With its promise of tailoring drugs and treatments to individual patients, personalized medicine is often touted as the next frontier in medicine. But there is at least one major concern that may slow, or even limit, this burgeoning field’s success. Recent legal decisions in the United States have put into question whether many of the inventions enabling personalized medicine will ultimately be found patentable.

Genetic diversity among individuals is well recognized, yet we traditionally expect medicines to have universal applicability. Personalized medicine rejects this “one-size-fits-all” approach that has, to date, largely characterized the research and development efforts of the pharmaceutical industry. Instead, research in personalized medicine focuses on identifying biomarkers that can predict an individual’s condition or response to treatment.

Personalized medicine promises to identify commonalities among smaller populations of individuals, allowing more tailored treatments.

Consider the utility of identifying a biomarker that predicts the likelihood of an adverse drug reaction to an otherwise effective drug. A screening test to measure the presence of this biomarker would identify those individuals who should not take the drug. Use of the screening test could permit approval of a drug which would previously have been unsafe and therefore unmarketable, despite the drug’s effectiveness. Identification of such a biomarker is just one example of the potential value the field of personalized medicine offers.

There is no reason to suggest that the fundamental quid pro quo of the patent system (providing a limited monopoly in exchange for disclosing the invention to the public) is not equally applicable to personalized medicine inventions. In the hypothetical example, the biomarker is arguably as valuable as the drug, and significant research and development dollars are required to identify and develop both. Yet, as a result of the recent decision In re Bilski, (545 F.3d 943 (C.A.F.C. 2008) (en banc)), the use of such a newly identified biomarker may not be considered subject matter capable of patent protection.

Bilski was a decision made in the context of a so-called “business method” patent. The patent was directed to a method of managing the risk costs relating to the buying and selling of commodities. The Court had to decide what constitutes a patentable “process” pursuant to s.35 U.S.C.§ 101. Section § 101 defines patentable subject matter as an invention or discovery of “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof”. Having found that a method of managing risk was not a machine, manufacture, or composition of matter, the majority proceeded to limit patentable processes (methods) to those that can meet the “machine or transformation test”. This test was originally suggested (and seemingly rejected) in Gottschalk v. Benson 409 U.S. 63 (1972). The test, as adopted in Bilski, is articulated as follows:

“a process must be tied to a particular machine or apparatus or must operate to change articles or materials to a different state or thing.”

Despite strong dissenting opinions, the majority found the patent in issue invalid for failing to claim patentable subject matter, arguing that no transformation of matter had occurred and no machine or apparatus was involved. The Court left undecided the extent to which a computer or machine would be required in order to meet the threshold of the newly imposed test.

Consider then the use of the hypothetical biomarker described above. A biomarker, by definition pre-exists in the human body, and a priori is not novel. The isolated biomarker, or the compound used to detect the biomarker, is also becoming more difficult to patent in light of recent efforts to sequence the entire human genome. A newly sequenced gene was recently found to be unpatentable in the United States on the grounds that the invention was considered obvious in light of the techniques well known to a person skilled in the art (see In re Kubin No. 2008-1184 (C.A.F.C. 2009)).

In the absence of an ability to protect the biomarker as novel, it may be necessary to rely on the protection afforded to the use of the biomarker. The decision in Bilski however, may make it difficult to protect the use of the biomarker, as this may be found to constitute unpatentable subject matter. A test to identify or quantify a single biomarker may not require the use of a machine or apparatus (although arguably the tendency towards use of multiple biomarkers with complicated algorithms does). In addition, the transformation branch of the Bilski test could be difficult to meet. The use of a biomarker to identify or predict a disease state or therapeutic response may not be considered to transform that biomarker into a different state or thing. If it is found that adding in a computer readable step into the testing process is not sufficient, then the measurement of the biomarker, and the use of that information to inform a decision regarding the utility of a given drug, is likely to fail both the machine and the transformation branches of the Bilski test.

Even before the decision in Bilski, there have been strong hints that the courts may be unwilling to uphold the patentability of methods directed to using a biomarker to predict an individual’s medical condition. In Lab. Corp. of Am. Holdings v. Metabolite Labs., Inc., 126 S. Ct. 2921 (2006), a case ultimately dismissed by the U.S. Supreme Court, the patent in issue claimed a new method to identify individuals suffering from cobalamin or folate deficiency. More particularly, the claim reads:

A method for detecting a deficiency of cobalamin or folate in warmblooded animals comprising the steps of: assaying a body fluid for an elevated level of total homocysteine; and correlating an elevated level of total homocysteine in said body fluid with a deficiency of cobalamin or folate (U.S. 4,940,658)

A strong dissent was issued by the minority of the court arguing that the subject matter of the claim was directed to a non-patentable “phenomenon of nature”. Although the case was ultimately dismissed, the aversion of certain members of the U.S. Supreme Court to consider the subject matter in Lab. Corp. patentable is concerning. Like the hypothetical case raised above, the homocysteine, and some methods of detecting homocysteine, were not novel. The invention, therefore, lay in the identification of the use of homocysteine as a biomarker of vitamin deficiency. Without any apparatus, and no apparent transformation, it is unlikely that the Lab. Corp. claim could survive the application of the Bilski test as currently formulated.

