chlorite. Claims 13 and 14
do not require any particular preservative, but they require
that the pH of the solution be above 7.0. The third patent,
U.S. Patent No. 6,641,834 (“the ’834 patent”), is a continua-
tion of the ’210 patent. Claims 7 and 16 of the ’834 patent
recite a 0.15% brimonidine solution with a pH of 7.0 or
greater with chlorite as a preservative. Although the ’834
patent specification discusses the use of CMC and other
solubilizers, none of the asserted claims requires the use of
CMC. The fourth patent, U.S. Patent No. 6,673,337 (“the
’337 patent”) is also a continuation of the ’210 patent. Each
of the two asserted claims of that patent is directed to the
general class of α-2 adrenergic agonists along with an
anionic solubility-enhancing component other than a cyclo-
dextrin. Neither claim requires the presence of chlorite, and
neither is specific as to pH.
Apotex points out that every asserted claim reads on a
combination of two Allergan products: Alphagan® (bri-
monidine) and Refresh Tears®. Refresh Tears® is a non-
medicated eyedrop adjusted to a pH of 7.2 to 7.9. It includes
SCD as a preservative and CMC as a viscosity agent.
Apotex argued to the district court that combining the two
solutions would have been obvious, but the district court
disagreed. The court found that one skilled in the art would
have expected brimonidine to present solubility problems at
the elevated pH of Refresh Tears®. The court did not agree
with Apotex that one skilled in the art would have expected
CMC to increase the solubility of brimonidine. And it found
that one of ordinary skill in the art would have expected
SCD to oxidize brimonidine. Apotex challenges those fac-
tual findings. Apotex further argues that, at a minimum,
the combination would have been obvious to try and that the
claims reciting that combination are therefore invalid for
obviousness.
11 ALLERGAN INC v. EXELA PHARMSCI
1. Solubility
The district court credited the testimony of Allergan’s
expert witness, Dr. Valentino Stella, and found that one
skilled in the art would not have expected therapeutically
effective concentrations of brimonidine to be soluble at the
slightly alkaline pH range of Refresh Tears®, 7.2 to 7.9.
Apotex challenges the court’s finding by focusing on a solu-
bility table that it did not rely on at trial. The table is
excerpted from a New Drug Application (“NDA”) filed by
Allergan with the FDA. The table recites that at the neu-
tral pH of 7.0, the water solubility of brimonidine is 1.94
mg/mL, or 0.194%. Every asserted claim reads on a solution
with a pH of at least 7.0. Claims 11-13 of the ’834 patent
are directed to a 0.15% brimonidine solution at a pH of 7.0
or above, and all of the other asserted claims are directed to
a therapeutically effective quantity. 1 Apotex and Allergan
1 The district court gave the phrase “therapeutically
effective ophthalmic composition” its ordinary meaning.
According to the dissent, those of ordinary skill in the art
knew brimonidine was therapeutically effective at concen-
trations below .2%, and would have been motivated to
combine a .15% brimonidine solution with Refresh Tears®.
As support for that position, the dissent points to a 1997
journal article entitled “Brimonidine Tartrate: A One-Month
Dose Response Study” (“Derick”), which was not mentioned
in either party’s brief. The dissent characterizes that article
as establishing that a 0.08% brimonidine solution was
known to be clinically effective and soluble at the elevated
pH range of Refresh Tears®. Derick, however, did not
indicate the pH of the carrier; because the therapeutic
efficacy of brimonidine varies with pH, the article is of little
value for that reason. In any event, Dr. Robert Noecker, an
Allergan expert witness, testified that the results of the
Derick study did not lead him to conclude that brimonidine
could be therapeutically effective at concentrations as low as
0.08%. He explained that clinicians evaluating such a
drug’s therapeutic efficacy look for at least a 20% reduction
ALLERGAN INC v. EXELA PHARMSCI 12
agree that brimonidine’s solubility decreases as the pH of a
solution increases. Apotex argues that the solubility table
establishes that the district court was wrong in finding that
brimonidine would have presented solubility problems at
the elevated pH of Refresh Tears®. But Apotex did not
focus on the table at trial. It did not provide any supporting
testimony calling the district court’s attention to the table
nor did it explain how one skilled in the relevant art would
have assessed the information from the table. Under these
circumstances, we do not see clear error in the district
court’s finding as to the expected solubility of brimonidine at
the 7.2 to 7.9 pH range. See H.H. Robertson, Co. v. United
Steel Deck, Inc., 820 F.2d 384, 389 (Fed. Cir. 1987) (“[Defen-
dants] argue that because this reference had first been
offered to the district court it is not in fact presented for the
first time on appeal. But this reference, although placed in
the record by the district court, was not the subject of testi-
mony or any other form of evaluation by that court. Initial
consideration of evidence is not the appellate role.”).
