United States: A Patent-Eligible Diagnostic Method Claim

Last Updated: October 10 2019
Article by Courtenay C. Brinckerhoff

On Friday I will be speaking at the AUTM Eastern Regional Meeting, on a panel discussing patent eligibility issues for life sciences inventions. My topic relates to what the USPTO refers to as "nature-based products," but while reviewing recent USPTO Patent Trial and Appeal Board (PTAB) decisions, I came across many more addressing diagnostic methods. It was depressing seeing so many novel and non-obvious diagnostic methods deemed ineligible—will the tests ever reach the market without patent protection? —but interesting to see the type of method claims the PTAB found to satisfy 35 USC § 101. 

A Patent-Eligible Diagnostic Method Claim 

One PTAB decision that reversed the examiner and found diagnostic method claims eligible for patenting under § 101 is In re Lee, Appeal 2017-011014 (Jan. 14, 2019). The claim discussed in the opinion is reproduced below: 

  1. A method of determining an increased risk of colorectal cancer or Crohn's disease in an asymptomatic human subject, comprising:
    1. collecting mucosal epithelial cells from the buccal area of the subject by swabbing the buccal area, and extracting RNA from the swab; 
    2. producing cDNA from the extracted RNA; 
    3. measuring the level of cDNA for a panel of polynucleotides comprising at least three cDNA sequences comprising SEQ ID NO: 1, 21 and 23 from the cDNA produced from the extracted RNA; 
    4. applying each of the measured cDNA levels of the panel of polynucleotides against a database of Mahalanobis-distance (M-dist) values created by analyzing measured cDNA levels of a control panel of polynucleotides from control subjects with no polyps and no family or self-history of cancer or known upper GI problems, wherein the control panel of polynucleotides and the panel of polynucleotides comprise the at least three cDNA sequences, and wherein the applying compares the same polynucleotides expression levels for each of the at least three cDNA sequences using global multivariate analysis of variance (ANOVA) and Mahalanobis-distance (M-dist), wherein the Mdist has chi-square distribution with degrees of freedom equal to the number of polynucleotides in the panel, and wherein the database comprises M-dist values for at least three cDNA sequences comprising SEQ ID NO: 1, 21 and 23, and wherein the database is stored on a computer system; 
    5. determining the M-dist values for each of the at least three polynucleotides comprising SEQ ID NO: 1, 21, and 23 of the panel of polynucleotides from the asymptomatic human subject; and 
    6. indicating that the asymptomatic human subject has an increased risk of colorectal cancer or Crohn's disease if each of the M-dist values for the cDNA levels for the at least three cDNA sequences of SEQ ID NO: 1, 21 and 23 are greater than the 95% percentile of the database's M-dist values. 

The Alice/Mayo Analysis

The PTAB reviewed the examiner's rejection, which was based on the Alice/Mayo framework.  The PTAB agreed with the examiner's determination at step one, that the claims were directed to "a law of nature," i.e., "a naturally occurring correlation between the naturally occurring expressions of SEQ ID NO. 1, 21, and 23 and risk of colorectal cancer or Crohn's disease." Although at step two the examiner had determined that the other claim limitations were "routine in the art," the PTAB disagreed that the other claim limitations, "particularly as an ordered combination," were "well-known, routine and conventional." 

The PTAB explained (emphasis in original): 

Although we agree with the Examiner that the cited prior art references may disclose, individually or even in some relevant combination, buccal swabbing, genetic testing, or other individually claimed steps, we conclude that the references cited by the Examiner do not indicate that the claimed individual steps, much less the ordered combination thereof, were necessarily routine and/or conventional in the art. To the contrary, the cited references describe the relevant techniques as inventive or unconventional.

For example, although the examiner had cited a reference disclosing extracting RNA from a buccal sample, the PTAB noted that the reference stated that "the research team was the first to extract RNA from buccal swab samples because, previously, ribonucleases in saliva rapidly degraded epithelial cell RNA during collection." Additionally, although the examiner had cited a reference that disclosed "detecting certain gene expression to determine whether asymptomatic individuals are at risk of colon cancer," that reference sampled cells from the colon and "specifically states that there are many cell types in colonic mucosa and it was 'not know[n] which cell type is responsible for the observed altered gene expression.'" Thus, the PTAB concluded: 

Thus, while the claims may be directed to a natural phenomenon or law of nature, on some level, and the prior art might teach or suggest individual steps recited by the appealed claims, the evidence on appeal does not support a conclusion that the claimed steps, as an ordered combination, constitute mere routine and customary actions that do not provide the "something more" than the natural law upon which they may rely so as to provide an inventive concept.

The Claim That Would Have Been Patentable Before Mayo 

The underlying patent application was the U.S. national stage of a PCT application filed in 2008. The first Office Action, issued in December of 2011, rejected one claim under the pre-Bilski "machine and transformation" test. That rejection was easily overcome, but it took several responses to overcome enablement and obviousness rejections. It appears that the response filed with an RCE in February 2013 overcome all previous rejections, but in the next Office Action the examiner newly rejected all claims under § 101, citing Mayo. At the time, claim 1 read as follows:

  1. A method of determining an increased risk of colorectal cancer or Crohn's disease in an asymptomatic human subject, comprising:
    1. collecting mucosal epithelial cells from the buccal area of the subject; 
    2. measuring the expression level of a panel of polynucleotides comprising at least three cDNA sequences comprising SEQ ID NO: 1, 21 and 23 in the collected cells; 
    3. comparing the expression level of the panel of polynucleotides to the level of the same polynucleotides in a normal control; and 
    4. determining that a subject has increased risk of colorectal cancer or Crohn's disease based upon a change of at least 15 percent in the expression level of each of the at least three polynucleotides comprising SEQ ID NO:1, 21, and 23 of the panel of polynucleotides of the subject in comparison to the normal control, wherein an increase in the expression level of SEQ ID NO:1, 21 and 23 in the subject in comparison to the normal control is indicative of an increased risk of colorectal cancer or Crohn's disease.

Comparing this claim to the claim that was allowed reveals the scope of patent protection lost under the Mayo/Alice framework. Here, the applicant was lucky to have described in the application specific embodiments that were not well-understood, routine, or conventional. 

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