The week of February 11 marks the start of the Molecular Medicine Tri-Conference in San Francisco. It’s an overwhelming array of topics related to molecular diagnostics. Just a partial list includes cancer diagnostic markers, immuno-oncology biomarkers and cancer immunotherapy, companion diagnostics, liquid biopsy, NGS-based molecular diagnostics, and big data analysis.
At a time where the breadth and complexity of diagnostics has expanded, it is ironic that protecting the intellectual property surrounding these tools and methods is challenging, and for some, quite frustrating. Take the example of Sequenom’s cell-free DNA assay set forth in U.S. Patent No. 6,258,540. Claim 1 states:
A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
When Sequenom accused certain prenatal and paternity testing labs of infringing claims of the its patent, the defendants countered that the claims were invalidity as ineligible subject matter. The courts agreed, reasoning that cell-free fetal DNA (cffDNA) is a naturally-occurring phenomenon and detecting it with routine conventional methods is not patentable.
Ironically, courts have recognized that discoveries of natural products and naturally-occurring phenomenon are valuable scientific contributions. However, then they turn around and say, even so, whether it be the BRCA-1 and BRCA-2 genes linked to breast cancer or the creative use of cffDNA in previously discarded plasma or serum, “such valuable contributions can fall short of statutory patentable subject matter.”
Some circumstances, which don’t seem too different, have met a better fate. For instance, the CellzDirect case appears to have some similarities, yet came out with a different result. The method at issue selects specific liver cells using multiple freeze-thaw cycles. Here is claim 1 of the patent (U.S. Patent No. 7,604,929):
A method of producing a desired preparation of multi-cryopreserved hepatocytes, said hepatocytes being capable of being frozen and thawed at least two times, and in which greater than 70% of the hepatocytes of said preparation are viable after the final thaw, said method comprising:
(A) subjecting hepatocytes that have been frozen and thawed to density gradient fractionation to separate viable hepatocytes from nonviable hepatocytes,
(B) recovering the separated viable hepatocytes, and
(C) cryopreserving the recovered viable hepatocytes to thereby form said desired preparation of hepatocytes without requiring a density gradient step after thawing the hepatocytes for the second time, wherein the hepatocytes are not plated between the first and second cryopreservations, and wherein greater than 70% of the hepatocytes of said preparation are viable after the final thaw.
The court found this method to be patent eligible even though the liver cells are a natural product and freeze-thaw is not exactly a high-tech novel technique. How can that be? CellzDirect wasn’t claiming the hepatocytes (i.e., the naturally occurring material) and the method went directly against the teachings in the literature about survival of freezing and thawing cells, making it novel, even if less exciting to some than discovering cffDNA.
So, where has this taken the field with respect to IP protection?
Several approaches have emerged.
One approach appears to rely on brute force and perseverance. This mode begins with essentially the same type of claims that have been challenged previously, such as PCR methods for detecting and monitoring disease based on 1 or more alleles, and then fights it out with the US Patent Office to see just how much more will be necessary to add to get an issued claim. What come out the other end varies from fairly narrowly tailored assays with specific primers and probes, to broader methods that look susceptible to later challenge.
Another approach is to focus on the complexity of the assay, and/or the data management supporting the detection. For example, some claims combine a number of primers for allele detection, with specific labeling and detection techniques and/or data analysis algorithms. The additions provide the “something more” to draw the diagnostic method using naturally occurring DNA sequences over to the side of patent eligibility. One argument supporting this approach is that the addition of these specifics does not preempt others from using alternative methods not covered by the claims to get to the same result. While likely helpful, the Federal Circuit has said that the absence of preemption is not enough to make a method or diagnostic tool patent-eligible subject matter.
A third approach has been the combination of a detection method coupled with a specific drug selection and administration. This last approach is more amenable to companion diagnostics. For example, claim 1 of US Patent No. 9,170,260:
A method for administering a lipid lowering agent to a human patient based on elevated levels of myeloperoxidase (MPO) mass and/or activity comprising:
(a) performing an enzyme linked immunosorbent assay (ELISA) comprising contacting a serum or plasma sample with an anti-MPO antibody and a peroxidase activity assay to determine MPO activity in the serum or plasma sample;
(b) selecting a patient who has elevated levels of MPO mass and/or activity compared to levels of MPO mass and/or activity in apparently healthy control subjects; and
(c) administering a lipid lowering agent to the selected human patient.