2. CMC as a Solubility-Enhancing Component
The district court found that one of ordinary skill in the
art would not have turned to CMC as a solubility enhancer.
In response, Apotex presents two arguments. First, it
points out that Alphagan® and Refresh Tears®, which
contains CMC, were routinely prescribed together. This fact
alone does not establish that it would have been obvious to
in baseline IOP and that he did not regard Derick’s results
demonstrating that threshold level of effectiveness at the
0.08% concentration level. While there was conflicting
expert testimony on that issue, on this record the Derick
article cannot be said to be a sufficiently clear teaching that
a brimonidine solution at the 0.08% level would be thera-
peutically effective as to require upsetting the trial court’s
ruling on obviousness.
13 ALLERGAN INC v. EXELA PHARMSCI
combine the two in a single formulation. Two ingredients
might be therapeutically effective when used separately as
part of an overall treatment regimen, yet be incompatible or
ineffective when combined in a single solution.
Second, Apotex argues that the claimed invention would
have been obvious in light of journal articles by Thorsteinn
Loftsson from 1994 and 1997. The district court found that
the Loftsson references do not disclose or suggest the use of
CMC in connection with any α-2 adrenergic agonist, let
alone brimonidine. We agree.
The earlier of the two Loftsson articles is entitled “The
Effect of Water-Soluble Polymers on Drug–Cyclodextrin
Complexation.” Cyclodextrin is a cylindrical molecule with
a hydrophobic center and hydrophilic exterior. It acts as a
carrier for hydrophobic drugs. Loftsson tested the effect of
polymeric solubility enhancers, including CMC, on the
water solubility of cyclodextrin–drug complexes. Notably,
many of the asserted claims of the “related patents” recite a
solution that is “substantially free of cyclodextrins.” Even in
the case of the claims that lack that proviso, we see no error
in the district court’s treatment of the Loftsson references.
Apotex relies heavily on Loftsson’s statement that “the
addition of a very small amount of [CMC] resulted in a
significant increase in the aqueous solubility of most of the
drugs tested.” While acknowledging that neither of the two
Loftsson articles discusses the use of CMC in connection
with brimonidine or even the generic class of α-2-adrenergic
agonists, Apotex argues that the articles “certainly would
have suggested as much to one of skill given that [they]
disclosed CMC enhancing the solubility of the many soluble
active ingredients with which it was tested.” However,
Apotex provided no expert testimony or other evidence to
support that proposition, and the generalization made by
ALLERGAN INC v. EXELA PHARMSCI 14
counsel on appeal does not undermine the district court’s
contrary determination following the trial.
Finally, Apotex argues that the district court imported
an unclaimed limitation to distinguish the Loftsson refer-
ences. Loftsson assessed the water solubility of various
mixtures, consisting of cyclodextrin, CMC, and a subject
drug, after heating the mixture at 120ºC for 20 minutes.
The 1997 Loftsson paper makes the need for the heating
step explicit: “[s]imply adding the polymers to the solutions
without heating does not enhance the complexation or the
drug availability.” The asserted claims that recite CMC
neither require nor exclude a heating step. Apotex contends
that the district court erroneously used the absence of a
heating step to distinguish the claims from the 1997 Lofts-
son reference. We disagree. Allergan’s expert testified that
the high temperature needed to observe the increase in
solubility can lead to decomposition of a drug such as bri-
monidine and to alterations in its crystalline structure. The
need for the heating step and its apparent incompatibility
with brimonidine further establishes that Loftsson does not
teach the combination of brimonidine and CMC. Accord-
ingly, we see no error in the district court’s findings based
on the Loftsson references.
