Wednesday, August 27, 2008

Courts grapple with the question of whether biological phenomena constitute unpatentable “natural phenomona”

It is black letter law that “natural phenomena, principles of nature and abstract ideas," as exemplified by fundamental physical relationships such as E=mc2 and the law of gravity, are unpatentable under section 101 of the patent statute. It is less clear what the criteria is for determining when a patent claim sufficiently embodies a natural phenomenon to be unpatentable; a series of recent decisions have interpreted Supreme Court precedent as establishing that a patent claim which wholly preempts a natural phenomenon is unpatentable. In LabCorp v. Metablolite (548 U.S. 124 (2006), Justice Breyer (joined by Souter and Stevens in a dissent from the Court’s decision to dismiss the case as improvidently granted) expressed his view that a patent claim that “embodies” a naturally existing biological phenomenon (in this case a correlation between homocysteine and vitamin B in the body) is unpatentable for improperly claiming a natural phenomenon.

Breyer’s Labcorp dissent has opened the door to challenging the validity of claims directed to biological phenomena under section 101. Of particular note, at least three subsequent district court decisions have weighed in on the question of whether a biological or physiological phenomenon is properly considered an unpatentable “natural phenomenon” – a question of particular importance to the biotechnology sector in the wake of LabCorp.

In one case, Ariad v. Lilly (529 F.Supp.2d 106 (D.Mass 2007)), the district court rejected Lilly’s argument that Ariad’s claim (directed to inhibition of the NF-kB pathway, a naturally occurring signal transduction pathway in humans) embodies a natural phenomonen. The court’s reasoning in Ariad was quite bizarre – first the court identified the relevant natural phenomenon narrowly as the so-called NF-kB “Autoregulatory Loop,” and then held that the Autoregulatory Loop is “an incomplete model ... subject to a significant amount of ambiguity and inconsistency” and “that Lilly has failed to prove by clear and convincing evidence that the Autoregulatory Loop exists in living cells in a way that is encompassed by Ariad's claims.” The existence of the NF-kB pathway is well established, as is the fact that its inhibition can have a physiological effect, and the claim at issue broadly covers inhibition of the pathway. The court appears to have been bamboozled into adopting an unduly narrow definition of the relevant natural phenomenon, and then found that the evidence supporting this narrowly defined phenomenon was insufficient to overcome the statutory presumption in favor of patent validity.

In two other recent decisions the district court came to the opposite conclusion, finding the claims at issue invalid for impermissibly claiming a physiological natural phenomenon. What is interesting about these cases is that the supposed natural phenomena actually relate to biological correlations that only exist as the result of human, medical intervention in the body, by either the administration of a vaccine or a drug. In contrast, the natural phenomena at issue in LabCorp and Ariad involve correlations and pathways that exist absent any human intervention.

In Classen v. Biogen (not reported), the patents are based on Dr. Classen’s purported discovery of a relationship between vaccination schedule (the timing of the administration of a series of vaccinations) and the development of a “chronic immune-mediated disorder,” and broadly claim methods of comparing vaccine schedules to determine the safest schedule. Defendant’s include manufacturers and distributors of vaccines, who allegedly infringe the patents (directly and/or indirectly) by participating in post-approval vaccination safety studies. In that case, the district court held that the relationship between vaccination schedule and autoimmune disorders is without question a natural phenomonen, and that the claims at issue impermissibly embodied that natural phenomonen. The court did not address the issue of whether a biological phenomenon that exists only as a result of human intervention (the introduction of vaccine in the human body) is accurately characterized as a natural phenomenon. Arguably, a phenomena that does not exist absent human intervention should not be considered a natural phenomenon in the same way as fundamental principles of nature that exist outside of human intervention, such as inhibition of the NF-kB pathway, or the correlation between homocysteine and vitamin B at the center of the claims at issue in LabCorp.

To my mind, perhaps the most troubling decision is the most recent, Prometheus v. Mayo (2008 WL 878910). In that case, the court held that the correlation between the level of thiopurine drug metabolites in the human body and therapeutic efficacy and safety is a “natural phenomonen,” and that Prometheus’ asserted claim were invalid under section 101 for “wholly preempting” this supposed natural phenomenon. Prometheus argued that since the drug metabolites only exist in the human body as the result of human intervention (i.e., by administration of the thiopurine drugs), the correlation cannot be considered a natural phenomonen. However, the court ruled that because thiopurine drugs “are converted naturally by enzymes within the patient’s body to form an agent that is therapeutically active, . . . the correlation results from a natural body process,” and is thus is an unpatentable “work of nature.”

Thus, the court in Prometheus finds that the mere involvement of a natural process renders a correlation that exists only as the result of human intervention an unpatentable natural phenomenon. This seems nonsensical – after all, what invention, in any area of technology, does not at some level involve natural processes? Any electronic invention relies on the fundamental nature of electrons and materials such as silicon. Mechanical inventions rely on the law of gravity and friction. And what biological invention does not involve natural biological processes?

