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Adams Respiratory Therapeutics, Inc. Vs. Perrigo Co.- Dispute Related to Pharmacokinetic Claim Terms
Adams Respiratory Therapeutics, Inc. (Adams)-“Plaintiff” holds patent 5,372,252 (‘252 patent), which covers an extended-release formulation containing guaifenesin (an expectorant used to thin, loosen, and helps expel mucus that causes congestion). Adams markets Mucinex® which is the preferred embodiment of the ’252 patent. Perrigo Co. (Perrigo)-“Defendant” sought FDA approval for a generic version of Adams’ product, Mucinex® to market 600 mg guaifenesin extended-release tables, with a paragraph IV certification to the ‘252 patent. Adams sued Perrigo for infringement of claims 26, 33, 34, and 39 of the ‘252 patent. After construing the claims, the District Court granted Perrigo a summary judgment of non-infringement. But later on, an appeal by Adams, the Federal Circuit panel reversed the grant of summary judgment and remanded because the court based its judgment of noninfringement on erroneous claim construction.
The claim terms in this dispute related to pharmacokinetic parameters. Such parameters are used to characterize the rate and extent of absorption of the active pharmaceutical ingredient (API). The primary term at issue was Cmax which indicates the maximum concentration of the API following dosing.
Basically, the dispute was over the meaning of the term “equivalent” in independent claim 24 and claims 26, 33, 34, and 39 depend on claim 24. Claim 24 recites:
“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 Adams’ statements 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]. But Adams argued that ‘equivalent’ meant within the 80 to 125% range, and not 90% confidence interval. Adams further stated that % confidence interval makes sense when seeking FDA approval, but not when proving infringement.
In response to Adams statement, Perrigo argued that 80 to 125% range “means absolutely nothing in terms of establishing bioequivalence under FDA’s guidelines without the 90% confidence interval, as, among other things, it is the confidence interval itself that must fall within the 80-125% range.”
The court agreed with Adams and construed “equivalent” to require a Cmax that is 80% to 125% of the value to which it is being compared and not meant (“equivalent”), meeting all of the requirements of the FDA’s bioequivalence guidelines.
Adams compared the accused product of Perrigo to Mucinex by citing the concept of A=B=C, therefore, A=C. Adams’ argued that the accused product was bioequivalent to Mucinex, and Mucinex was bioequivalent to a standard immediate release (“IR”) product, then the accused product had a Cmax equivalent to the IR product.
Adams also presented PK and Cmax data, which made it more evident that Perrigo’s product was equivalent to Adam’s product. In this way, summary judgment for Perrigo was therefore reversed on this ground.
Construction of “Bioavailable”
Next, Perrigo highlighted that the claim term “Bioavailable” of the ‘252 patent is ambiguous in its meaning. Perrigo’s alternative way to seek the summary judgment of noninfringement by District court was also rejected by the Federal circuit. The dispute revolved over the fact of whether the phrase “fully bioavailable in the subject’s stomach” meant “both release and availability in the stomach for absorption, wherever that absorption might occur.”
Perrigo did not agree on the point of infringement, that the ANDA product with IR portion of guaifenesin would become “fully bioavailable in the subject’s stomach” as claimed in claim 24 of Adams patent. Perrigo further argued stating “bioavailable” is commonly understood to mean absorption, thus requiring the guaifenesin to be absorbed in the stomach. But as guaifenesin is primarily absorbed in the small intestine, this construction of “Bioavailable” would not suffice a finding of infringement.
In response to this, 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. The Federal Circuit agreed to Adams’ consistency in using/construction of this term in the specification and denied Perrigo’s approach. The panel highlights that although the specification never expressly defines bioavailable, it uses the term when describing the availability of the drug for absorption, not the actual absorption.
Doctrine of Equivalents
Finally, Adams argued that Perrigo’s ANDA product would infringe the dependent claim 34 under the “doctrine of equivalents”.
Claim 34 recited:
“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.”
This appeal of Adams to show infringement under the doctrines of equivalent was agreed by the Federal Circuit panel that an amount of 3494.38 hr*ng/mL was equivalent to 3500 hr*ng/mL.
We all know that a particular patented drug for commercialization/marketing finally needs a FDA approval to enter the medical market. Hence, according to me, it is practically meaningless to specify a numerical range without a confidence interval and not importing/considering the FDA values and guidelines into the claim construction. However, I would appreciate Adams’ explanation over the numerical values of doctrines of equivalent because biologically speaking, such minor variations in pharmacokinetic parameters are practically acceptable in humans and animals.
Minusmita Ray, Patent Associate, IIPRD. Minusmita@iiprd.com