By
Andrew Williams —

Can
a method of treatment claim be inherent in the prior art if neither the
formulation nor the method of using the formulation twice a day were in the
prior art?  Earlier today,  the Federal
Circuit determined in Allergen
v. Sandoz that a claimed method for treating glaucoma (which
differed from the three-times-a-day dosage regimens required of the individual
components) was not inherently obvious, and thereby prevented a group of generic challengers from being
able to market their own versions of Combigan^® before the expiration
of the patent containing the claimed method.  However,
Judge Dyk, dissenting-in-part, found no difference between the instant case and Federal Circuit
precedent — although the precedent relied upon was all directed to inherent
anticipation.  Nevertheless, the majority
and dissent agreed that the claims directed to the formulation itself were
obvious in view of the prior art, and therefore reversed the lower court's
finding of validity of all the claims.

This
case involved Allergan's formulation for a combination eye-drop product marketed
as Combigan^®, a product which combines a well-known alpha₂-agonist
Alphagan^® (0.2% brimonidine) and a well-known beta-blocker Timoptic^®
(0.5% timolol).  Allergan had found that
by co-formulating these drugs, patient compliance increased because the drugs
could now be administered at the same time, and because (unexpectedly) the
number of daily administrations could be dropped from 3 to 2.  The inventors obtained four patents on this
formulation and methods of its use, all stemming from an application filed on
April 19, 2002, which Allergan listed in
the Orange Book.  For the purposes of the
appeal, the parties treated almost all of the asserted claims as one group, referring
to claim 1 of U.S. Patent No. 7,323,463 ("the '463 patent") as the
representative claim, which read:

1.  A composition comprising about 0.2% timolol by weight and about 0.5%
brimonidine by weight as the sole active agents, in a single composition.

The
only other asserted claim was claim 4 of U.S. Patent No. 7,030,149 ("the '149
patent"), which read:

4.  A method of reducing the number of daily topical ophthalmic doses of
brimondine administered topically to an eye of a person in need thereof for the
treatment of glaucoma or ocular hypertension from 3 to 2 times a day without
loss of efficacy, wherein the concentration of brimonidine is 0.2% by weight,
said method comprising administering said 0.2% brimonidine by weight and 0.5%
timolol by weight in a single composition.

Sandoz
Inc., Alcon Laboratories, Inc., Alcon Research Ltd., Alcon, Inc., and Falcon
Pharmaceuticals, Ltd. (collectively, "Sandoz"), and the other
defendants Apotex Inc. and Apotex Corp., and Watson Laboratories, Inc., each
filed Abbreviated New Drug Applications with the FDA seeking to market generic
versions of Combigan^®.  In
turn, Allergan sued them under 35 U.S.C. § 271(e)(2)(A).  After a claim construction determination, the
lower court granted summary judgment of non-infringement as to claims 1-3 of
the '149 patent, and the parties stipulated to infringement of the remaining
claims.  After a bench trial, the District Court found all of the claims nonobvious over the prior art.  The defendants appealed.

The
Formulation Claims – Claim 1 of the '463 Patent as Representative

The
lower court had rejected an invalidity allegation that Claim 1 of the '463
patent was obvious primarily in view of U.S. Patent No. 5,502,052 ("DeSantis").  This reference taught the use of a
combination of alpha₂-agonists and beta-blockers for treating
glaucoma, but did not teach that brimonidine could be one of those alpha₂-agonists.  Nevertheless, DeSantis incorporated by
reference a publication by Timmermans, which disclosed brimonidine and its
tartrate salt.  Also, even if not
mentioned by name, the ranges of the components of claimed formulations fell
within the ranges as taught by DeSantis — 0.02 to 2.0% alpha₂-agonist
and 0.01 to 3.0% beta-blocker.  Also in
the art was a reference that taught the topical administration of 0.2%
brimonidine with 0.5% timolol in combination, although spaced five minutes
apart, and the fact that it was common to dose the serial application of these
two drugs twice a day.  Moreover, there
were only three known pharmaceutically acceptable alpha₂-agonists at
the time for the treatment of glaucoma — clonidine, apraclonidine, and
brimonidine.  The Federal Circuit did not
necessarily disagree with any of the factual findings of the lower court
related to obviousness, but instead reversed because it believed that the facts
instead supported a finding of obviousness.

Motivation
to Combine

The
lower court relied heavily on the fact that there would be no motivation to
develop fixed combination products, even though such formulations might improve
patient compliance, because the FDA does not consider patient compliance as a
factor when approving new formulations.  The Federal Circuit noted that FDA approval might be a factor in an
obviousness determination, for example when determining whether there was
motivation to develop a drug or whether there was skepticism regarding
efficacy.  However, it also noted that motivation
to combine may be found in many different places, not just in the rationale used
by the FDA as a basis for its approvals.  In view of the overwhelming amount of prior art related to the claimed
formulation, the Federal Circuit thought there was sufficient support to find a
motivation to combine, notwithstanding the FDA's approval process.  Somewhat lacking in the analysis, however, was
how the FDA's position regarding patient compliance does factor into the
obviousness determination.

