Dose reduction patent affirmed.

Hatch Waxman’s beauty, and its careful balance of innovative research and generic competition, never ceases to amaze me. Earlier this month, a generic challenger argued that a dose reduction patent owned by Vanda Pharmaceuticals was invalid because Vanda had only performed drug metabolism work that FDA demanded for approval.  Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 2018 U.S. App. LEXIS 9360 (Fed. Cir. Apr. 13, 2018).  The generic’s argument sounded simple, but it ignored well-established standards for patentability, which protect hard work and the discovery of unexpected results, and was rightly rejected by the trial court and the Federal Circuit Court of Appeals. The fact that FDA demanded the work was not relevant to patentability.

The patent at issue, U.S. Patent 8,586,610 (“the ‘610 patent”), relates to a method of dosing schizophrenia patients with iloperidone based on the patient’s genotype for an enzyme that metabolizes iloperidone, CYP2D6. If the patient has low CYP2D6 activity the patent teaches that the dose of iloperidone should be reduced.  From a safety perspective, this reduction is beneficial because high blood concentrations of iloperidone can cause QTc prolongation and cardiac complications. 

Claim 1 of the ‘610 patent is representative and reads as follows:

A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of: 

            determining whether the patient is a CYP2D6 poor metabolizer by: 

            obtaining or having obtained a biological sample from the patient; and 

            performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and 

            if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and

            if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day, 

            wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be if the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.

The generic drug company in this case, West-Ward Pharmaceuticals, sought to make use of the ‘610 patent invention to gain approval of its drug under section 505(j)(2) of the Federal Food Drug and Cosmetic Act.  (FD&C Act).  The label West-Ward submitted to FDA stated:

loperidone is indicated for the treatment of adults with schizophrenia.” 

“[t]he recommended target dosage of iloperidone tablets is 12 to 24 mg/day.” 

“The iloperidone dose should be reduced by one-half for poor metabolizers of CYP2D6 [see Pharmacokinetics (12.3) ].” 

“Iloperidone was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily.” 

At trial West-Ward argued that the claimed invention was obvious “because it was known that CYP2D6 is important for the metabolism of iloperidone, [and] a person ordinarily skilled in the art would be motivated to study it further.” According to West-Ward, “as of September 2004, these types of studies would be performed for any drug for which CYP2D6 was an important metabolic route of elimination.” 

The fact that FDA would have required the studies did not matter to the trial court. What mattered were the predictability in the art, and the amount of testing needed to arrive at the invention. As stated by the trial court: 

“the level of clinical testing required and inherent unpredictability in this field make certain that the invention was not obvious. The court is particularly persuaded by the fact that Novartis abandoned iloperidone in development because of QTc prolongation. … Even if [the prior art] provided a basis for a POSA to focus a study on the implications for iloperidone metabolism of mutations in the genes for the CYP2D6, it would have been impossible to predict the results. … A solution is not obvious simply because it was obvious to conduct experiments to try to solve the problem. In re Dow Chemical Co., 837 F.2d 469,473 (Fed. Cir. 1988) (“[S]elective hindsight is no more applicable to the design of experiments than it is to the combination of prior art teachings.”). In conclusion, the ‘610 Patent is not invalid as obvious.”

As for infringement, the trial court had little difficulty finding that the language in the generic label would induce infringement of the ‘610 patent, and the Federal Circuit had little difficulty affirming that decision.  As stated by the Federal Circuit:

“The district court made factual findings that the proposed label ‘recommends’ that physicians perform the claimed steps… and its analysis of the proposed label to assess potential direct infringement by physicians was proper under our precedent.”

Notably, West-Ward infringed even though the prevalence of infringing activity was not high. In this case, less than 10% of iloperidone users would take the reduced dose.  As stated by the Court: “We have not required evidence regarding the general prevalence of the induced activity.”  All that the patent owner needs to prove to demonstrate infringement is that “language in the ANDA label would inevitably lead some consumers to practice the claimed method.”

The decision included a very nice discussion on patent subject matter eligibility, and the difference between this case and Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012), that we will report on next week.