Iloperidone – USA

On Apr. 13, 2018, Federal Circuit affirmed district court’s decision in Fanapt® finding patent valid & infringed by ANDA filer in Hatch-Waxman litigation.

Vanda owns New Drug Application for Fanapt® (iloperidone), an atypical antipsychotic approved by the USFDA in 2009 for the treatment of patients with schizophrenia. Vanda owns US 8,586,610 patent, which will expire on November 2, 2027. The ’610 patent relates to a method of treating schizophrenia patients with iloperidone wherein the dosage range is based on the patient’s genotype. The ’610 patent teaches “that treatment of a patient, who has lower CYP2D6 activity than a normal person, with a drug [such as iloperidone] that is pre-disposed to cause QT2 prolongation and is metabolized by the CYP2D6 enzyme, can be accomplished more safely by administering a lower dose of the drug than would be administered to a person who has normal CYP2D6 enzyme activity.”

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.

In 2013, West-Ward filed Abbreviated New Drug Application (“ANDA”) seeking approval to commercially manufacture, use, offer to sell, and sell a generic version of Fanapt® in 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg strengths. The proposed ANDA label is substantially identical in all material respects to the Fanapt® label. The proposed label provides that the “[i]loperidone dose should be reduced by one-half for poor metabolizers of CYP2D6 [see Pharmacokinetics (12.3)].” Section 5.2, entitled “QT Prolongation,” explains: “iloperidone was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily” and that “[c]aution is warranted when prescribing iloperidone . . . in patients with reduced activity of CYP2D6 [see Clinical Pharmacology (12.3)].” Following a bench trial, the district court found that West-Ward’s proposed products induce infringement of the asserted claims of the ’610 patent, but do not contributorily infringe them. The court found that the proposed ANDA label “recommends”: (1) “practitioners use iloperidone to treat patients suffering from schizophrenia”; (2) “oral administration of iloperidone tablets at 12 to 24 mg/day to nongenotypic CYP2D6 poor metabolizers and 12 mg/day or less to genotypic CYP2D6 poor metabolizers”; and (3) “practitioners perform or have performed a genotyping assay to determine whether patients are CYP2D6 poor metabolizers.”

The district court also held that the asserted claims were not invalid under § 101, § 103, or § 112 for lack of written description. The court did conclude that “the asserted claims depend upon laws of nature,” specifically, “the relationship between iloperidone, CYP2D6 metabolism, and QTc prolongation.” But the court explained that the ’610 patent “addresses natural relationships to which the claims add conducting CYP2D6 genotyping tests to determine the appropriate dose of iloperidone to reduce QTc-related risks.” “The court f[ound] that while it may have been conventional to investigate for side-effects, [West-Ward] has not proven by clear and convincing evidence that the precise test and the discovered results were routine or conventional.” West-Ward appealed from the district court’s final judgment.

Induced Infringement:

During appeal, West-Ward argued that the district court clearly erred in finding that it would induce infringement because Vanda failed to prove the requisite direct infringement and specific intent to induce infringement. Specifically West-Ward argued that the district court clearly erred in finding that its proposed label “satisfies” the asserted claims because the language of the label itself cannot constitute direct infringement of the asserted method claims. Turning to specific intent, West-Ward argued that Vanda failed to prove that its proposed label would “‘encourage’ or ‘recommend’ a direct infringer (a psychiatrist or other physician) to perform each step of the claimed methods.” West-Ward contended that the substantial number of noninfringing uses precludes a finding of specific intent as a matter of law.

Federal circuit, however agreed with Vanda that the district court did not clearly err in finding induced infringement of independent claims 1, 9, and 13.8.  Section 2.1 of label entitled, “Usual Dose,” states: Iloperidone must be titrated slowly from a low starting dose . . . . The recommended starting dose for iloperidone tablets is 1 mg twice daily. Dose increases to reach the target range of 6 to 12 mg twice daily (12 to 24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg/day). The maximum recommended dose is 12 mg twice daily (24 mg/day). . . . Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of iloperidone”. Section 12.3 of the proposed label, entitled “Pharmacokinetics,” states: Approximately 7 to 10% of Caucasians and 3 to 8% of Black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of iloperidone with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3 fold increase in iloperidone plasma exposure, and therefore one-half of the iloperidone dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with [extensive metabolizers] and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs.

