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Personalized Medicine Gets a Boost from Federal Circuit’s Vanda Pharma Decision - PART I

The Federal Circuit provided a welcome boost for stakeholders in the field of personalized medicine with its recent decision in Vanda Pharm. Inc. v West-Ward Pharm. Intl. Ltd. (2016-2702, 2016-2708 April 13, 2018). Vanda Pharma’s asserted claims relate to a method of treating schizophrenia patients with iloperidone in which the dose is adjusted based upon the patient’s CYP2D6 genotype. The Federal Circuit agreed with the lower court that these claims were both directed to patent eligible subject matter and infringed.

This decision is a breath of fresh air for patent applicants and patentees alike. The decision is particularly good news for those struggling with eligibility issues for claims involving diagnostic tests which inform treatment decisions and for those concerned with their enforcement once granted. This kind of subject matter underpins much of the personalized medicine space and has been widely viewed as in jeopardy following recent changes in subject matter eligibility requirements.

Of note, and perhaps as a point of caution, the claims at issue in Vanda Pharma were similar enough to those found ineligible in Mayo to warrant significant attention in both the majority opinion and by the dissent. The majority characterized Vanda Pharma’s claims as “a novel method of treating a disease” and therefore patent eligible and distinguishable from the claims found ineligible in Mayo which were “directed to a diagnostic method” based on “entirely natural processes.” In dissent, Judge Prost contends that “[t]he majority fails to reconcile [the] substantive similarity between our case and Mayo.” Judge Prost would have found the claims ineligible as directed to a natural law.

It is worth delving into the details here.

Vanda Pharma’s asserted claims were directed to a “method of treating” a patient suffering from schizophrenia with a drug called iloperidone. Iloperidone is metabolized by the liver cytochrome P450 enzyme, CYP2D6, and high levels of iloperidone or its metabolites were known to cause a serious side effect in the form of a heart arrhythmia, QT prolongation, which is referred to as QTc when corrected for the patient’s heart rate.

According to the specification of the ‘610 Patent, the inventors discovered “an association between genetic polymorphisms in the CYP2D6 locus, corresponding increases in the concentrations of iloperidone or its metabolites, and the effect of such increases in concentrations on corrected QT (QTc) duration relative to baseline.” The asserted claims recite active steps relating to determining whether a patient is a CYP2D6 poor metabolizer and administering an appropriate dose based on metabolizer status. In brief, the active steps recited in the claim are “determining” whether the patient is a poor metabolizer by “obtaining” a biological sample and “performing” a genotyping assay followed by “administering” to the patient a specific dose of “12 mg/day or less” for poor metabolizers or “an amount that is greater than 12 mg/day, up to 24 mg/day” for a patient that lacks a CYP2D6 poor metabolizer genotype.

As many readers will be aware, the Supreme Court established a two step inquiry for determining subject matter eligibility, commonly referred to as “the Mayo/Alice inquiry.” Under Step 1, the question is whether the claimed subject matter is “directed to” a judicial exception, such as a law of nature, a natural product, or an abstract idea. If it is not, then the inquiry ends there and the claim is deemed patent eligible. However, if the claim is found to be “directed to” a judicial exception, then the inquiry proceeds to Step 2, in which the claim is examined to determine whether or not it adds “significantly more” to the judicial exception, or is merely an attempt to claim the law of nature, natural product, or abstract idea itself.

Here, the majority of the Federal Circuit found the claims to be eligible under Step 1. Quoting Mayo and the Federal Circuit decision in CellzDirect, the majority notes the following: 

[T]oo broad an interpretation of ineligible subject matter could eviscerate patent law because all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas. Accordingly, at step one, it is not enough to merely identify a patent-ineligible concept underlying the claim; we must determine whether that patent-ineligible concept is what the claim is ‘directed to.’

