By Donald Zuhn --
In Adams Respiratory Therapeutics, Inc. v. Perrigo Co., decided last Thursday, the Federal Circuit vacated and remanded a determination by the District Court for the Western District of Michigan that the guaifenesin product described in Defendants-Appellees' ("Perrigo") Abbreviated New Drug Application (ANDA) would not infringe the asserted claims of Plaintiffs-Appellants' ("Adams") U.S. Patent No. 6,372,252. The panel's decision to vacate was based in part on the District Court's erroneous claim construction.
The '252 patent relates to controlled-release formulations of guaifenesin (at left), an expectorant used to thin, loosen, and help expel mucus that causes congestion. The preferred embodiment of the '252 patent is Mucinex®, an extended release guaifenesin tablet that contains an immediate release (IR) portion and a sustained release portion. Seeking approval to market 600 mg guaifenesin extended-release tablets, Perrigo filed an ANDA with the FDA. In response to Perrigo's ANDA filing, Adams brought suit against Perrigo for infringement of claims 26, 33, 34, and 39 of the '252 patent.
After construing the claims, the District Court granted summary judgment of noninfringement to Perrigo. At issue before the District Court was the meaning of the term "equivalent" in claim 24, from which each of the asserted claims depends. Claim 24 recites (emphasis added):
24. A modified release product having two portions, wherein a first portion comprises a first quantity of guaifenesin in an immediate release form which becomes fully bioavailable in the subject's stomach and a second portion comprises a second quantity of guaifenesin in a sustained release form wherein the ratio of said first quantity to said second quantity provides a Cmax in a human subject equivalent to the Cmax obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period and wherein said product also provides therapeutically effective bioavailability for at least twelve hours after a single dose in a human subject according to serum analysis.
The District Court construed "equivalent" as "within 80% to 125% of the value with which it is being compared, at a 90% confidence interval," basing its construction on statements made by Adams during reexamination proceedings on the '252 patent. According to the Court, "Adams explicitly stated during reexamination that 'equivalent' meant 'the FDA bioequivalence guidelines' [i.e., the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations," which reflect both an 80 to 125% range and a 90% confidence interval]." In addition, the Court noted that a declaration submitted by Adams during reexamination indicated that one of ordinary skill in the art would understand the term "equivalent" to mean within the FDA bioequivalent range of 80 to 125%.
On appeal, Adams challenged the requirement of a 90% confidence interval, noting that the '252 patent does not require or mention such an interval. While acknowledging that it defined "equivalent" to mean within the 80 to 125% range, Adams argued that a 90% confidence interval was never included in that definition. Adams asserted that the 90% confidence made sense in the context of drug approval, but not in the context of proving infringement, and that by requiring a 90% confidence interval, the District Court was requiring Adams to prove that Perrigo's guaifenesin product would infringe the '252 patent 90% of the time (rather than simply showing that it was more likely than not that Perrigo's ANDA, if approved, would permit Perrigo to market a product that infringes the '252 patent). Perrigo countered that Adams "expressly defined 'equivalent' as FDA's bioequivalence guidelines, i.e., 'within 80% to 125% of the value with which it is being compared, at a 90% confidence interval."
In vacating the District Court's summary judgment of noninfringement, the Federal Circuit construed "equivalent" to require a Cmax that is 80% to 125% of the value to which it is being compared, adding that "[c]ontrary to Perrigo's assertion, Adams did not define equivalent as meeting all of the requirements of the FDA’s bioequivalence guidelines," but rather referred specifically to the 80 to 125% range of the FDA guidelines. The panel noted that "[t]he range and the confidence interval are independent concepts," explaining that "[t]he range reflects 'a medical decision that, for most drugs, a -20%/+25% difference in the concentration of the active ingredient in blood will not be clinically significant,'" and that "the 90% confidence interval reflects the FDA's concern that a generic drug consistently match the performance of the branded drug." With respect to the District Court's construction, the panel stated that:
Patent infringement does not require bioequivalence, and Adams did not import the 90% confidence interval into its claim. Requiring a 90% confidence interval would inappropriately raise the bar for establishing infringement. Adams must show that it is more likely than not that Perrigo's ANDA product will have a Cmax within the 80 to 125% range. Adams is not required to show that Perrigo's product will meet this requirement 9 times out of 10.
Turning to the issue of equivalence, the panel noted that before the lower court, Adams had failed to present evidence of equivalence sufficient to create a genuine issue of material fact of infringement. In particular, Adams had attempted to show that Perrigo's ANDA product would have a Cmax equivalent to a standard IR product by showing that Perrigo's ANDA product was bioequivalent to Mucinex® and that Mucinex® was bioequivalent to a standard IR product. The District Court found fault with Adams' comparison, in particular because Adams had compared Perrigo's ANDA product to Adams' commercial embodiment. The lower court determined that equivalence must be shown by a two-way crossover study comparing Perrigo's ANDA product and a standard IR product, as required by the FDA to establish bioequivalence (a study that Adams had not performed).
