Absolutely, Totally, and in All Other Ways Inconceivable? Nope, Says the Federal Circuit in YASMIN Hatch-Waxman Method Patent Litigation

By Kurt R. Karst –      

In a 2-1 panel decision handed down by the U.S. Court of Appeals for the Federal Circuit earlier this week, the Court affirmed a September 2010 Judgment on the Pleadings by the U.S District Court for the Southern District of New York in favor of the ANDA sponsors (Defendants-Appellees) concerning U.S. Patent No. 5,569,652 (“the ‘652 patent”), which is listed in the Orange Book for the contraceptive drug YASMIN (drospirenone 3 mg/ethinyl estradiol 0.03 mg) Tablets (NDA No. 021098) as a method-of-use patent.  Based on Federal Circuit precedent (i.e., Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003) and Allergan Inc. v. Alcon Labs., 324 F.3d 1322 (Fed. Cir. 2003), which have been used to support the proposition that a method-of-use patent infringement claim against an ANDA sponsor cannot stand where that use is not approved by FDA), and FDA’s labeling regulations at 21 C.F.R. § 201.57(c) (stating in part that “[i]ndications or uses must not be implied or suggested in other sections of the labeling if not included in this section”), among other things, the New York District Court determined that the ‘652 patent does not claim an FDA-approved use for YASMIN because the patented use does not appear in the “Indications and Usage” section of the YASMIN labeling, but rather in the “Clinical Pharmacology” section of the labeling.  As we previously reported, the case is important enough that PhRMA filed an amicus brief in support of Plaintiffs-Appellants. 

The ‘652 patent has two independent claims – claims 1 and 11 – that recite that the claimed method achieves three effects simultaneously: (1) a contraceptive effect; (2) an anti-androgenic effect; and (3) an anti-aldosterone effect (also known as an anti-mineralocorticoid effect.  Plaintiffs-Appellants argued that FDA approved the ‘652 patent’s claim of simultaneous gestagenic, anti-androgenic, and anti-aldosterone effect, and that that approval is found in the “Clinical Pharmacology” section of the YASMIN labeling, which states in relevant part that “[d]rospirenone is a spironolactone analogue with antimineralocorticoid activity.  Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity.  Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.”  Defendants-Appellees argued that the only approved use for YASMIN included in the product’s labeling is contraception, and that the New York District Court decision should be affirmed.

In affirming the New York District Court’s decision, Circuit Judges S. Jay Plager and William C. Bryson said that the Court’s Warner-Lambert and Allergan decisions provide the framework for analyzing the case and are on point:

Based on Warner-Lambert and Allergan, the defendants’ conduct would constitute infringement under section 271(e)(2)(A) (or inducement of infringement under section 271(b)) only if the defendants’ ANDAs sought approval for the use protected by the ’652 patent, i.e., for the combination of a gestagenic effect, an anti-androgenic effect, and an anti-aldosterone effect in patients needing that combination of effects. . . .  The question to be answered, then, is whether the FDA has approved the use of Yasmin to achieve the combination of the three effects claimed in the ’652 patent.

Referring to the “Clinical Pharmacology” section of the YASMIN labeling quoted above, the Court said in its decision that:

While that passage states that Yasmin exhibits anti-mineralocorticoid activity and has the potential for anti-androgenic activity based on animal studies, neither that passage nor anything else on the label provides any safety or efficacy information associated with the possible use of Yasmin in treating patients who are in need of those effects.  Thus, while the label mentions potential anti-mineralocorticoid and anti-androgenic activity, it does not do so in any way that recommends or suggests to physi-cians that the drug is safe and effective for administration to patients for the purposes of inducing these effects.

Moreover, FDA’s labeling regulation at 21 C.F.R. § 201.57 “makes clear that the FDA has not approved the use of Yasmin to produce the pharmacological effects that are listed in the Clinical Pharmacology section of the label,” said the Court. 

The reference in the Clinical Pharmacology section of the label to the anti-mineralocorticoid and anti-androgenic activity of drospirenone is certainly not a direct indication of an appro-priate use for Yasmin, and even if it could be considered an “implied or suggested” indication of an appropriate use, the regulation expressly states that such implied or suggested uses do not constitute approved uses.