3. SCD as a Preservative
The district court found that one skilled in the art would
not have been motivated to combine Refresh Tears® and
Alphagan® because of concerns that SCD would oxidize
brimonidine. Apotex challenges that finding by citing an
article by Charles P. Thompson entitled “Mechanisms of
Adrenergic Agonist Induced Allergy Bioactivation and
Antigen Formulation.” That article, according to Apotex,
proves the oxidative stability of brimonidine. In the article,
Thompson describes having incubated brimonidine and
15 ALLERGAN INC v. EXELA PHARMSCI
other α-2 agonists with a hydrogen peroxide-producing
species for 120 hours and finding that brimonidine “proved
stable to the enzymatic oxidation conditions.” The district
court found the Thompson reference “unpersuasive because,
among other things, it teaches nothing about the oxidative
stability of brimonidine in a Purite®-containing formulation
that needs to be shelf-stable for two years.” Purite® is
Allergan’s trade name for an SCD solution.
First, Apotex argues that the district court improperly
imported a two-year shelf-stability limitation into the claims
and used that limitation to avoid the teachings of the prior
art. It is true that the claims do not require a particular
period of shelf stability, but that was not the only basis for
the district court’s finding that one skilled in the art would
not have expected brimonidine and SCD to be compatible.
Dr. Stella, whose testimony was accepted by the court,
explained that prior art documents described Purite® as a
“strong” oxidant. Even in light of Thompson’s findings, Dr.
Stella testified that one skilled in the art would have been
“extremely hesitant, if not, I would say, directed away from .
. . formulating brimonidine with a chlorite compound,” i.e.,
Purite®.
Apotex challenges Dr. Stella’s testimony, contending
that it is contradicted by Allergan documents. Apotex
points to promotional literature associated with Purite®
that describes Purite® as having a relatively low oxidation
potential compared to hydrogen peroxide. In response to a
question about what it means to describe a component or an
excipient as a strong oxidant, Dr. Stella replied that “it
basically says it’s capable of oxidizing drugs, any chemical.”
When Apotex’s attorney asked Dr. Stella about the relative
oxidative potentials of hydrogen peroxide and Purite®, Dr.
Stella stated that hydrogen peroxide is a strong oxidant and
Purite® is a relatively weaker oxidant, but he also stated
ALLERGAN INC v. EXELA PHARMSCI 16
that Purite® “is a very good” oxidant. While we recognize
that hydrogen peroxide may be a stronger oxidant than the
SCD in Purite®, the fact that Allergan touted Purite® as
being less reactive than hydrogen peroxide does not estab-
lish that one skilled in the art would not have expected SCD
to oxidize brimonidine.
C
Apotex faults the district court for considering each as-
serted reference in isolation. It argues that the modifica-
tions that Allergan made to the original Alphagan®
formulation consisted essentially of combining of Refresh
Tears® and Alphagan®. It contends that the combination
would have been obvious to try, rendering the asserted
claims invalid for obviousness.
Where “the problem is known, the possible approaches
to solving the problem are known and finite, and the solu-
tion is predictable through use of a known option,” a solu-
tion that is obvious to try may indeed be obvious. Abbott
Labs. v. Sandoz, Inc., 544 F.3d 1341, 1351 (Fed. Cir. 2008),
citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
Apotex points out that both SCD and CMC were components
of Refresh Tears®. It argues that in light of the dose-
dependent allergenic conjunctivitis associated with the 0.2%
brimonidine in the original Alphagan®, there was strong
market pressure to reduce the brimonidine concentration of
that product. By increasing the pH of the brimonidine
solution to that of Refresh Tears®, the formulators could
reduce the brimonidine concentration while maintaining
therapeutic efficacy. The elevated pH is also more compati-
ble with the human eye than the pH of the original Al-
phagan®.
17 ALLERGAN INC v. EXELA PHARMSCI
Apotex’s “obvious to try” arguments, based on KSR, are
unavailing in light of the district court’s factual findings.
The district court found that the solutions that Allergan
identified and eventually claimed would not have been an
“anticipated success.” See Rolls-Royce, PLC v. United Techs.
Corp., 603 F.3d 1325, 1339 (Fed. Cir. 2010). The court
found that one of ordinary skill would not have been ex-
pected to disregard those roadblocks. Because the court’s
findings are well supported, we do not agree with Apotex
that the trial court’s conclusion as to the “obvious to try”
issue must be overturned.
D
Apotex’s final argument relates to post-trial issues. Af-
ter trial, both Apotex and Allergan submitted their proposed
findings of fact and conclusions of law. In those filings,
Apotex made obviousness arguments based on references
that were admitted into evidence but that Apotex did not
support with expert testimony or otherwise rely on at trial.
