By Kevin E. Noonan —

Whether
ANDA litigation has had a positive or negative impact on generic drug
availability is an open question, in view of several recent reports looking at
the effects such litigation has had on both branded and generic drugs over the
past thirty years.  Indeed, the current squabble
over "reverse payment" settlement agreements of lawsuits under the
ANDA provisions of the Hatch-Waxman Act (codified at 35 U.S.C. § 271(e)(2))
involves many of these same issues, revolving around the question of whether it
is prudent for both branded and generic parties of ANDA lawsuits to settle
rather than wage protracted, often pyrrhic, patent litigation (see "FTC Releases Another Report on Reverse Payment Settlement Agreements in ANDA Litigation").  Occasionally, of
course, both parties get an outcome they can live with, and one such occasion
occurred today in Cephalon v. Watson
Pharmaceuticals, where the Federal Circuit affirmed a District Court
decision that the generic drug did not infringe the patent-in-suit but reversed
the District Court on the issue of whether the patents were invalid for lack of
enablement.

The
case involved a formulation of fentanyl, an opioid sold by NDA holder Cephalon
under the brand name FENTORA®.  Cephalon
listed U.S. Patent Nos. 6,200,604 and 6,974,590 in the Orange Book and asserted
both patents in response to Watson's ANDA filing; claim 1 of the '604 patent:

1.  A method of
administering at least one systemically distributable pharmaceutical agent
across the oral mucosa comprising:
    a) providing a
solid oral dosage form including a pharmaceutically effective amount of an
orally administerable medicament; and at least one effervescent agent in an
amount sufficient to increase absorption of said orally administerable
medicament across the oral mucosa; wherein said orally administerable medicament
is not substantially encompassed by or dispersed in a material that prevents
absorption of said medicament across the oral mucosa;
    b) placing said
solid oral dosage form in the mouth of a patient so that saliva in said patient's
mouth activates said at least one effervescent agent in said tablet; and
    c) holding said
solid oral dosage form and the dissolving contents of said solid oral dosage
form in the mouth of a patient whereby said at least one effervescent agent
promotes absorption of said orally administerable medicament across the oral
mucosa.

and
claim 1 of the '590 patent:

1. A method of administration of
fentanyl to a mammal across the oral mucosa thereof, said method comprising:
    providing a solid
oral dosage form comprising fentanyl or a pharmaceutically acceptable salt
thereof and at least one saliva activated effervescent agent in an amount
sufficient to increase absorption of said fentanyl or pharmaceutically
acceptable salt thereof across said oral mucosa, at least one pH adjusting
substance, and wherein said amount of said at least one effervescent agent is
between about 5% by weight and about 80% by weight; and buccally, sublingually
or gingivally administrating said solid oral dosage form to said mammal.

are
representative (emphases in original
opinion).

The
formulation involved orally administered fentanyl designed to use the mucosal
membranes of the mouth and oral cavity to introduce the drug into the body
(thus avoiding the gastrointestinal tract).  The claims of the patents-in-suit were directed to the use of effervescent
agents as penetration enhancers to promote uptake of fentanyl (or other drugs)
into the oral mucous membranes.  In
addition, the patent claims included in the formulation a "pH adjusting
substance" that worked together with the effervescent agent in promoting
drug uptake.  As explained in the
Federal Circuit opinion, effervescence agents falling within the scope of the
patent claims included "at least one compound that evolves a gas,"
typically via a chemical reaction between the agent and water (saliva) in the
mouth.  These agents included an acid
source, such as citric acid, and a carbon dioxide source (such as carbonate or
bicarbonate), wherein the reaction resulted in carbon dioxide production.  The pH adjusting substance was included
because the effervescence reaction reduces the pH of saliva in the mouth, which
can affect the solubility of fentanyl or other drug in the formulation.