In characterizing Vanda Pharma’s claims as “a new way of using an existing drug that is safer for patients because it reduces the risk of QTc prolongation,” the majority referenced the well-known dicta in Mayo distinguishing the claims found to be ineligible there as “[u]nlike, say, a typical patent on a new drug or a new way of using an existing drug, the patent claims do not confine their reach to particular applications of those laws.” Emphasis added.

Viewed through the lens of the majority opinion, Vanda Pharma’s claims represent a new way of using iloperidone that applies a ‘natural law’ in order to reduce the risk of a serious side effect, QTc prolongation, in a high risk population, CYP2D6 poor metabolizers. In support of this position, the majority took note of the teachings in the specification highlighting “the significance of the specific dosages by explaining how certain ranges of administered iloperidone correlate with the risk of QTc prolongation.”

As stated by Judge Lourie writing for the majority:

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.

For now, the take-home message for applicants trying to vault the 101 hurdle with similar subject matter is “specificity.” Here, claims directed to treating a specific disease (schizophrenia) with a specific drug (iloperidone) in a specific patient population (CYP2D6 poor metabolizers, or not) in a specific way (by administering a defined dose to each patient population) to achieve a specific result (lower risk of a serious side effect) were patent eligible at Step 1 of the Mayo/Alice inquiry.

As noted above, Chief Judge Prost dissented from the decision upholding the subject matter eligibility of the claims, plainly stating “I would find the asserted patent claims to be directed to a law of nature.” Judge Prost points out the similarities in the asserted claims and those at issue in Mayo and finds no reason to distinguish.

Judge Prost acknowledges the evidence below regarding the unpredictability of whether any dosage adjustment of iloperidone would be needed for CYP2D6 poor metabolizers, and equally important the lack of any teaching as to the amount that would be needed to achieve the desired pharmacokinetic profile seen in patients having a normal metabolizer status.

Nevertheless, Judge Prost finds “no inventive concept in the claims once the natural law at issue is properly understood in view of Mayo.” In Judge Prost’s view, the natural law is “the fact that a reduction of iloperidone dosage in poor metabolizers to the [sic] may reduce QTc prolongation.” She finds that “[t]he recitation of specific dosages adds no more than a conventional application of that natural law.”

To be fair, it seems at least unclear how the claimed specific dosages can properly be considered a “conventional application” in view of the evidence below establishing that it was not known whether any dose adjustment was needed for the at-risk population of poor metabolizers, much less was there any direction regarding the specific dose that would be required to achieve the desired pharmacokinetic profile in this population.

Currently, Examiners seeking to reject a claim under Step 2 must provide evidence establishing that the claim elements other than those pertaining to the judicial exception were routinely practiced in the prior art. A similar analysis here would seem to tilt in favor of patent eligibility since the active steps of obtaining a biological sample, performing genotyping, and administering the specified amounts of iloperidone were not being practiced.

Judge Prost also found scant weight in the majority’s argument insofar as it pertained to the specificity of the claims at issue here relative to those at issue in Mayo.

But a reasonable person could find that the difference is real and not insignificant. For example, the claims at issue in Mayo were directed to treating an undefined disorder (“an immune-mediated gastrointestinal disorder”) with a class of drug (i.e., thiopurine drugs—those “providing” the metabolite 6-thioguanine) in a vague way, simply by “administering” the drug to the patient and “determining” the level of the metabolite. Unlike the underlying facts here, in Mayo therapeutic dose monitoring was already routinely practiced for thiopurine drugs. In other words, the active steps of “administering” the drug and “determining” its metabolite levels in order to adjust the dosage were already being practiced by doctors treating patients. The remainder of the claim, as has oft been discussed, merely states the levels of the biomarker indicating a need to generically “increase” or “decrease” the amount of the drug subsequently administered, without any further active steps requiring such subsequent administration of the drug, much less at any specified dose.

Judge Prost contends that the difference in specific administering steps between the asserted claims here and those in Mayo is “of no moment.” While many patent applicants and owners likely hope this remains a minority position, a clear answer remains in the future.

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