The court granted Allergan’s motion for judgment of a
matter of law with respect to Apotex’s obviousness argu-
ments made on those references. Apotex contends that it
was entitled to make post-verdict arguments that the claims
would have been obvious in light of two of these references
because (1) the references were admitted into evidence, and
(2) the references were incorporated by reference in the
patents in suit.
There is no invariable requirement that a prior art ref-
erence be accompanied by expert testimony. E.g., Wyers v.
Master Lock Co., 616 F.3d 1231, 1242 (Fed. Cir. 2010)
(“expert testimony is not required when the references and
the invention are easily understandable”). But it is well
within a trial judge’s discretion to require expert testimony
supporting technical references that are relied on to estab-
ALLERGAN INC v. EXELA PHARMSCI 18
lish obviousness. That the references at issue in this case
were incorporated by reference in Allergan’s asserted pat-
ents means only that they are treated as if set forth in their
entirety in the patents; the incorporation of those references
is not relevant to whether the district court erred in disre-
garding them because of the lack of supporting testimony.
We hold that the district court did not abuse its discretion in
refusing to consider those references in its obviousness
analysis in light of the absence of testimony explaining their
relevance to the obviousness issue.
E
To conclude, we reverse the district court’s determina-
tion that the asserted claims of the ’078 patent are not
invalid. We affirm the district court’s determination that
Apotex failed to satisfy its burden to show that each as-
serted claim of the “related patents” is invalid as a matter of
law, and we therefore sustain the court’s issuance of an
injunction against Apotex, which has stipulated to in-
fringement.
III
Exela is in a different position. Unlike Apotex, Exela
appeals the district court’s finding that the product pro-
posed in its ANDA infringes Allergan’s patent rights.
Allergan asserted only the ’834 patent against Exela.
Claims 7 and 16 of that patent recite a 0.15% brimonidine
solution including SCD as a preservative adjusted to a pH of
7.0 or greater. The only issue in this case is whether the
product described in Exela’s ANDA infringes that pH limita-
tion. Both Exela and Allergan agree that the highest pH at
which Exela requests permission to manufacture and sell its
proposed product is 6.7. The district court found that the
19 ALLERGAN INC v. EXELA PHARMSCI
lowest pH at which Exela requests permission to manufac-
ture and sell its proposed drug at is 6.5. 2 Both parties agree
that to the extent the pH of the formulation changes over
time, it will fall, not rise.
The district court found that the pH of Exela’s formula-
tion will drop by approximately 0.5 pH units over a period of
six months. The court based that finding on the testimony
of Allergan’s expert witness, Dr. Stella, as well as on a
stability study that Exela included in its ANDA. That study
showed a drop in pH from an initial pH of 6.7 to a final pH
of 6.2 over a six-month period. The district court reasoned
that Exela would take this 0.5 unit drop in pH into account
when manufacturing its brimonidine formulation. To
produce a product that will maintain a pH greater than 6.5,
the district court concluded that Exela would necessarily
manufacture its product at an infringing pH of 7.0 or above.
A
The infringement provision of the Hatch-Waxman Act,
35 U.S.C. § 271(e)(2)(A), states that it is an act of infringe-
ment to submit an ANDA that describes “a drug claimed in
2 Exela’s ANDA presents two pH ranges: the pH
range at which Exela proposes to manufacture the drug, and
the pH range at which Exela proposes to sell the drug (the
“label pH”). The parties agree that the manufacturing pH
in Exela’s ANDA is 6.5 to 6.7. The parties also agree that
the highest label pH set forth in Exela’s ANDA is 6.7. The
parties do not, however, agree on what the lowest label pH
represented in Exela’s ANDA is. The district court found
that it is 6.5. On appeal, Exela argues that the lower bound
of the label pH is 5.5. This factual dispute is ultimately
irrelevant to the disposition of this appeal, because we
cannot assume that Exela will deviate from the stated upper
bound of both the manufacturing and the labeling pH, which
is 6.7.
ALLERGAN INC v. EXELA PHARMSCI 20
a patent.” The infringement action is a hypothetical case
that asks the factfinder to determine whether the drug that
will be sold upon approval of the ANDA will infringe the
asserted patent. Bayer AG v. Elan Pharm. Research Corp.,
212 F.3d 1241, 1249 (Fed. Cir. 2000). In Abbott Laborato-
ries v. TorPharm, Inc., we explained that “[b]ecause drug
manufacturers are bound by strict statutory provisions to
sell only those products that comport with the ANDA’s
description of the drug, an ANDA specification defining a
proposed generic drug in a manner that directly addresses
the issue of infringement will control the infringement
inquiry.” 300 F.3d 1367, 1373 (Fed. Cir. 2002).
