By Andrew Williams —

Last
week, in Pozen Inc. v. Par
Pharmaceutical, Inc., the Federal Circuit affirmed the decision of the U.S.
District Court for the Eastern District of Texas that two patents that describe
treating migraines by combining two known drugs in a single dose had not been shown
to be obvious or inadequately described, and that in addition to these patents
being infringed by three separate ANDA filers, two generic drug companies were also
found to infringe a third patent to a co-formulated tablets under the doctrine
of equivalents.  The Federal Circuit
agreed that the prior art would not have provided a motivation to combine these
two drugs to a person of skill in the art, and therefore could not render the
patent invalid for obviousness.  The
Court also agreed that one of ordinary skill in the art would understand that
the inventors had possession of packaging or instructions for the use of their
tablet.  With regard to infringement, the
Federal Circuit agreed that Pozen did not need to show testing to establish that
the limitation "independent dissolution" was met by the doctrine of
equivalents.  Finally, the majority held
that even though "substantially all" was already a "fuzzy"
term, it was still entitled to equivalents.

The
reference drug product at issue in this case was Treximet®, which is a
combination of sumatriptan, a 5-HT receptor agonist effective at treating
migraines, and naproxen, a widely known non-steroidal anti-inflammatory drug ("NSAID").  Pozen markets Treximet® in partnership with
GlaxoSmithKline, and holds three patents to the co-administration of these
drugs.  The claims at issue in this case
include:

•
claim 15 of U.S. Patent No. 6,060,499 ("the '499 patent"), drawn to
therapeutic packages for dispensing one or more unit doses of sumatriptan and
naproxen at specific concentrations;

•
claims 11, 12, 24, 26, 27, 29, and 30 of U.S. Patent No. 6,586,458 ("the '458
patent"), drawn to pharmaceutical compositions in unit dosage forms which
comprise a 5-HT agonist and a long-acting NSAID; and

•
claim 2 of U.S. Patent No. 7,332,183 ("the '183 patent"), drawn to a
multilayer pharmaceutical tablet in which "substantially all" of the
5-HT agonist is in the first layer, and "substantially all"  of the naproxen is in the second layer, and
in which the dissolution of the naproxen occurs independently of the other
drug.

Three
generic companies, Par Pharmaceuticals, Inc. ("Par"), Alphapharm Pty
Ltd. ("Alphapharm"), and Dr. Reddy's Laboratories, Inc. ("DRL")
(collectively "Appellants") filed three separate ANDAs to market
generic versions of Treximet®.  In turn,
Pozen filed suit in the Eastern District of Texas.  The lower court held a claim construction
hearing, followed by a five-day bench trial in which the patents-in-suit were
held to be valid and infringed, either literally or under the doctrine of
equivalents.  However, after the claim
construction ruling and before trial, Pozen stipulated to a judgment of
non-infringement of the '183 patent in favor of Alphapharm, and therefor
Alphapharm's only interest in the appeal was the validity of the '499 and '458
patents.

Validity –
Non-obviousness

The
first issue related to the lower court's non-obviousness determination that the
Federal Circuit addressed was whether the claims required "simultaneous
administration" of the two drugs.  Par pointed out that all of the claims recited the limitation "concomitant
administration," and because the District Court construed this term to
mean "[g]iven in close enough temporal proximity to allow their individual
therapeutic effects to overlap," than the two drugs in the prior art need
not have been administered at the same time.  However, the Federal Circuit was not persuaded, because all of the
asserted claims also contained the limitation "unit dose form," "unit
doses," or "unit dosage form(s)," and all parties agreed that
these terms meant "single drug administration entity(ies)."  Therefore, irrespective of the fact that the
claims had the broader term, the "unit dose" limitation necessarily
limited the claims to "simultaneous administration."

Even
though this claim construction issue would have been determinative for an
anticipation allegation, a reference that discloses administration of two
drugs, albeit not at the same time, could still render a simultaneous-administration
claim obvious to one skilled in the art.  Therefore, the Court analyzed each of the four cited references.  Interestingly, most, if not all, of these
references evidenced the actual administration of these two drugs to at least
one patient in "temporal proximity" to each other.  Nevertheless, because these references did
not tout the advantages of the combination of these drugs, they could not be
used as motivation to combine sumatriptan and naproxen.  In fact, most of the references highlighted
other factors for the patients' positive response.  For example, one of the patients in one of
the references was also receiving acupuncture, and the authors attributed this
to the successful treatment of the patient's migraines.  A second factor considered by the Court for
at least some of these references was that they did not disclose the "efficacy
limitations" recited in the claims.  One could argue that the particular efficacy would be "inherent"
in the co-administration of the drugs, but it is important to keep in mind that
one skilled in the art would not have been motivated to combine these drugs to
obtain this result without an explicit teaching.  As a result, the panel agreed with the District Court that appellants failed to meet their burden to rebut the
presumption that one of ordinary skill in the art would not have combined these
two drugs in order to benefit from the longer lasting efficacy as compared to
taking either agent alone.

Par
also alleged that the '183 multilayer tablet patent was obvious in view of the '499
patent combined with the prior art or the knowledge of a person of ordinary
skill in the art.  Par argued that the
prior art taught that naproxen has low solubility in the stomach, which would
impede the dissolution of sumatriptan if co-administered, and that multilayer
tablets were well known in the art.  However, during prosecution, the Patent Office had allowed these claims
even in view of similar art.  Moreover,
the fact that multilayer tablets were commonly used did not necessarily mean
that Pozen's claimed dosage form of these two drugs was obvious.  Par also alleged that the lower court used
two different meanings of "independent dissolution" in its
infringement analysis and its validity analysis, but the Federal Circuit failed
to see the difference.  Therefore, the
Court concluded that appellants had failed to rebut the presumption of validity
of these claims.

