In Cephalon, Inc. v. Watson Pharmaceuticals, Inc., the Federal Circuit reversed the district court’s finding that two Orange Book-listed patents for Cephalon’s FENTORA® product were invalid, but affirmed the district court’s finding that Watson’s ANDA product would not infringe the patents. The Federal Circuit decision reviews the “undue experimentation” standard for lack of enablement, and underscores the importance of aligning evidence of infringement with the governing claim construction.

The Patents At Issue

The two Orange Book-listed patents at issue were U.S. Patent 6,200,604 and U.S. Patent 6,974,590. The patents are directed to methods of administering a drug across the oral mucosa. The methods use formulations comprising effervescent agents that promote penetration across the buccal, sublingual, and gingival mucosae.

Claim 1 of the ’604 patent recites:

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.

(emphasis as added by the Federal Circuit)

Claim 1 of the ’590 patent recites:

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.

(emphasis as added by the Federal Circuit)

According to the patents, an “effervescent agent” includes at least one compound that evolves gas, and the “preferred effervescent agents evolve gas by means of a chemical reaction triggered by exposure of the effervescent agent (an effervescent couple) to water and/or saliva in the mouth.” For example, a reaction between a soluble acid source, such as citric acid, and a basic source of carbon dioxide, such as an alkaline carbonate or bicarbonate, would evolve carbon dioxide gas.

According to the patents, “the dosage form preferably includes an effervescent couple comprising both the acid source and a source for carbon dioxide.” However, the district court construed the claims as reciting only a single effervescent agent.

The ANDA Litigation

FENTORA® is a fentanyl buccal tablet approved for the treatment of breakthrough cancer pain. As set forth in the Federal Circuit decision, FENTORA® contains fentanyl citrate, mannitol, sodium starch glycolate, magnesium stearate, citric acid, sodium bicarbonate, and sodium carbonate, with the sodium bicarbonate and citric acid forming an effervescent couple that react to evolve carbon dioxide.

Watson filed an Abbreviated New Drug Application (“ANDA”) seeking approval to market a generic version of FENTORA®, and including a Paragraph IV certification against the patents. As set forth in the Federal Circuit decision, Watson’s ANDA products contain the active ingredient fentanyl citrate and the inactive ingredients mannitol, sodium starch glycolate, potassium bicarbonate, and magnesium stearate.

In response to Watson’s Paragraph IV certification, Cephalon, Inc. and CIMA Labs, Inc. (collectively, “Cephalon”) brought suit in the U.S. District Court for the District of Delaware. The district court found that the patents were invalid for lack of enablement and would not be infringed by Watson’s product. On appeal, the Federal Circuit reversed on enablement and affirmed on non-infringement.

Enablement

As noted above, the district court construed “effervescent agent” as requiring the presence of a single compound that “evolves gas by means of an effervescent reaction.” The enablement issue therefore turned on whether the patents enabled methods where the soluble acid source of the effervescent reaction is administered in a separate dosage form from the effervescent agent.

The Federal Circuit found two main faults with the district court’s determination of lack of enablement:

First, the district court improperly shifted the burden to Cephalon:

As an initial matter, the district court determined that Watson established a “prima facie” case of lack of enablement and that Cephalon failed to “rebut” Watson’s prima facie case. …. Actually, the burden of proof was Watson’s alone. Because we must presume a patent enabled, the challenger bears the burden, throughout the litigation, of proving lack of enablement by clear and convincing evidence.

Second, the district court found lack of enablement based on the need to carry out some experimentation, without any factual basis for finding that it would require an undue amount of experimentation to provide the effervescent agent and acid in separate dosage forms:

The question of undue experimentation is a matter of degree, and what is required is that the amount of experimentation not be “unduly extensive.” … For example, the fact that a clinician’s involvement may be necessary to determine effective amounts of the single compound effervescent agent and its corresponding soluble acid source does not itself constitute undue experimentation. …. In addition, extensive experimentation does not necessarily render the experiments unduly extensive where the experiments involve repetition of known or commonly used techniques. …. Thus, the focus “is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance. ….

The Federal Circuit acknowledged that “[p]ermissible experimentation is, nevertheless, not without bounds,” but found that Watson had not met its burden of presenting “testimony or documentary evidence [of] the amount of experimentation needed to calculate a formulation for coadministering a soluble acid source in one form of dosage with a carbonate source in another form to achieve the claimed effervescent reaction.” The Federal Circuit emphasized that Watson’s expert’s conclusory testimony that “co-administration would be ‘difficult’ and ‘complicated’ cannot be enough to constitute clear and convincing evidence.

Non-Infringement

The infringement issue turned on whether the potassium bicarbonate and mannitol in the Watson products would undergo an effervescent reaction in saliva. Because Cephalon only had provided evidence on the acid properties of mannitol in water, the Federal Circuit upheld the district court’s finding of non-infringement.

Thus, Cephalon was able to restore the validity of these patents. And, even though Cephalon lost on the infringement claims, according to Watson’s press release, a third patent will keep Watson’s ANDA products off the market until October of 2019.

What About Written Description?

The Federal Circuit decisions states that the district court found that the patents “lacked teachings directed to formulating and co-administering two separate dosage forms—one including a soluble acid source and the other containing the effervescent agent—to achieve an effervescent reaction.” Would Watson have been able to invalidate the patents based on lack of written description?