B
Exela argues that the district court erred by assuming
that Exela would manufacture a drug outside of the pa-
rameters of the ANDA. In support of the district court’s
judgment, Allergan argues that in an infringement action
provoked by the filing of an ANDA, the court may consider
not only the proposed drug as described in the ANDA, but
also other relevant information, including the pH drop that
the court identified.
We agree with Exela. In Bayer AG v. Elan Pharmaceu-
tical Research Corp., we considered an analogous situation
in a different procedural posture. 212 F.3d at 1247-50.
Bayer’s patent on the reference drug claimed nifedipine
crystals with a solid surface area ("SSA”) between 1-4 m2/g.
Id. at 1247. Elan submitted an ANDA requesting permis-
sion to make and sell nifedipine in a crystalline form with
an SSA of 5 m2/g or above. The district court entered sum-
mary judgment of noninfringement in favor of Elan, and
Bayer appealed. Bayer suggested that there were genuine
issues of material fact as to whether Elan would be able to
produce a product with the noninfringing SSA as described
21 ALLERGAN INC v. EXELA PHARMSCI
in its ANDA. We affirmed. We pointed out that Elan was
bound by the representations in its ANDA and noted that
substantial penalties, including criminal sanctions, flow
from noncompliance. Id. at 1249-50. We further explained
that “Elan, under its current ANDA specification, will either
market a drug with a SSA of 5 m2/g or greater . . . or Elan
will not, legally, market any drug under its ANDA.” Id. at
1250. The same is true here: the highest pH at which Exela
will manufacture and sell its proposed product is 6.7 or
Exela will not, legally, market anything at all.
Allergan likens this case to Abbott Laboratories v. Tor-
Pharm, Inc., and relies on the following quotation from
Abbott: “[O]ther evidence may directly contradict the clear
representations of the ANDA and create a dispute of mate-
rial fact regarding the identity of the compound that is
likely to be sold following FDA approval.” 300 F.3d at 1373.
But Abbott addressed a different issue, and the quoted
sentence is not relevant to Allergan’s appeal. In Abbott, the
claims of the patent on the reference drug recited an oli-
gomeric compound with about 4-6 repeating subunits. Id. at
1376-77. TorPharm’s ANDA did not specify the number of
subunits in the generic formulation. Id. at 1376. We va-
cated the district court’s award of summary judgment of
noninfringement in favor of TorPharm because there was a
disputed issue of fact concerning the number of subunits in
the formulation that TorPharm would produce if it operated
in compliance with its ANDA. In that instance, we held
that it might be appropriate for the court to consider mate-
rial outside the four corners of the ANDA to determine
whether the ANDA describes an infringing product. Here,
neither party disputes that if Exela complies with its
ANDA, it will never manufacture or sell a product at a pH
above 6.7. We cannot assume that Exela will not act in full
compliance with its representations to the FDA, and we
ALLERGAN INC v. EXELA PHARMSCI 22
accordingly reverse the district court’s judgment finding
that Exela’s filing of the ANDA is an act of infringement.
Each party shall bear its own costs for this appeal.
AFFIRMED IN PART and REVERSED IN PART
United States Court of Appeals
for the Federal Circuit
__________________________
IN RE BRIMONIDINE PATENT LITIGATION
-------------------------------------------------
ALLERGAN, INC.,
Plaintiff-Appellee,
v.
EXELA PHARMSCI INC. AND EXELA PHARMSCI
PVT., LTD.,
Defendants-Appellants,
and
APOTEX INC. AND APOTEX CORP.,
Defendants-Appellants.
__________________________
2010-1102, -1103
__________________________
Appeals from the United States District Court for the
District of Delaware in case no. 07-MD-1866, Chief Judge
Gregory M. Sleet.
__________________________
DYK, Circuit Judge, concurring-in-part and dissenting-in-
part.
I join Parts IIA and III of the majority’s opinion.
However, I respectfully dissent from Parts IIB, IIC, and
IID. In my view, the asserted claims of U.S. Patent Nos.