All three decisions are on track for review by the Federal Circuit. I think it is particularly important that the court reverse the Prometheus courts unduly broad definition of unpatentable natural phenomenon, which in combination with its “wholly preempted” test could render many important biotechnology or pharmaceutical patents susceptible to challenge under section 101. For example, a patent claiming a drug product could be characterized as wholly preempting the “natural phenomenon” of the drugs pharmacologic effect in the human body. A method of treatment claim might be challenged for wholly preempting the correlation between administration of the drug and therapeutic effect.

The approach adopted by the Prometheus court would seem to bode particularly ill for the patentability of personalized medicine inventions. In a broad sense, personalized medicine refers to assessment of an individual patient’s safety and efficacy profile for a drug, and selecting drugs and dosage regimens based on this assessment. Fundamentally, personalized medicine relies on the discovery of correlations between biomarkers and the safety and efficacy of drugs in an individual. But under the Prometheus court’s approach, such correlations would seem to be natural phenomena, since they are based on natural processes, even though the correlations would not exist absent human intervention by administration of a drug to a patient. This approach would render questionable the validity of any patent broadly claiming the use of such a correlation.

It is unclear to what role the patenting of such man-made correlations will play in the development of personalized medicine. Perhaps some would argue that broad personalized medicine patents will actually deter innovation and commercialization in this important area. But I question whether the blunt tool of the patentable subject matter doctrine is the appropriate mechanism for determining the patentability of such inventions. This interpretation of Section 101 would seem to open up the door to challenging a number of important issued patents in the biological realm, leading at the very least to increased litigation and uncertainty in this important technology sector.

Tuesday, August 5, 2008

Federal Circuit Interprets the 271(e)(1) Regulatory Approval Exemption Narrowly, a Welcome Development for the Developers of Research Tools

Today in Proveris Scientific v. Innovasystems the Federal Circuit construed the Section 271(e)(1) regulatory approval exemption narrowly, holding that the sale of a device known as an Optical Spray Analyzer (“OSA”)" does not fall within the 271(e)(1) safe harbor. As discussed in a previous post, the defendant argued that because the device is intended solely for use in generating data for submission to FDA under the FDCA and is only sold to pharmaceutical companies or FDA, sales of the OSA falls squarely within the plain language of the statute, which states in relevant part that “[i]t shall not be an act of infringement to . . . offer to sell, or sell . . . a patented invention solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.” However, in a unanimous decision penned by Judge Schall, the Federal Circuit rejected this argument, holding that the OSA is not a “patented invention” because it is not a product that requires FDA premarket approval.

Citing to Eli Lilly v. Medtronic, a 1990 Supreme Court decision which held that the 271(e)(1) safe harbor applies to class III medical devices, Judge Schall noted that Congress had enacted 271(e)(1) primarily as a means of addressing two unintended “distortions” of the effective patent term of drugs. As the result of the second of these distortions, prior to the enactment of 271(e)(1) (as part of the Hatch-Waxman Act) drug patent owners enjoyed a de facto patent term extension resulting from the lag between patent expiration and the time required to secure FDA approval for a generic version of a drug (or other FDA regulated product.” However, the court held that “[b]ecause the OSA device is not subject to FDA premarket approval, and therefore faces no regulatory barriers to market entry upon patent expiration, [the defendant] is not a party who, prior to enactment of [271(e)(1)], could be said to have been adversely affected by the second distortion. For this reason, we do not think Congress could have intended that the safe harbor of section 271(e)(1) apply to it.”

Of course, in its 2005 Merck v. Integra decision, the Supreme Court held that the 271(e)(1) exemption applied to patented peptides used as research tools in preclinical drug discovery. Thus, the “patented invention” in Merck was not subject to FDA premarket approval but nevertheless fell within 271(e)(1). So although on its face Proveris suggests that 271(e)(1) only applies to products that require premarket approval, this would appear to be inconsistent with Merck - although in principle one might argue that one could seek FDA approval for Integra’s patented peptides, from a practical point of view these were never true drug candidates. Notably, Proveris does not mention the nature of the “patented invention,” in Merck, or attempt to reconcile the two decisions. But if the court had held that 271(e)(1) applied to the patented OSA, the decision would have raised serious doubts as to the value of a host of patents claiming instruments used in drug development research, and research tool patents in general. In his dissent to the Federal Circuit’s decision in Merck on remand, Judge Rader suggested that in that case the majority had effectively eliminated patent protection for research tools, but judging from the court’s decision in Proveris this clearly does not seem to be the case. A great deal of uncertainty remains with respect to where the court’s will draw the line between the “patented inventions” falling within the exemption (such as the peptides in Merck), and research tools falling outside the safe harbor.