In addition, the FDA regulation requires the label to provide a summary of the essential scientific information needed for the safe and effective use of the drug.  See 21 C.F.R. § 201.56(a)(1).  The Yasmin label does not provide physicians with such a summary with respect to the drug’s anti-androgenic and anti-mineralocorticoid effects, which is a further indication that the FDA did not approve the use of Yasmin to exploit those effects in treating patients.

Although Defendants-Appellees argued that approved methods of use do not always appear in the “Indications and Usage” section of drug labeling, but may appear in other labeling sections such as the “Dosage and Administration” section, the Court said that fact is not helpful in this case:

The ’652 patent is narrowly focused on simultaneously achiev-ing three effects in premenopausal or menopausal pa-tients in need of all three effects; as the parties stipulated, the claim limitation referring to a “patient in need thereof” means a patient with a “perceived need for” all three effects.  The patent does not claim a method of achieving a contraceptive effect in a patient in need of contraception in which the drug used to achieve the contraceptive effect has two generally beneficial addi-tional effects.  To practice the method claimed in the ’652 patent, a physician must determine that all three effects are needed by a specific premenopausal or menopausal patient.  FDA approval of that method of use would require a showing that Yasmin was safe and effective for simultaneously obtaining those three effects in patients needing those effects.  Acknowledgement of the safety and efficacy of that specific method of use would be evidenced by including it in the Indications and Usage section of the label.  Therefore, the point is not simply that the method of use was not described in the Indications and Usage section that shows lack of FDA approval; the point is that the label, taken in its entirety, fails to recommend or suggest to a physician that Yasmin is safe and effective for inducing the claimed combination of effects in patients in need thereof. [(Emphasis added)]

As to the various pieces of evidence Defendants-Appellees proffered to support their argument that the references to anti-mineralocorticoid and anti-androgenic activity in the YASMIN “Clinical Pharmacology” labeling section indicate that FDA approved YASMIN to induce those effects, including FDA’s Orange Book patent listing regulations, the Court commented that:

That evidence, however, demonstrates only that the FDA was aware that Yasmin could cause the effects discussed in the ’652 patent.  It does not go to the critical question of whether the FDA has found Yasmin to be safe and effective for the purpose of inducing those effects in a premenopausal or menopausal patient with a specific need for those effects.  Absent that finding of safety and efficacy, and the recognition of such safety and efficacy on the Yasmin label, the Yasmin label cannot instruct (and the ANDA proposed label cannot induce infringement of) the method of use claimed in the ’652 patent.

Channeling what might be characterized as her “inner Vizzini” (from The Princess Bride), Circuit Judge Pauline Newman says in her dissenting opinion that the majority panel decision is simply incorrect and contrary to the purposes of the Hatch-Waxman Amendments and “the premises of FDA generic drug practices.”

The court holds that the listing of some of the Yasmin® properties in the Clinical Pharmacology section of the FDA label, instead of the Indications and Usage section, removes the generic counterpart of the Yasmin® product from the scope of the ’652 claims.  That ruling is in error, for the portion of the FDA label in which a product’s properties are described is irrelevant to whether the patent is infringed by sale or use of the product.  The court also finds, albeit incorrectly, that “the label, taken in its entirety, fails to recommend or suggest to a physician that Yasmin is safe and effective for inducing the claimed combination of effects in patients in need thereof,” maj. op. 16, and holds that this also requires non-infringement on the pleadings, as a matter of law. Neither the district court, nor this court, conducted a standard infringement analysis.

Moreover, writes Judge Newman, the Court’s Warner-Lambert decision does not support dismissal in this case.  “In Warner-Lambert the patented neurodegenerative use was not the label-approved use, and was not the use for which the ANDA was submitted. . . .  In contrast, for Yasmin® it is not disputed that the three properties recited in the patent claim are coextensive with the FDA-approved label. . . .  The court errs in ruling as a matter of law that the FDA-approved label for Yasmin® does not encompass the three effects stated in the label and claimed in the ’652 patent.”

The Federal Circuit’s decision seems destined to further appeal.  In the meantime, companies may be (re)considering product labeling in light of the product’s patent estate.