Tag: supreme court

26
Mar

Supreme court vacates ruling on BRCA gene patent!

As Reeves alluded to in his post about the Mayo personalized medicine case, the Supreme Court just vacated the lower court’s ruling in Association for Molecular Pathology v. Myriad Genetics (No. 11-725). The case has been sent back down to the Federal Circuit for reconsideration in light of the Court’s decision in Mayo.  This means that the Supreme Court thought the two cases were sufficiently similar that the lower courts should take another look using the new direction from Mayo.

 It’s looking more and more like the Supreme Court is strongly opposed to personalized medicine patents. 

20
Mar

Laws of Nature and the Law of Patents: Supreme Court Rejects Patents for Correlations

This is a guest post by Reeves Anderson, an associate at Arnold and Porter LLP. Reeves Anderson is a member of the Appellate and Supreme Court practice group at Arnold & Porter LLP in Washington, D.C.  The views expressed herein are those of the author alone and not of Arnold & Porter LLP or any of the firm’s clients. Stay tuned for follow-up posts by the Simply Statistics crowd on the implications of this ruling for statistics in general and personalized medicine in particular. 

With the country’s attention focused on next week’s arguments over the constitutionality of President Obama’s health care law, the Supreme Court slipped in an important decision today concerning personalized medicine patents.  In Mayo Collaborative Services v. Prometheus Laboratories, the Court unanimously struck down medical diagnostic patents that concerned the use of thiopurine drugs in the treatment of autoimmune diseases.  Prometheus’s patents, which provided that doctors should increase or decrease a treatment dosage depending on metabolite correlations, was ineligible for patent protection, the Court held, because the patents “simply stated a law of nature.” 

As Jeff aptly described the issue in December, Prometheus’s patents sought to control a treatment process centered “on the basis of a statistical correlation.”  Specifically, when a patient ingests a thiopurine drug, metabolites form in the patient’s bloodstream.  Because the production of metabolites varies among patients, the same dosage of thiopurine causes different effects in different patients.  This variation makes it difficult for doctors to determine optimal treatment for a particular patient.  Too high of a dosage risks harmful side effects, whereas too low would be therapeutically ineffective. 

But measurement of a patient’s metabolite levels—in particular, 6-thioguanine and its nucleotides (6-TG) and 6-methyl-mercaptopurine (6-MMP)—is more closely correlated with the likelihood that a particular dosage of a thiopurine drug could cause harm or prove ineffective.  As the Court explained today, however, “those in the field did not know the precise correlations between metabolite levels and the likely harm or ineffectiveness.”  This is where Prometheus stepped in.  “The patent claims at issue here set forth processes embodying researchers’ findings that identified those correlations with some precision.”  Prometheus contended that blood concentrations of 6-TG or of 6-MMP above 400 and 7,000 picomoles per 8x108 red blood cells, respectively, could be toxic, while a concentration of 6-TG metabolite less than 230 pmol per 8x108 red blood cells is likely too low to be effective. 

Prometheus utilized this correlation by patenting a three-step method by which one (i) administers a drug providing 6-TG to a patient with an autoimmune disease; (ii) determines the level of 6-TG in the patient; and (iii) the administrator then can determine whether the thiopurine dosage should be adjusted accordingly.  Significantly, Prometheus’s patents did not include a treatment protocol and thus applied regardless of whether a doctor actually altered his treatment decision in light of the test—in other words, even if the doctor thought the correlations were wrong, irrelevant, or inapplicable to a particular patient.  And in fact, Mayo Clinic, the party challenging Prometheus’s patents, believed Prometheus’s correlations were wrong.  (Mayo’s toxicity levels were 450 and 5700 pmol per 8x108 red blood cells for 6-TG and 6-MMP, respectively.  At oral argument on December 7, 2011, Mayo insisted that its numbers were “more accurate” than Prometheus’s.) 

Turning to the legal issues, both parties agreed that the correlations were “laws of nature,” which, by themselves, are not patentable.  As the Supreme Court has explained repeatedly, laws of nature, like natural phenomena and abstract ideas, are “manifestations of … nature, free to all men and reserved exclusively to none.”  This principle reflects a concern that patent law ought not inhibit further discovery and innovation by tying up the “basic tools of scientific and technological work.” 

In contrast, the application of a law of nature is patentable.  The question for the Court, then, was whether Prometheus’s patent claims “add enough to their statements of correlations to allow the process they describe to qualify as patent-eligible processes that apply natural laws.” 