ALLERGAN INC v. EXELA PHARMSCI 2
6,562,873; 6,627,210; 6,641,834; and 6,673,337 (collec-
tively, the “related patents”) are invalid as obvious over
the combination of Alphagan® and Refresh Tears® in
view of the related prior art.
A finding of obviousness under the “obvious to try”
standard “does not require absolute predictability of
success . . . all that is required is a reasonable expectation
of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir.
2009) (quoting In re O’Farrell, 853 F.2d 894, 903–04 (Fed.
Cir. 1988)) (emphasis altered). I think that standard was
satisfied here. It is undisputed that all asserted claims of
the related patents read on a combination of Alphagan®
and Refresh Tears®. The undisputed evidence further
establishes that, at the time of the invention, a person
having ordinary skill in the art (“PHOSITA”) would have
known that: (1) Alphagan® had common side effects, two
of which included eye irritation and dry eye (known to be
exacerbated by its bezalkonium chloride (“BAK”) pre-
servative); (2) the higher pH of Refresh Tears®, nearer to
that of the human eye, would likely reduce irritation; (3)
the “gentle” stabilized chlorine dioxide (“Purite®”) pre-
servative in Refresh Tears® would likely be less harmful
than Alphagan’s® “toxic” BAK preservative; (4) inclusion
of Refresh Tears’® carboxymethylcellulose (“CMC”) vis-
cosity agent would likely further reduce eye irritation;
and (5) physicians were routinely prescribing Refresh
Tears® to glaucoma patients on Alphagan® to help allevi-
ate irritation and dry eye, two of Alphagan’s® known side
effects.
Under these circumstances, I think a PHOSITA would
have found a combination of these two commercially
successful products “obvious to try.” KSR Int’l Co. v.
Teleflex, Inc., 550 U.S. 398, 421 (2007).
3 ALLERGAN INC v. EXELA PHARMSCI
Despite the extensive evidence of the motivations for
a PHOSITA to combine Alphagan® and Refresh Tears®,
the district court held that the combination was not
obvious to try because a PHOSITA would have had con-
cerns regarding the solubility and oxidation of bri-
monidine in Refresh Tears®, thereby preventing a
PHOSITA from having any anticipated success in combin-
ing the products. However, I think the district court
made clearly erroneous findings of fact regarding these
purported concerns.
The district court first found that “a [PHOSITA]
would not have expected effective concentrations of bri-
monidine to be soluble in [the elevated] pH range” of
Refresh Tears®. In re Brimonidine Patent Litigation, 666
F. Supp. 2d 429, 442 (D. Del. 2009). The court viewed
brimonidine concentrations of 0.2% to 0.5% as necessary
for therapeutic effect, and it concluded that a PHOSITA
would not have expected these concentrations to be solu-
ble at the 7.2–7.9 pH range of Refresh Tears®. This was
based on Dr. Stella’s testimony that a PHOSITA would
have expected “0.2 percent and 0.5 percent” brimonidine
to have solubility problems at higher pHs. J.A. 7922–23.
The difficulty with this finding is that the district court
improperly assumed that the 0.2% brimonidine in Al-
phagan® was the lowest dosage concentration that could
achieve efficacy. The Derick reference (entitled “Bri-
monidine Tartrate: A One-Month Dose Response Study”)
confirms brimonidine’s effectiveness at lower dosages.
The authors of the Derick reference conducted “a multi-
centered, double-masked, randomized, placebo-controlled,
parallel, 1-month dose response evaluation of brimonidine
0.5%, 0.2%, and 0.08% in patients with open-angle glau-
coma or ocular hypertension.” J.A. 25670. The study
concluded that “[a]ll concentrations of brimonidine sig-
nificantly reduced IOP, compared to baseline and placebo,
ALLERGAN INC v. EXELA PHARMSCI 4
at all follow-up visits.” J.A. 25669. A PHOSITA would
have understood Derick as disclosing that brimonidine
can be therapeutically effective at concentrations as low
as 0.08%. There is also no basis for finding that 0.08%
brimonidine would be insoluble at the higher pH range of
Refresh Tears®.
The majority dismisses the Derick reference by citing
Dr. Robert Noecker’s testimony that Derick’s findings
were “not compelling” evidence of 0.08% brimonidine’s
efficacy and that he would not prescribe 0.08% bri-
monidine to his patients based on the Derick study. J.A.
