Cadence Pharms., Inc. v. Exela PharmSci Inc.

Federal Circuit affirms district court’s findings that the patents-in-suit are valid and infringed.

Spring 2015

GENERICally Speaking

Case Name: Cadence Pharms., Inc. v. Exela PharmSci Inc., 2014-1184, 2015 U.S. App LEXIS 4700 (Fed. Cir. Mar. 23, 2015) (Circuit Judges Reyna, Linn, and Wallach presiding; Opinion by Lynn, J.) (Appeal from D. Del., Stark, J.)

Drug Product and Patents-in-Suit: Ofirmev® (aqueous, injectable acetaminophen); U.S. Patents Nos. 6,028,222 (“the ’222 patent”) and 6,992,218 (“the ’218 patent”)

Nature of the Case and Issue(s) Presented: In aqueous solutions, acetaminophen decomposes into products that are potentially toxic to humans. The ’222 patent addresses the toxicity by adding a buffering agent and a free-radical-capturing agent to the acetaminophen solution. Relatedly, the ’218 patent teaches a method of stabilizing aqueous acetaminophen by bubbling the solution with an inert gas and/or placing the solution under a vacuum until the oxygen concentration of the solution is less than 2 parts per million. Further, the ’218 patent’s claims describe optionally topping the solution with inert gas.

The district court found that both patents were valid in light of the prior art, and ruled that the ’222 patent was literally infringed. Although Exela did not literally infringe the ’218 patent, the method of creating its ANDA product was insubstantially different from the patented method. Thus, Exela infringed the ’218 patent under the doctrine of equivalents. Exela appealed the district court’s decision that the patents-in-suit were infringed by their ANDA product, and also appealed the district court’s determination that the ’218 patent was valid. The Federal Circuit affirmed.

Why Cadence Prevailed:  Exela’s argument on appeal relating to the ’222 patent was based solely on the district court’s construction of the term “buffering agent” in that patent’s only independent claim. The district court construed the term to mean “[a]n agent that helps the formulation resist change in pH.” Exela argued—as it did during claim construction below—that the buffering agent must be present in a concentration sufficient to “resist material changes in pH.” Exela relied on statements in the specification that buffer concentration “may be” between 0.1 and 10 mg/ml, specific embodiments disclosed by the patent, and the fact that the term “buffering agent” was added to overcome an office action during the prosecution of the patent. The Federal Circuit, like the district court, disagreed. The Federal Circuit found that the specification’s references to concentrations that “may be” within a specific range was not enough to import an additional limitation into the claims. Similarly, the specification’s description of buffer concentrations in particular embodiments also did not limit the claims. Finally, while the term “buffering agent” was added to the claim during prosecution, the amendment required only that a buffering agent be present in the solution, but did not require a particular concentration.

Next, Exela challenged the district court’s rulings on three grounds: (i) reducing the amount of oxygen before acetaminophen is added solution is substantially different from reducing the amount of oxygen after acetaminophen is added; (ii) the district court erred in construing the “vacuum stoppering step” utilizing a layer of inert gas as “optional;” and (iii) the claims of the ’218 patent should be deemed obvious in light of the prior art.

The Federal Circuit rejected each argument in turn. The district court appropriately credited Cadence’ expert testimony that it was irrelevant whether acetaminophen was added to the solution before or after the solution was deoxygenated. In either case, the preparation of the solution involved bubbling for a prolonged period of time to reach an oxygen concentration less than 2 ppm. Further, the fact that Exela’s ANDA product—which deoxygenates the solution prior to the addition of acetaminophen—is stable was further evidence that its formulation was not substantially different from the process described by the ’218 patent. Exela argued that deoxygenating prior to adding an active ingredient was the antithesis of deoxygenating after the ingredient was added and that so doing would vitiate the claim. The Federal Circuit found that Exela’s vitiation argument was misplaced, holding that vitiation is not a threshold determination for equivalents, but rather a conclusion that is drawn based on the evidence presented. Here, there was no vitiation. Exela’s process infringed the ’218 patent because Exela’s process was insubstantially different from the process taught by the patent.

Exela also argued that the “vacuum stoppering step” was not optional, despite clear language in the claim to the contrary (“optionally the aforementioned aqueous solution with an active principle is topped with an inert gas atmosphere heavier than air. . .”). Exela again pointed to the prosecution history of the patent, in which the applicants mentioned vacuum stoppering as a factor in providing a stable solution. But the Federal Circuit found no clear evidence the applicants were using vacuum stoppering as a contrast to overcome the cited reference. Faced with the plain language of claim, which explicitly stated vacuum stoppering was optional, the Federal Circuit was not prepared to find a disclaimer sufficient to change the meaning of the claim. Absent a clear and unmistakable disavowal, the claims were given their plain and ordinary meaning.

Finally, Exela argued that the ’218 patent was obvious in light of the ’222 patent in combination with an article by A. Palmieri. It was undisputed that the only difference between the ’222 patent and the ’218 patent was the latter’s disclosure to reduce the oxygen content of the acetaminophen solution to a concentration less than 2 ppm. The Palmieri article taught that deoxygenating a pyrogallol solution below 0.05 ppm increased the stability of the solution. It would have been obvious, Exela argued, for a person of ordinary skill to combine the references and apply Palmieri’s teachings to acetaminophen solutions. The Federal Circuit disagreed. Pyrogallol solutions degrade by oxidation, whereas acetaminophen degrades primarily through hydrolysis. As such, a skilled person would not have looked to Palmieri to solve the degradation problems of acetaminophen solutions. Further, the unexpected success in stabilizing the solution, as well as licensing the product, supported a finding of nonobviousness.

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