The Court’s answer was no.  Distilled down, Prometheus’s “three steps simply tell doctors to gather data from which they may draw an inference in light of the correlations.”  The Court determined that Prometheus’s method simply informed the relevant audience (doctors treating patients with autoimmune diseases) about a law of nature, and that the additional steps of “administering” a drug and “determining” metabolite levels were “well-understood, routine, conventional activity already engaged in by the scientific community.”  “[T]he effect is simply to tell doctors to apply the law somehow when treating their patients.”   

Although I leave it to Jeff & company to assess the impact of today’s decision on the practice of personalized medicine, I have two principal observations.  First, it appears that the Court was disturbed by Mayo’s insistence that the correlations in Prometheus’s patents were wrong, and that patent protection would prevent Mayo from improving upon them.  Towards the end of the opinion, Justice Breyer wrote that the patents “threaten to inhibit the development of more refined treatment recommendations (like that embodied in Mayo’s test), that combine Prometheus’s correlations with later discovered features of metabolites, human physiology or individual patient characteristics.”  The worry of stifling future innovation applies to every patent, but the Court seemed especially attuned to that concern here, perhaps due in part to Mayo’s insistence that its “better” test could not be used to help patients. 

Second, Mayo argued that a decision in its favor would reduce the costs of challenging similar patents that purported to “apply” a natural law.  Mayo’s argument was in response to the position of the U.S. Government, which participated in the case as amicus curiae (“friend of the court”).  The Government urged the Court not to rule on the threshold issue of whether Prometheus’s patents applied a law of nature, but rather to strike down the patents because they lacked “novelty” or were “obvious in light of prior art.”  The questions of novelty and obviousness, Mayo argued, are much more fact-intensive and expensive to litigate.  Whether or not the Court agreed with Mayo’s argument, it declined to follow the Government’s advice.  To skip the threshold question, the Court concluded, “would make the ‘law of nature’ exception … a dead letter.” 

Many Supreme Court watchers will now turn their attention to another patent case that has been waiting in the wings, Association for Molecular Pathology v. Myriad Genetics, which asks the Court to decide whether human genes are patentable.  Predictions anyone?

20
Mar

Supreme court unanimously rules against personalized medicine patent!

Just a few minutes ago the Supreme Court released their decision in the Mayo case, see here for the Simply Statistics summary of the case. The court ruled unanimously that the personalized medicine test could not be patented. Such a strong ruling likely has major implications going forward for the field of personalized medicine. At the end of the day, this decision was based on an interpretation of statistical correlation. Stay tuned for a special in-depth analysis in the next couple of days that will get into the details of the ruling and the implications for personalized medicine. 

12
Dec

The Supreme Court's interpretation of statistical correlation may determine the future of personalized medicine

Summary/Background

The Supreme Court heard oral arguments last week in the case Mayo Collaborative Services vs. Prometheus Laboratories (No 10-1150). At issue is a patent Prometheus Laboratories holds for making decisions about the treatment of disease on the basis of a measurement of a specific, naturally occurring molecule and a corresponding calculation. The specific language at issue is a little technical, but the key claim from the patent under dispute is:

1. 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 level of 6-thioguanine less than about 230 pmol per 8x10^8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and  

wherein the level of 6-thioguanine greater than about 400 pmol per 8x10^8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

So basically the patent is on a decision made about treatment on the basis of a statistical correlation. When the levels of a specific molecule (6-thioguanine) are too high, then the dose of a drug (thiopurine) should be decreased, if they are too low then the dose of the drug should be increased. Here (and throughout the post) correlation is interpreted more loosely as a relationship between two variables; rather than the strict definition as the linear relationship between two quantitative variables. 

This correlation between levels of 6-thioguanine and patient response was first reported by a group of academics in a paper in 1996. Prometheus developed a diagnostic test based on this correlation. Doctors (including those at the Mayo clinic) would draw blood, send it to Prometheus, who would calculate the levels of 6-thioguanine and report them back. 

According to Mayo’s brief, some Doctors at the Mayo, who used this test, decided it was possible to improve on the test. So they developed their own diagnostic test, based on a different measurement of 6-thioguanine (6-TGN) and reported different information including:

  • A blood reading greater than 235 picomoles of 6-TGN is a “target therapeutic range,” and a reading greater than 250 picomoles of 6-TGN is associated with remission in adult patients; and
  • A blood reading greater than 450 picomoles of 6-TGN indicates possible adverse health effects, but in some instances levels over 700 are associated with remission without significant toxicity, while a “clearly defined toxic level” has not been established; and
  • A blood reading greater than 5700 picomoles of 6-MMP is possibly toxic to the liver.