It is too early to measure the full impact of the Bilski decision. There have only been a few biotechnology cases reviewed under Bilski at this time, and only one of particular relevance. The results of that case are not promising. In Classen Immunotherapies, Inc., v. Biogen Idec (Federal Circ. 2006-1634 (unreported) affirming 381 F. Supp. 2d 452 (2005)), the Bilski decision was relied on to summarily affirm a district court’s grant of summary judgment. The decision was based on the determination that the claims did not encompass proper statutory subject matter. In Classen, the main claim was directed to a method of determining whether an immunization schedule affects the incidence or severity of a chronic immune mediated disorder. The claim reads:

A method of determining whether an immunization schedule affects the incidence or severity of a chronic immune-mediated disorder in a treatment group of mammals, relative to a control group of mammals, which comprises immunizing mammals in the treatment group of mammals with one or more doses of one or more immunogens, according to said immunization schedule, and comparing the incidence, prevalence, frequency or severity of said chronic immune-mediated disorder or the level of marker of such a disorder, in the treatment group, with that in the control group (U.S. 5,723,283).

Arguably, the subject matter of the Classen claim is quite different from the subject matter in Lab. Corp. While the Lab. Corp. claim attempts to capture the new application of a useful biomarker, the subject matter of Classen merely represents a method of identifying biomarkers. In essence, the Classen patent is directed to a plan to perform a research study without any current tangible results. No distinction, however, was noted in the one paragraph decision by the Court of Appeal, which readily dismissed the Classen appeal, citing Bilski.

Prometheus Labs., Inc. v. Mayo Collaborative Svcs., 86 U.S.P.Q. 2d 1705 (S.D. Cal.) (Mar. 28, 2008) is another decision of key importance, although this case was decided prior to the release of the Bilski. In Prometheus, the District Court invalidated claims directed to a method of determining the most appropriate, and least toxic therapeutic dose range for drugs used to treat immune-mediated gastrointestinal disorders. Of interest, the invention originated in Canada. One of the key claims of the U.S. patent reads:

A method of optimizing therapeutic efficacy for treatment of an immune mediated gastrointestinal disorder, comprising:

(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

(b) determining the level of 6- thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the levels of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject, and wherein the levels of 6- thioguanine greater than about 400pmol per 8 x 108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject. (U.S. 6,680,302)

The District Court relied on the reasoning outlined by the dissent in Lab. Corp. and found the subject matter not patentable. More specifically, the District Court argued: “at most, respondents have simply described the natural law at issue in the abstract patent language of a ‘process’. But they cannot avoid the fact that the process is no more than an instruction to read some numbers in light of medical knowledge”.

It was decided that the main purpose of the claimed invention was to correlate the level of 6-thioguanine with the therapeutic effect, and as such, the invention was directed to a non-patentable “natural phenomenon.” The characterization of the invention as a “mere reading of numbers in light of medical knowledge” fails, however, to recognize the contribution of the identification of the utility of the biomarker. The finding is even more concerning because the metabolite was not “naturally occurring”, but rather a metabolite of the drug, and thus produced solely as a result of ingestion of a man made composition. This later point was raised, but rejected by the Court as being irrelevant to the analysis. Furthermore, the plaintiff attempted to rely on In re Comiskey, (499 F.3d 1265 (Fed. Cir. 2007)) to argue that the inclusion of a machine would automatically make the claims patentable. Although the claims do not refer to an apparatus or machine per se, the plaintiff argued that the claims inherently required the use of “specific machines” to detect the level of the metabolites (for example, the use of a high performance liquid chromatography device). The Court rejected this argument, indicating that a mere incidental involvement of a machine to the process does not save an otherwise unpatentable method. This decision, at least, suggests that the incorporation of a machine or apparatus, if no more than peripherally relevant, will not be of assistance if the Bilski test is applied.

The Prometheus decision is currently under appeal and at issue, amongst other items, will be whether the test formulated in Bilski is applicable. The outcome of the Prometheus appeal is therefore of primary importance to the personalized medicine industry. To date, numerous intervenors, including the American Intellectual Property Institute, BIO, Novartis and Myriad Genetics, have filed amicus briefs, arguing in favor of patent protection for diagnostic and personalized medicine inventions. With Labcorp, Classen, and a lower court decision in Prometheus all suggesting that the correlation of biomarker to an individual’s state is not patentable, there is reason for concern.

It is hoped that the Bilski test will ultimately be found not to apply to biotechnology inventions. The Court of Appeal in Bilski did indicate that the machine or transformation test may be inappropriate for certain technologies. More particularly, the Court at p.14 states:

“Nevertheless, we agree that future developments in technology and the sciences may present difficult challenges to the machine-ortransformation test, just as the widespread use of computers and the advent of the Internet has begun to challenge it in the past decade. Thus, we recognize that the Supreme Court may ultimately decide to alter or perhaps even set aside this test to accommodate emerging technologies. And we certainly do not rule out the possibility that this court may in the future refine or augment the test or how it is applied.”

Furthermore, it is possible that the decision in Bilski will be overturned. A petition has been filed requesting certiorari be granted by the U.S. Supreme Court to hear the appeal, and if granted, it is hoped that the U.S. Supreme Court will overturn, or at least modify, the machine or transformation test to take into account technologies such as those developing in the field of personalized medicine.

The stakes, however, are high. Myriad’s comments (p. ix), filed in support of the Appellant, Prometheus Laboratories, Inc., highlight the dangers of the current state of the law to the advancement of the industry:

“Much like the drug industry, personalized medicine relies on expensive and risky clinical trials to decipher and confirm useful correlations between molecule markers and specific disease characters. In the post-Human Genome Project era, claims to diagnostic applications of such correlations are usually the only claims available to adequately protect the large investment needed to bring a personalized medicine product to market. …Claims like those at issue in this case, therefore, are virtually all that remain to incentivize the research and development of new personalized medicine products.” [emphasis in the original]

It is hoped that the appeal of the Prometheus case will yield a more favorable result. In the meantime, it is suggested that special care is taken with current patent applications in this area to ensure that various alternative claim strategies are utilized and the right to make future amendments is preserved.

A version of this article originally appeared in the May/June 2009 issue of the Burrill Report.