This claim was challenged during litigation – but not on subject matter eligibility. For context, its fellow claims from a related patent were found to be patent ineligible. For example, claim 11 of U.S. Patent No. 7,223,552 uses MPO levels to assess a link to cardiovascular disease, but does not include a step of administering a drug:
A method of assessing a test subject’s risk of having atherosclerotic cardiovascular disease, comprising
comparing levels of myeloperoxidase in a bodily sample from the test subject with levels of myeloperoxidase in comparable bodily samples from control subjects diagnosed as not having the disease, said bodily sample being blood, serum, plasma, blood leukocytes selected from the group consisting of neutrophils, monocytes, sub-populations of neutrophils, and sub-populations of monocytes, or any combination thereof;
wherein the levels of myeloperoxidase in the bodily from the test subject relative to the levels of myeloperoxidase in the comparable bodily samples from control subjects is indicative of the extent of the test subject’s risk of having atherosclerotic cardiovascular disease.
Was the addition of the drug administration step the answer to a successful claiming strategy? Not really. Instead of finding the claim invalid due to subject matter ineligibility, the court determined the claim was not infringed by the lab carrying out the MPO measurements. The disconnect was the step of administering the drug. The lab only provided the first 2 steps. Doctors performed the final step of the claim.
This type of division, where more than one entity performs steps within the same claim, is termed “divided infringement.” To prove infringement, all of the steps must be attributable to one of the entities (such as a joint enterprise or where one party controls the actions of another). This is generally difficult (and sometimes impossible) if there is no evidence of control, e.g., no facts to show that the lab directs the doctors’ decisions.
With the diagnostic claim here, Cleveland Clinic tried another approach, arguing that the lab was selling the results to the doctors and thus contributing to the infringement. But the way the patent statute is worded, selling a diagnostic service doesn’t qualify. The Clinic also argued that the lab induced the doctors to infringe the claim by relying on the reports and prescribing lipid lowering drugs. This could be a potentially plausible basis, but it demands proof of the connection between the lab and the doctors’ actions.
Where does this land us? Between a rock and a hard place. Adding more steps and details can move the claims into patent eligible landscape. But at the same time, the claims can become quite limited to very specific tools and methods. This may allow others to take advantage of a new and valuable discovery using variations outside of the claim scope. Or if the new steps add actions from multiple entities, then the claim may be patent eligible but difficult to enforce against competitors.
Is there a solution? One possibility is that the pendulum may swing back and restore some aspects of patentability for methods that use natural phenomena for new uses or in new ways. For instance, the Cleveland Clinic has challenged the invalidation of its diagnostic methods and is asking the Supreme Court to reverse the holding. Absent a shift in the law, the other approach is creativity in claiming diagnostic tools and methods, and in deciding what aspects make good trade secrets and provide a competitive edge without patent protection.
Interested in more? Join me, Travis Wohlers (Assistant General Counsel, Luminex Corporation), and Amy McCourt, Director, IP and Commercial Litigation, Illumina) for a breakout panel discussion at the Tri-Conference on February 13th at 5 pm at Table 15.
I’ll also have a poster on this topic at the conference entitled “I Didn’t Ask for Extra Mayo: The Evolution of Patent Protection for Diagnostics.” I am happy to send you an electronic copy of the poster if it peaks your curiosity, just send me an email request at firstname.lastname@example.org or reach me on LinkedIn.
 Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015).
 Ariosa, 788 F.3d at 1380.
 Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042 (Fed. Cir. 2016).
 See Ariosa, 788 F.3d at 1379 (“While preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility.”).
 Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352 (Fed. Cir. 2017)
 Akamai Techs., Inc. v. Limelight Networks, Inc., 797 F.3d 1020, 1022 (Fed. Cir. 2015)