7507; see Maj. Op. at 11 n.1. But notably, Dr. Noecker
said nothing as to whether a PHOSITA would have con-
sidered it obvious to try concentrations lower than 0.2% in
light of Derick’s findings regarding the 0.08% concentra-
tion. Dr. Noecker himself acknowledged that the efficacy
of a particular drug concentration can never be known for
certain “without having . . . the actual concentration
tested.” J.A. 7508. Derick’s plain findings that “23 (51%)
of 45 patients in the 0.08% group . . . showed a reduction
of 20% or more from baseline at one or more scheduled
visits over the course of the study” clearly suggested
trying concentrations lower than 0.2%. J.A. 25671.
The majority further dismisses the Derick reference
because “the therapeutic efficacy of brimonidine varies
with pH,” and the study “did not indicate the pH of the
carrier.” Maj. Op. at 11 n.1. But if the carrier in Derick
had a higher pH than Alphagan®, then it demonstrated
the likely success of combining Alphagan® and Refresh
Tears® using some brimonidine concentration lower than
0.2%. Conversely, if the carrier had a pH lower than
Alphagan®, a PHOSITA would have known that the
0.08% concentration would be even more effective at the
higher pH range of Refresh Tears® due to the pH Parti-
5 ALLERGAN INC v. EXELA PHARMSCI
tion Theory discussed below. Either way, a PHOSITA
concerned with the solubility of 0.2% brimonidine at the
higher pH of Refresh Tears® would have been prompted
by Derick to simply try using a lower dosage.
Quite apart from Derick, there was no reason for a
PHOSITA to be deterred from combining Alphagan® and
Refresh Tears® because of solubility problems with
brimonidine concentrations in the 0.2% to 0.5% range. As
the majority recognizes, the pH Partition Theory estab-
lishes that an ocular drug’s bioavailability (the percentage
of the drug that reaches the targeted tissue) increases in
correlation with pH, which means that increasing pH
lowers the minimum dosage concentration required for
efficacy. See Maj. Op. at 3–4. The district court failed to
recognize that a PHOSITA with knowledge of the pH
Partition Theory would have known that some concentra-
tion of brimonidine less than 0.2% could still achieve
efficacy at the higher pH range of Refresh Tears®, and
that the lower brimonidine concentration would in turn
help offset the expected decrease in the maximum soluble
concentration. A PHOSITA thus would have been moti-
vated to lower the dosage concentration below 0.2%. 1
1 A PHOSITA also would have found a lower dosage
preferable because Alphagan’s® high 0.2% brimonidine
concentration commonly caused allergic conjunctivitis
(inflammation of the inner eyelid tissue), and it was
known at the time of the invention that reducing the
brimonidine concentration would help alleviate this side
effect. See J.A. 7486–87, 7493–96, 7512 (Dr. Noecker);
J.A. 6737–38 (Dr. Tanna); J.A. 6416 (Dr. Whitcup); J.A.
7580 (Dr. Banker). The pH Partition Theory thus pro-
vided an additional affirmative motivation for a
PHOSITA to exploit the higher pH range of Refresh
Tears® to make a dosage reduction possible.
ALLERGAN INC v. EXELA PHARMSCI 6
In short, solubility problems with brimonidine concen-
trations in the 0.2% to 0.5% range, as found by the dis-
trict court, would not have deterred a PHOSITA from
trying a lower concentration of brimonidine at the higher
pH range of Refresh Tears®.
The district court next found that a PHOSITA would
have had “concerns that the Purite® preservative in
Refresh Tears® would oxidize the brimonidine in Al-
phagan[ ]®.” In re Brimonidine Patent Litigation, 666 F.
Supp. 2d at 444. However, the court based this holding
on two clearly erroneous fact findings.
The court’s first error regarding oxidation concerns
was its dismissal of the Thompson reference. Thompson
discloses a study in which the oxidative effect of hydrogen
peroxide on brimonidine and other drugs was tested using
electrochemical oxidation. This included placing an
electrode in a formulation of hydrogen peroxide and a
drug, pouring electrons into the system, and observing
how long it took to oxidize the drug. The test lasted for
120 minutes before it was terminated “due to the destruc-
tion of the [hydrogen peroxide] under the experimental
conditions.” J.A. 27315. The least oxidatively stable drug
tested was amodiaquine, which oxidized in under one
minute; the most oxidatively stable drugs were clonidine
and brimonidine, which did not oxidize during the 120
minute test. Id. Thompson ultimately concluded that
“[c]lonidine and brimonidine proved to be oxidatively
stable in sharp contrast to [the other drugs tested].” J.A.