The District Court found that Watson's ANDA
product did not infringe, based on its construction of the claim term "at
least one [saliva activated] effervescent agent in an amount sufficient to
increase absorption . . . across [the] oral mucosa."  In the District Court's construction, the
effervescent agent was required to be activated by contact with saliva, which
raised the question of whether the potassium bicarbonate and mannitol
components of Watson's accused infringing generic drug reacted to have this
effect.  (Cephalon's Fentora® product
contained fentanyl citrate, mannitol, sodium starch glycolate, magenesium
stearate, citric acid, sodium bicarbonate, and sodium carbonate, wherein the
sodium bicarbonate and citric acid are an effervescent couple that react to
evolve carbon dioxide, whereas Watson's generic version contained fentanyl
citrate and mannitol, sodium starch glycolate, potassium bicarbonate, and
magnesium stearate.)  The District Court
did not credit Cephalon's expert's testimony that mannitol was the acidic
component of an effervescent agent, despite testimony that the higher the
mannitol concentration levels the more acidic a water solution containing it, in part because Cephalon provided no
evidence of the effect of mannitol on saliva.  Rather, the Court determined that Watson's
expert was more persuasive when he testified that "the important piece of information that
is missing [in this case] is what the potential or alleged acidity of mannitol
in either artificial saliva or, even more important, in the human mouth . . .
and there is no evidence that mannitol would be acidic under those conditions."

Regarding invalidity, the District Court
construed the term "effervescent agent" to require that "at
least one compound that evolves gas by means of an effervescent reaction"
(emphasis in original opinion) and further determined that the claim language
required the "effervescent agent" to be a single compound.  Watson argued that the "effervescent
agent" is disclosed in the Cephalon patents as comprising a "couple"
(the acidic compound and the carbon dioxide-releasing compound) and thus that
the term should require "a combination of two or more compounds that
evolve gas."  Under the District Court's construction, the soluble acid
source must be in a separate dosage form from the effervescent agent itself and
that these separate dosage forms be co-administered.  Using this construction, the District Court
found that the patents-in-suit were not enabling, being devoid of any
disclosure relating to co-administration of two separate dosage forms and thus
requiring undue experimentation.

The Federal Circuit reversed in part and
affirmed in part, in an opinion by Judge Wallach joined by Judges Bryson and
Reyna.  The opinion affirmed the finding
of no infringement on the grounds that there was no clear error by the District Court in deciding in Watson's favor on this issue.  With regard to invalidity, the panel noted
that the District Court erred by reasoning that Watson had raised a prima facie case of non-enablement
against Cephalon's claims, which Cephalon did not rebut at trial.  The panel, citing Morton Int'l, Inc. v.
Cardinal Chem. Co., 5 F.3d 1464, 1469–70 (Fed. Cir. 1993), invoked the
statutory presumption of validity in asserting that this was error, and that
the challenger (Watson) bore the burden of proving invalidity by clear and
convincing evidence.  Turning to this
question, the panel considered the District Court's reliance on Watson's
proffered expert testimony that amounted (according to the Federal Circuit) to
mere "ipse dixit" opinion
that did not rise to the level of clear and convincing evidence.  And the District Court's interpretation of
Cephalon's expert's testimony regarding whether experimentation per se would be required to satisfy the
enablement portion of the statute in view of the District Court's claim
construction was also improper, according to the opinion, because the mere fact
of experimentation is not the standard; the question is whether whatever
experimentation that may be required is undue.  Here, the Federal Circuit considered Watson's showing that the extent of
experimentation that might be required was undue to be insufficient to arise to
the level of clear and convincing evidence.  Specifically, the panel stated that "[u]nsubstantiated statements
indicating that experimentation would be 'difficult' and 'complicated are not
sufficient" to establish undue experimentation.  Thus, Watson had failed to establish
non-enablement as a matter of law and the panel reversed.

Cephalon, Inc. v. Watson
Pharmaceuticals, Inc.
(Fed. Cir. 2013)
Panel: Circuit Judges Reyna, Bryson, and Wallach
Opinion
by Circuit Judge Wallach