Thus, the district court did not clearly err in finding that § 12.3 “recommends that practitioners perform or have performed a genotyping assay to determine whether patients are CYP2D6 poor metabolizers.” Experts for both parties testified that the referred-to “laboratory tests” are “genotyping tests.” The district court thus found that “when the label states that ‘laboratory tests’ are available to identify poor metabolizers, the label is referring to ‘genotyping tests.’” The label instructs practitioners that “PMs should have their dose reduced by one-half. [Genotyping tests] are available to identify CYP2D6 PMs.” The court did not clearly err in finding that this constitutes a recommendation to perform genotyping tests on iloperidone patients.

Court further held that if the proposed ANDA product has “substantial noninfringing uses,” West-Ward may still be held liable for induced infringement. “Section 271(b), on inducement, does not contain the ‘substantial noninfringing use’ restriction of section 271(c), on contributory infringement.” Sanofi, 875 F.3d at 646. Thus, “a person can be liable for inducing an infringing use of a product even if the product has substantial noninfringing uses . . . .”(citing Grokster, 545 U.S. at 934–37).

Patent Subject Matter Eligibility:

Court next addressed whether the asserted claims are directed to patent-eligible subject matter. West-Ward argued that the asserted claims are ineligible under § 101 because they are directed to a natural relationship between iloperidone, CYP2D6 metabolism, and QT prolongation, and add nothing inventive to those natural laws and phenomena. Vanda responded that the asserted claims are patent eligible under § 101 at both steps of Mayo/Alice. Consistent with Supreme Court precedent, federal circuit agreed with Vanda that the asserted claims are not directed to patent-ineligible subject matter. Court further said that, first the claims in Mayo were not directed to a novel method of treating a disease. Instead, the claims were directed to a diagnostic method based on the “relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.”

In this case, the ’610 patent claims are directed to a method of using iloperidone to treat schizophrenia. The inventors recognized the relationships between iloperidone, CYP2D6 metabolism, and QTc prolongation, but that is not what they claimed. They claimed an application of that relationship. Unlike the claim at issue in Mayo, the claims here require a treating doctor to administer iloperidone in the amount of either (1) 12 mg/day or less or (2) between 12 mg/day to 24 mg/day, depending on the result of a genotyping assay. The specification further highlights the significance of the specific dosages by explaining how certain ranges of administered iloperidone correlate with the risk of QTc prolongation. Thus, the ’610 patent claims are “a new way of using an existing drug” that is safer for patients because it reduces the risk of QTc prolongation. At bottom, the claims here are directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome. They are different from Mayo. They recite more than the natural relationship between CYP2D6 metabolizer genotype and the risk of QTc prolongation. Instead, they recite a method of treating patients based on this relationship that makes iloperidone safer by lowering the risk of QTc prolongation. Accordingly, the claims are patent eligible.

Written Description:

West-Ward’s argued that the district court erred in finding that the claims are not invalid for lack of adequate written description. Specifically, West-Ward argued that the asserted claims are invalid for lack of written description because nothing in the ’610 patent demonstrates possession of the claimed dosage ranges for poor and non-poor CYP2D6 metabolizer genotypes. West-Ward contended that the description does not contain experiments with doses of 12 mg/day or less given to poor metabolizers, and reports data that does not support the claimed poor-metabolizer dose range. However, Federal circuit agreed with Vanda that the district court did not clearly err in finding that the ’610 patent contains adequate written description for the claimed “12 mg/day or less” dosage range for poor metabolizers. The ’610 patent further explains that the reported results “show that patients can be more safely treated with iloperidone if the dose of iloperidone is adjusted based on the CYP2D6 genotype of each patient.”

Thus for the foregoing reasons, Federal circuit affirmed the district court’s decision.