27312. There was no testimony that the Thompson test
was in any way inaccurate.
The sole reason the district court gave for dismissing
the Thompson reference was that it “teaches nothing
about the oxidative stability of brimonidine in a Purite®-
7 ALLERGAN INC v. EXELA PHARMSCI
containing formulation that needs to be shelf-stable for
two years.” In re Brimonidine Patent Litigation, 666 F.
Supp. 2d at 444 (emphasis added). But as the majority
appears to acknowledge, it was improper for the district
court to distinguish Thompson based on the fact that its
oxidation test lasted for only 120 minutes, rather than
two years, because “the claims [of the related patents] do
not require a particular period of shelf stability.” Maj.
Op. at 15.
Having accepted the fact that no shelf stability time
limit is mandated by the asserted claims of the related
patents, the majority must agree that, in view of the
teachings of Thompson, a PHOSITA would have known
that brimonidine would not oxidize in hydrogen peroxide
for a period of at least 120 minutes. The undisputed
evidence—including Dr. Stella’s testimony and Allergan’s
own promotional documents—establishes that a
PHOSITA would have known that hydrogen peroxide was
a stronger oxidant than Purite®. Because hydrogen
peroxide was known to be a stronger oxidant than Pu-
rite®, and Thompson disclosed that brimonidine is “oxida-
tively stable” in hydrogen peroxide for at least 120
minutes, a PHOSITA must have known that brimonidine
would be oxidatively stable in Purite® for at least 120
minutes. Even if the claims had included a two year
stability limitation, the knowledge that brimonidine
would be oxidatively stable in Purite® for some time
exceeding 120 minutes should have still been enough for a
PHOSITA to consider the combination of Alphagan® and
Refresh Tears® at least obvious to try.
While the district court’s dismissal of the Thompson
reference itself provides a sufficient ground for reversal
on the oxidation issue, the court made a second clearly
erroneous fact finding regarding oxidation. As an af-
ALLERGAN INC v. EXELA PHARMSCI 8
firmative basis for finding that a PHOSITA would have
had concerns that brimonidine would oxidize in Purite®,
the court credited Dr. Stella as having “testified that at
the time of these inventions, it was well-known in the art
that . . . the structural features of brimonidine made it
particularly susceptible to oxidation.” In re Brimonidine
Patent Litigation, 666 F. Supp. 2d at 444 (emphasis
added). Allergan agreed at oral argument that the testi-
mony the district court attributed to Dr. Stella regarding
brimonidine being “particularly susceptible” to oxidation
was “important” to the court’s finding of non-obviousness.
See Oral Arg. at 14:47–19:57, available at
http://www.cafc.uscourts.gov/oral-argument-
recordings/2010-1102/all. However, Dr. Stella did not
testify that brimonidine was “particularly susceptible” to
oxidation. The relevant portion of Dr. Stella’s testimony
reads:
[I]f you look at the structure of brimonidine, . . .
there are elements in the structure, for example,
there are nitrogens in a ring structure . . . .
That section of the molecules lends itself to, in
fact, what we call chlorination as well as N-oxide
formation.
J.A. 7918 (emphasis added). While Dr. Stella stated that
the structure of brimonidine “lends itself” to N-oxide
formation, he said nothing as to whether brimonidine was
“particularly susceptible” to oxidation in comparison to
other drugs. This is significant because the Thompson
reference disclosed that “brimonidine proved to be oxida-
tively stable in sharp contrast to [the other drugs tested],”
J.A. 27312 (emphasis added), which Dr. Stella’s actual
testimony does not refute. The district court’s finding
that oxidation concerns would teach away from the com-
9 ALLERGAN INC v. EXELA PHARMSCI
bination of Alphagan® and Refresh Tears® was simply
not supported by the record.
Because the undisputed evidence establishes that a
PHOSITA would have been motivated to try a combina-
tion of Alphagan® and Refresh Tears® to arrive at the
claimed formulation, and because the district court made
clearly erroneous fact findings in determining that solu-
bility and oxidation concerns would have deterred a
PHOSITA from trying this combination, I think that the
“obvious to try” standard has been satisfied. I respect-
fully dissent from the majority’s contrary conclusion.