They subsequently created their own proprietary test and started to market that test. At which point Prometheus sued the Mayo Clinic for infringement. The most recent decision on the case was made by a federal circuit court who upheld Prometheus’ claim. A useful summary is here

The arguments for the two sides are summarized in the briefs for each side; for Mayo

Whether 35 U.S.C. § 101 is satisfied by a patent claim that covers observed correlations between blood test results and patient health, so that the patent effectively preempts use of the naturally occurring correlations, simply because well-known methods used to administer prescription drugs and test blood may involve “transformations” of body chemistry.

and for Prometheus

Whether the Federal Circuit correctly held that concrete methods for improving the treatment of patients suffering from autoimmune diseases by using  individualized metabolite measurements to inform the calibration of the patient’s dosages of synthetic thiopurines are patentable processes under 35 U.S.C. §101. 

Basically, Prometheus claims that the patent covers cases where doctors observe a specific data point and make a decision about a specific drug on the basis of that data point and a known correlation with patient outcomes. Mayo, on the other hand, says that since the correlation between the data and the outcome are naturally occurring processes, they can not be patented. 

In the oral arguments, the attorney for Mayo makes the claim that the test is only patentable if Prometheus specifies a specific level for 6-thioguanine and a specific treatment associated with that level (see page 21-24 of the transcript). He then goes on to suggest that the Mayo would then be free to pick another level and another treatment option for their diagnostic test. Justice Breyer disagrees even with this specific option (see page 38 of the transcript and his fertilizer example). He has made this view known before in his dissent to the dismissal of the Labcorp writ of certori (a very similar case focusing on whether a correlation can be patented). 

Brief summary: Prometheus is trying to patent a correlation between a molecule’s level and treatment decisions. Mayo is claiming this is a natural process and can’t be patented.  

Implications for Personalized Medicine (a statistician’s perspective)

I believe this case has major potential consequences for the entire field of personalized medicine. The fundamental idea of personalized medicine is that treatment decisions for individual patients will be tailored on the basis of data collected about them and statistical calculations made on the basis of that data (i.e. correlations, or more complicated statistical functions).

According to my interpretation, if the Supreme Court rules in favor of Mayo in a broad sense, then this suggests that decisions about treatment made on the basis of data and correlation are not broadly patentable. In both the Labcorp dissent and the oral arguments for the Prometheus case, Justice Breyer argues that the process described by the patents:

…instructs the user to (1) obtain test results and (2) think about them. 

He suggests that these are natural correlations and hence can not be patented, just the way a formula like E = mc^2 can not be patented. The distinction seems to be subtle, where E=mc^2 is a formula that exactly describes a property of nature, the observed correlation is an empirical estimate of a parameter calculated on the basis of noisy data. 

From a statistical perspective, there is little difference between calculating a correlation and calculating something more complicated, like the Oncotype DX signature. Both return a score that can be used to determine treatment or other health care decisions. In some sense, they are both “natural phenomena” - one is just more complicated to calculate than the other. So it is not surprising that Genomic Health, the developers of Oncotype, have filed an amicus in favor of Prometheus. 

Once a score is calculated, regardless of the level of complication in calculating that score, the personalized decision still comes down to a decision made by a doctor on the basis of a number. So if the court broadly decides in favor of Mayo, from a statistical perspective, this would seemingly pre-empt patenting any personalized medicine decision made on the basis of observing data and making a calculation. 

Unlike traditional medical procedures like surgery, or treatment with a drug, these procedures are based on data and statistics. But in the same way, a very specific set of operations and decisions is taken with the goal of improving patient health. If these procedures are broadly ruled as simply “natural phenomena”, it suggests that the development of personalized decision making strategies is not, itself, patentable. This decision would also have implications for other companies that use data and statistics to make money, like software giant SAP, which has also filed an amicus brief in support of the federal circuit court opinion (and hence Prometheus).

A large component of medical treatment in the future will likely be made on the basis of data and statistical calculations on those data - that is the goal of personalized medicine. So the Supreme Court’s decision about the patentability of correlation has seemingly huge implications for any decision made on the basis of data and statistical calculations. Regardless of the outcome, this case lends even further weight to the idea that statistical literacy is critical, including for Supreme Court justices. 

Simply Statistics will be following this case closely; look for more in depth analysis in future blog posts.