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Pharmacokinetic Claim Terms Need Not Refer to Complete FDA Regulations, and Infringement May Be Proven with Indirect Evidence and Through DOE

August 05, 2010
Stanley, Robert C.

Decision icon Decision

Last Month at The Federal Circuit - September 2010

Judges: Linn, Moore (author), Friedman

[Appealed from: W.D. Mich., Judge Quist]

In Adams Respiratory Therapeutics, Inc. v. Perrigo Co., No. 10-1246 (Fed. Cir. Aug. 5, 2010), the Federal Circuit vacated the district court’s claim construction and grant of SJ of noninfringement in favor of defendant Perrigo Company (“Perrigo”).

Guaifenesin is an expectorant used to combat mucus that causes lung congestion.  Adams Respiratory Therapeutics, Inc. (“Adams”) filed an NDA for an extended release guaifenesin product, Mucinex®, containing both an immediate release (“IR”) and extended release (“ER”) portion for twice-daily dosing.  Adams’s NDA included pharmacokinetic data showing its product was bioequivalent to, and in particular had approximately the same maximum blood concentration (Cmax) of guaifenesin as, an IR-only product taken every four hours for twelve hours.  In 2002, Adams obtained U.S. Patent No. 6,372,252 (“the ’252 patent”) covering its particular ER product, with claims reciting a Cmax that is “equivalent” to the multiple twelve-hour dosing schedule of the IR-only product. 

Perrigo filed an ANDA containing a Paragraph IV Certification alleging that the ’252 patent was invalid or not infringed, and with pharmacokinetic data showing its product was bioequivalent to, and had approximately the same Cmax as, Mucinex®.  Adams filed suit against Perrigo for infringement of the ’252 patent.  After construing the claims, the district court granted SJ of noninfringement, and Adams appealed the claim construction and infringement determinations.

The parties disputed the meaning of the term “equivalent” Cmax.  During a presuit ex parte reexamination of the ’252 patent, Adams stated that “one of ordinary skill in the art would recognize ‘equivalent’ as being the FDA bioequivalence guidelines of 80-125%,” along with an expert declaration supporting that definition.  Slip op. at 3.  Adams also submitted a copy of FDA guidelines regarding bioequivalence for ANDA applicants, which stated that 80-125% range but also required that the pharmacokinetic data “must show that a 90% confidence interval for the ratio of the mean response (usually AUC and Cmax) of its product to that of the innovator is within the limits of 0.8 to 1.25.”  Id. at 4.  In light of Adams’s statements, the district court interpreted “equivalent” as including both the 80-125% and the 90% confidence interval.

On appeal, Adams challenged the requirement of a 90% confidence interval, which only made sense in the context of drug approval.  By including the confidential interval, Adams asserted that the district court required Adams to prove that Perrigo’s product infringed 90% of the time, instead of merely showing that it was more likely than not that Perrigo’s product would infringe.  Perrigo countered that Adams’s reference to FDA guidelines during reexamination meant that Adams adopted them entirely, including the confidence interval.  The Federal Circuit agreed with Adams, finding that Adams referred specifically to the 80-125% range in the guidelines and that Adams never adopted or mentioned the confidence interval.  Moreover, the Court opined that infringement does not require a strict finding of bioequivalence, and that including the confidence interval would “inappropriately raise the bar for establishing infringement.”  Id. at 8.


“Our case law does not contain a blanket prohibition against comparing the accused product to a commercial embodiment.”  Slip op. at 10.

The Court also addressed Adams’s evidence of equivalence.  Adams presented evidence from Perrigo’s ANDA showing that Perrigo’s generic product would have a Cmax equivalent to Mucinex®, and additional evidence showing that Mucinex® was bioequivalent to an IR-only product.  Or, as the district court put it, “Adams argue[d] that if A is equivalent to B, and B is equivalent to C, then A must be equivalent to C,” id. (alteration in original) (citation omitted), and rejected that approach as improperly comparing the accused product to a commercial product instead of the claim language.  The district court reasoned that only a two-way crossover study comparing Perrigo’s ANDA product directly to the IR-only product mentioned in the ’252 patent claims could establish “equivalence.”  The Federal Circuit rejected this approach, finding no blanket prohibition against comparing an accused product to a commercial embodiment, relying in part on Glaxo Group Ltd. v. Torpharm, 153 F.3d 1366 (Fed. Cir. 1998), and finding that “when a commercial product meets all of the claim limitations, then a comparison to that product may support a finding of infringement,” slip op. at 11.  The Court noted that reliance on the mere fact of bioequivalence would not be enough to survive SJ.  Because bioequivalence indicates a range of values, the comparison of A to B and then B to C would not necessarily show that A is equivalent to C.  However, Adams presented actual pharmacokinetic and Cmax data in addition to evidence of bioequivalence, which was sufficient to preclude grant of SJ of noninfringement.

The Federal Circuit also dealt with two other issues on appeal.  First, Perrigo disputed the district court’s construction of the claim term “immediate release form which becomes fully bioavailable in the subject’s stomach” as meaning “a form intended to rapidly release in the stomach substantially all of the active pharmaceutical ingredient for absorption.”  Id. at 13-14.  Perrigo argued that “bioavailable” is commonly understood by those of skill in the art to mean absorption, not merely release for absorption.  The Federal Circuit stated that Perrigo’s construction was reasonable in the abstract, but upheld the district court’s definition, noting that “[a]lthough the specification never expressly defines bioavailable, it uses the term when describing the availability of the drug for absorption, not the actual absorption.”  Id. at 14.  The Court also noted that Perrigo’s construction, which would require absorption in the stomach, would exclude “the preferred embodiment and essentially all guaifenesin formulations, as the specification explains that absorption occurs in the intestinal tract.”  Id.

Second, the Court addressed Adams’s argument that it should be permitted to establish infringement of the claim term “said product has an AUCinf of at least 3500 hr*ng/mL” under DOE.  Id. at 15.  The district court had interpreted “at least” to indicate the absolute lower limit, and found that allowing Adams to establish infringement by DOE would vitiate the express claim language.  The Federal Circuit disagreed, noting prior cases such as U.S. Philips Corp. v. Iwasaki Co., 505 F.3d 1371 (Fed. Cir. 2007), and Abbott Laboratories v. Dey, L.P., 287 F.3d 1097 (Fed. Cir. 2002), which held that DOE can apply to a range or numerical limitation in a claim.  Thus, the Court vacated the grant of SJ of noninfringement so that the district court could consider under DOE whether Adams’s evidence of an AUC value of 3493.38 hr*ng/mL in Perrigo’s generic product was insubstantially different from the claimed 3500 hr*ng/mL.

Summary authored by Robert C. Stanley, Esq.