The Federal Circuit agreed with Adams that a two-way crossover study was unnecessary and that Adams had provided sufficient evidence of infringement to create a genuine issue of material fact. With respect to Adams' comparison of Perrigo's ANDA product to Adams' commercial embodiment, the panel stated that "[o]ur case law does not contain a blanket prohibition against comparing the accused product to a commercial embodiment," and added that "when a commercial product meets all of the claim limitations, then a comparison to that product may support a finding of infringement."
Perrigo also argued that one could not establish infringement based on the available data. However, the panel noted that while Perrigo's argument appears to assume that the claim requires a 90% confidence interval, Perrigo had offered no explanation why Adams' evidence failed to establish infringement under the correct construction of "equivalent." In addition, the Court noted that Adams presented more than just the fact of bioequivalence of the two sets of products (i.e., Perrigo's ANDA product and Mucinex®; Mucinex® and a standard IR product), explaining that:
If Adams had relied on the mere fact of bioequivalence of the two sets of products (and no PK data or Cmax values), that would not be enough to survive summary judgment. If product A is bioequivalent to B, and B is bioequivalent to C, then it is entirely possible that A is not equivalent to C because bioequivalence indicates a range of values (80 to 125%). Bioequivalence values on the low or high end of the range would not indicate equivalence (e.g., if A is consistently 80% of B, and B is consistently 80% of C, then A is likely to be 64% of C). However, here, in addition to its evidence of bioequivalence, Adams presented actual PK data and Cmax values. In light of this evidence, a fact-finder could reasonably conclude that it is more likely than not that Perrigo's ANDA product will have a Cmax equivalent to that of a standard IR product. Therefore, Adams has raised a genuine issue of material fact on infringement under the proper construction of the term equivalent, sufficient to preclude summary judgment.
The Federal Circuit also rejected Perrigo's alternative basis for affirming the District Court's finding of noninfringement: that Adams cannot establish that Perrigo's ANDA product has an IR portion of guaifenesin that becomes "fully bioavailable in the subject's stomach" as required by claim 24. On appeal, Perrigo asserted that "bioavailable" means absorption, and Adams contended that it means release into the stomach, rather than absorption into the body. In support of its position, Adams pointed to the specification, which repeatedly states that the IR portion of guaifenesin is released in the stomach, but never states that it is absorbed in the stomach. While acknowledging that "Perrigo and Adams each proposed a reasonable construction of the term bioavailable in the abstract," the panel concluded that:
Adams' construction is consistent with the use of this term in the specification; Perrigo’s is not. Claim terms are not construed in a vacuum divorced from the specification. Although the specification never expressly defines bioavailable, it uses the term when describing the availability of the drug for absorption, not the actual absorption.
. . .
Adams' construction -- requiring release and availability for absorption -- covers the preferred embodiment. Perrigo's construction -- requiring both release and actual absorption -- excludes the preferred embodiment and essentially all guaifenesin formulations, as the specification explains that absorption occurs in the intestinal tract.
The last section of the opinion addresses Adams argument that it should be allowed to establish infringement of claim 34 under the doctrine of equivalents. According to the panel, claim 34 recites:
34. The modified release product of claim 26 [which claims the modified release product of claim 24 wherein the total quantity of guaifenesin is 600 mg] wherein the Cmax of said product is at least 1000 ng/mL and said product has an AUCinf of at least 3500 hr*ng/mL.
Adams noted that the highest AUCinf (the area under a plasma concentration versus time curve, i.e., the total amount of guaifenesin absorbed by the subject) for Perrigo's ANDA product was 3493.38 hr*ng/mL, which was within 0.189% of the recited value. Citing Abbott Labs. v. Dey, L.P., 287 F.3d 1097, 1100, 1105-08 (Fed. Cir. 2002), Adams argued that the Federal Circuit had previously concluded that infringement under the doctrine of equivalents could apply to claims requiring a specific numeric range. The District Court, however, had determined that the term "at least" in claim 34 indicates an absolute lower limit of the range (citing Quantum Corp. v. Rodime, PLC, 65 F.3d 1577 (Fed. Cir. 1995)), and that allowing Adams to show infringement under the doctrine of equivalents would vitiate the 3500 hr*ng/mL limitation.
The panel noted that the limitation "at least 3500 hr*ng/mL" was comparable to the specific numerical ranges in Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc); Abbott Labs. v. Dey, L.P.; and Jeneric/Pentron, Inc. v. Dillon Co., 205 F.3d 1377 (Fed. Cir. 2000), and that these cases indicate that "[t]he recitation of a specific numerical value does not by itself foreclose the application of the doctrine of equivalents." Determining that "[t]he addition of 'at least' in this case does not change this analysis," and further that "[t]he fact that the claim does not contain words of approximation (i.e., 'about at least 3500 hr*ng/mL') does not affect the analysis," the Court stated that the proper inquiry is whether the accused value is insubstantially different from the claimed value. The panel concluded that Adams had introduced sufficient evidence from which a reasonable fact-finder could conclude that an AUC value of 3493.38 hr*ng/mL is insubstantially different from a value of 3500 hr*ng/mL, and therefore vacated the District Court's grant of summary judgment of noninfringement of claim 34 under the doctrine of equivalents.
Adams Respiratory Therapeutics, Inc. v. Perrigo Co. (Fed. Cir. 2010)
Panel: Circuit Judges Linn, Moore, and Friedman
Opinion by Circuit Judge Moore
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