Validity – Written
Description

Appellants
also alleged that claim 15 of the '499 patent lacked an adequate written
description because it contained the limitations "therapeutic package,"
"finished pharmaceutical container," and "said container further
containing or comprising labeling directing the use of said package in the
treatment of migraine," all of which were added during prosecution, but
none of which appear in the specification.  The Federal Circuit, however, did not take such a narrow view of the
requirement of 35 U.S.C. § 112, ¶ 1.  Instead, what is required is that the specification reasonably convey to
a skilled artisan that the inventor had possession of the invention.  Moreover, a person comes to the patent with
the knowledge of what has come before.  Therefore, because it was well known in the art that pharmaceutical
dosages are administered in containers or packaging with labels and inserts containing
instructions, such information need not be explicitly disclosed in the
specification.

The
slightly troubling aspect of the Court's decision is that it appears to have taken
the position that because the use of packaging or instructions would have been
obvious at the time of filing, such information need not have been included in
the specification.  Unfortunately, what
is missing from the decision is why these limitations were added in the first
place.  If they were added to overcome cited
art, it would be somewhat inconsistent to say that the other prior art can
provide the support for the new limitation being used to distinguish the
invention.  Nevertheless, appellants did
not make such an argument, so any potential inconsistency was not in front of
the Federal Circuit.

Infringement

Because
the Court affirmed the lower court's finding of validity of the '499 and '458
patent claims, and because apparently none of the three defendants challenged
the finding of infringement with regard to these two patents, the injunction
preventing all three ANDA filers from making or selling their respective
products would have been maintained based solely on these patents.  Nevertheless, Par and DRL appealed the
finding that their respective ANDA products infringed claim 2 of the '183
patent multilayer tablet patent under the doctrine of equivalents.  Pozen had stipulated to a judgment of
non-infringement of the '183 in favor of Alphapharm, and so it had no interest
in this part of the appeal

The following is a reproduction of claims 1
and 2 of the '183 patent:

1. 
A multilayer pharmaceutical tablet comprising naproxen and a triptan and,
wherein: a) substantially all of said triptan is in a first layer of said
tablet and substantially all of said naproxen is in a second, separate layer;
and b) said first layer and said second layer are in a side by side arrangement
such that the dissolution of said naproxen occurs independently of said
triptan.

2.  The tablet of claim 1, wherein said naproxen is in the form of naproxen
sodium at between 200 and 600 mg.

Par
and DRL first challenged the finding of infringement with respect to the "independent
dissolution" limitation.  The
parties had agreed that this limitation required that "[d]issolution of
naproxen . . . and triptan from the multilayer tablet occurs in the same amount
of time ± 10% as when the same amount of naproxen . . . and triptan are given
separately."  Both Par and DRL
complained that no evidence was presented at trial demonstrating that the
comparison as required by the claims was ever undertaken.  The District Court, however, found the
required evidence in the FDA filings of these two companies, as well as the
expert testimony.  The Federal Circuit
took it a step further, noting that under the doctrine of equivalents, Pozen
was not required to show an actual comparison.  Instead, Pozen only needed to show that the ANDA products performed the
same function in the same way to achieve the same result as the claimed
element.  This, of course, begs the
question of how you can show the same result without testing, but the Court
nevertheless concluded that Par and DRL presented no basis for setting aside
the finding of infringement.

In
addition, Par and DRL challenged the finding of equivalents to the claim term "substantially
all."  This term was construed consistent
with the specification to mean that "at least 90%, and preferably greater
than 95%, of the total triptan present in the tablet is included within one distinct
layer and at least 90%, and preferably greater than 95%, of the naproxen
present in the tablet is included within a second distinct layer."  Par formulated its tablet to avoid
infringement, putting only 85% of the tablets naproxen in the second layer.  Conversely, DRL formulated its tablet to have
only 85% of its sumatriptan in one of the layers.  Par argued that the word "substantially"
was "fuzzy," and itself was already being used to capture values
lower than 100%.  Therefore, it argued,
the claims should not be found to encompass equivalents of equivalents.  DRL argued that the scope of equivalents was
already within the scope of the claim, and therefore the District Court had erred
in granting a range beyond this.  The
majority pointed out, however, that the doctrine of equivalents is not
foreclosed just because a range is claimed.  As such, the change from 90% to 85% could be fairly characterized as an insubstantial
change.  Moreover, the Court did not find
that the District Court had erred in finding that the ANDA products had the
same function of having "separate, distinct layers of sumatriptan and
naproxen," that they achieved this function in the same way, by creating
physical barriers, and that the result was the same — separating the naproxen
from the sumatriptan.

Judge
Clevenger dissented with respect to this finding.  He noted that the District Court never
directly addressed the issue whether a layer with 85% was an equivalent to a
layer of 90%, and preferably 95%.  Instead,
he believed that the lower court skirted the numerical equivalents issue by
only asking whether the accused product had the equivalent of a second layer
with substantially all of the required ingredient.  He, therefore, would not have affirmed this
finding.

Pozen Inc. v. Par
Pharmaceutical, Inc. (Fed. Cir. 2012)
Panel:
Circuit Judges Newman, Clevenger, and Wallach
Opinion
by Circuit Judge Wallach; dissenting-in-part opinion by Circuit Judge Clevenger