Reasonable
Expectation of Success

The
lower court found that the unpredictability in the chemical arts weighed in
favor of a finding of nonobviouness.  As
a factor, the District Court considered Allergan's challenges formulating Combigan^®.  The Federal Circuit did not agree, because
some degree of unpredictability is fine, provided there is a reasonable
probability of success.  In this case,
DeSanits provided that reasonable probability.  Moreover, Allergan's formulation
difficulties stemmed from the fact that it was attempting to use a proprietary
preservative.  There is no record of
continued difficulties once its scientists switched to a commonly used
preservative.  The fact that the claims were not drawn to the precise
formulation Combigan^® was important, because there is no requirement
that there be a reasonable expectation of success in formulating Combigan^®.

Teaching
Away

The
lower court had found factors that taught away from the claimed formulation,
including the potential side effects, differing dosing regimens, and disparate
half-lives of brimonidine and timolol.  However, as the Federal Circuit explained, the District Court did not
consider the impact that these factors would have on the clear motivation to
combine (probably because it did not find a motivation to combine).  Interestingly, the Federal Circuit pointed
out that the lower court did not find that the prior art as a whole taught away from the claimed invention.  The Court, therefore, accepted the factual
findings from below, but concluded that they did not render the invention
nonobvious.

Secondary
Factors

Finally,
the Federal Circuit accepted all the lower court's factual findings with regard
to secondary considerations of nonobviousness, but still found that they did
not weigh heavily enough to overcome obviousness of the claims.  With regard to long-felt need, the District Court's findings were apparently entirely conclusory.  With regard to unexpected results, the lower
court had found that the claimed formulations were able to overcome previous
difficulties in treating patients with twice-per-day dosage regimens.  The Federal Circuit thought this was somewhat
irrelevant.  The Court did agree that
these results were unexpected.  However, while
such results might be meaningful to method of treatment claims, they were not
as relevant to the formulation claims.

The
Method-of-Treatment Claim – Claim 4 of the '149 Patent

As
shown above, the treatment claim has a couple of relevant limitations,
including the above-referenced formulation of brimonidine and timolol, and the
use of this formulation twice a day with the same efficacy as brimonidine administration three times a day.  The problem with administering brimonidine only twice a day was that efficacy would drop eight to nine
hours after administration, in a phenomenon referred to as "afternoon
trough."  The majority found that
the defendants did not establish by clear and convincing evidence that the
claimed method would have been obvious.  Importantly, the defendants apparently did not argue that the "efficacy
limitation" is inherent to all fixed combination products containing brimonidine
and timolol, or that a dose reduction would inherently flow from the obvious
formulation included in the claims.  And,
the defendants' citation to the success in using timolol with other non-alpha₂-agonist
ophthalmic drugs with reduced doses was found to be irrelevant, because there
was no reason why the use of these unrelated drugs would make the claimed
method obvious.

Judge
Dyk, in dissent, disagreed — he would have also reversed the finding of
nonobviousness of this claim.  He relied
heavily on his belief that the method claim only contained one step — applying
a fixed combination of 0.2% brimonidine and 0.5% timolol twice a day.  It was not explained, however, why he
considered two administrations to be a single step.  Nevertheless, Judge Dyk believed that the twice-a-day
dosing of a formulation that was not in the prior art would have nonetheless
been obvious to one skilled in the art, and that the alleged avoiding-"loss
of efficacy" limitation was just the result of the claimed method.  As support for this proposition, Judge Dyk
cited to three Federal Circuit cases:  Abbott
Labs. v. Baxter Pharm. Prods., 471 F.3d 1363 (Fed. Cir. 2006); In re Cruciferous Sprout Litig., 301
F.3d 1343 (Fed. Cir. 2002), and Bristol-Myers
Squibb Co. v. Ben Venue Labs., 246 F.3d 1368 (Fed. Cir. 2001).  However, each of these cases relates to
inherent anticipation, not inherent obviousness.  It is not self-evident that the reasoning
behind allowing the inherent result flowing from the use of a prior art
composition or method to anticipate a claim would apply with equal force to a
composition or method that was only obvious in view of the prior art.  In other words, citation of these cases,
without more, is like comparing apples with oranges.

Moreover,
Judge Dyk does not appear to consider the fact that there were two limitations
that were not taught in the prior art — the formulation and its method of
use.  It should not be sufficient to
conclude that, just because a formulation was obvious, any method of using it
must also be.  Granted, this case would
have been completely different if the claimed formulation was taught in the
prior art, and the only potentially obvious limitation was its use twice a
day.  In such a case, it is possible that
its use might have been obvious, and the "efficacy" result that
flowed from it could therefore have been inherent.  This is, perhaps, why the majority agreed in
footnote 1 that "the inherency doctrine may apply to an otherwise obvious
claim" in some situations.  Nevertheless, this was not the case and, without more, the majority's
position was more grounded in the facts of the case, and in the Court's
precedent.

Allergan,
Inc. v. Sandoz Inc. (Fed. Cir. 2013)
Panel: 
Circuit Judges Dyk, Prost, and O'Malley
Opinion
for the court by Circuit Judge Prost; opinion concurring-in-part and
dissenting-in-part by Circuit Judge Dyk