The U.S. Patent and Trademark Office recently issued U.S. Patent No. 8,642,270, which is entitled "Prognostic biomarkers to predict overall survival and metastatic disease in patients with triple negative breast cancer." The '270 patent, which is assigned to the VM Institute of Research (Montreal, Canada), contains claims to a method of treating breast cancer in a subject having triple negative breast cancer.
For some time doctors and scientists hypothesized that the diversity observed among breast tumors might be accompanied by diversity in gene expression patterns. Over ten years ago, Perou and colleagues published their work on the "Molecular portraits of human breast tumours" (Perou et al., 2000 Nature 406: 747-52) classifying human breast tumors based their gene expression profiles. This work was soon followed up with studies that linked the gene expression profiles of each breast cancer subtype with patient overall survival and disease free survival. One of the subtypes identified was the basal-like subtype. The basal-like subtype is also described as triple-negative breast cancer because it generally does not express estrogen receptor (ER), progesterone receptor (PR), and expresses only normal, but not amplified, levels of the human epidermal growth factor receptor 2 (HER2). Given the nature of the triple-negative breast tumors, this subtype does not respond to cancer drugs that target ER, PR or HER2 (i.e., Taxol® or Herceptin®), and has poorer overall survival and disease-free survival than other breast cancer subtypes. The triple negative paradox (Carey et al., 2007 Clin Cancer Res. 13(8): 2329-34) is that these tumors often respond well to the initial chemotherapy treatments, and yet patients have significantly poorer overall survival. The work by the inventors of the `270 patent helps to develop effective methods to determine whether a triple negative breast cancer patient is likely to have a recurrence or progress to the aggressive, metastatic disease in order to aid clinicians in deciding the appropriate course of treatment.
The '270 patent provides a method of treating breast cancer in a subject having a triple negative breast cancer. The inventors were able to identify a 12 gene set that correlates with overall survival of the triple negative breast tumors. More specifically, the inventors determined that the expression of STK3, KLF6, CD24 and KRAS, could be indicative of a recurrent triple negative breast tumor.
The '270 patent has one independent claim which recites:
1. A method of treating breast cancer in a subject having a triple negative (TN) breast cancer, the method consisting of the steps:
(a) quantifying mRNA expression level of biomarkers STK3 and KLF6, and at least one biomarker selected from CD24 and KRAS in a test sample from a subject using a biological assay;
(b) comparing said mRNA expression level of said biomarkers selected from STK3, KLF6, and at least one of CD24 and KRAS quantified in step (a) to the expression level of said biomarkers quantified using the biological assay in a standard sample indicative of a recurrent TN breast cancer; and
(c) administering an aggressive cancer treatment regimen to the subject based on an increase in the expression level of the biomarkers between the standard sample and the test sample.
A review of the file history of the '270 patent indicates that a rejection under 35 U.S.C. § 101 rejection was issued in the first Office Action. The Action stated that the claimed invention is directed to non-statutory subject matter because it is not a patent-eligible practical application of a law of nature and because the claimed method does not result in a physical transformation of matter. Specifically, the Action asserted that the claims do not recite additional elements or steps such that the method is sufficient to ensure that the claim amounts to significantly more than the natural principle itself or merely more than mental tasks.
The original claim 1 as filed recited:
1. A method of predicting the overall survival (OS) potential of a triple negative (TN) breast cancer in a subject, the method comprising the step:
(a) comparing expression level of at least one biomarker determined in a test sample from a subject to the expression level of the at least one biomarker in a standard sample indicative of a recurrent TN breast cancer, wherein the at least one biomarker is chosen from ANK3, CD24, EIF1, KLF6, KRAS, KRT1, MAP2K4, SDC4, SLC2A3, STK3, TFAP2C, and WRN; and wherein a difference in the expression level of the at least one biomarker between the standard sample and the test sample is used to predict the OS potential of the TN breast cancer in the subject.
In response, the Applicant amended claim 1 to introduce an additional step of modifying a treatment regimen of the subject based on the results of step (a). The Applicant asserted that with the new step, the method as amounted to "significantly more than the application of a natural principle."
Claim 1 as amended recited:
1. (Currently Amended) A method of predicting the overall survival (OS) potential of a triple negative (TN) breast cancer in a subject, the method comprising the step:
(a) comparing a mRNA expression level of at least threeone biomarkers chosen from STK3, KLF6, and one of CD24 or KRAS determinedquantified using a biological assay in a test sample from a subject to the expression level of the at least threeone biomarkers quantified using the biological assay in a standard sample indicative of a recurrent TN breast cancer, wherein the at least one biomarker is chosen from ANK3, CD24, EIF1, KLF6, KRAS, KRT1, MAP2K4, SDC4, SLC2A3, STK3, TFAP2C, and WRN; and
(b) modifying a treatment regimen of the subject based on the results of step (a) wherein a difference in the expression level of the at least one biomarkers between the standard sample and the test sample is used to predict the OS potential of the TN breast cancer in the subject.
In the next and final Office Action mailed July 30, 2013, the Office maintained the rejection of the claims under 35 U.S.C. § 101 because the invention was not a patent-eligible practical application of a law of nature. The Action noted that the claims recited methods steps for detecting or determining and comparing marker levels from samples, but asserted that these steps are routine or conventional, and do not add anything substantial to the claim that amounts to significantly more than observing the natural principle itself. Regarding the step of "modifying a treatment regimen," the Action stated that such a step can be "accomplished mentally by thinking or designing a new treatment plan, and does not set forth any physical steps."
Furthermore, in the final Office Action, the Examiner suggested "amending the claims to recite an active step of administering a specified treatment regimen based on specific results (specific results such as increased or decreased mRNA levels of STK3, KLF6, and CD24 or KRAS relative to specific controls) to a patient population identified by such specific results." Additionally, the Action stated that "prediction of survival rates as correlated to naturally occurring mRNA levels are considered an observation of a naturally occurring principle and an active step must be added to the claimed method that amounts to significantly more than the observation of the natural principle."
On September 17, 2013, in the response to the final Office Action, the Applicant stated "without conceding the correctness of the Examiner's position and for the purpose of expediting prosecution, Claim 1 has been amended to introduce an additional step (c), as suggested by the Examiner." Claim 1 was amended claim 1 as shown below:
1. (Currently Amended) A method of predicting the overall survival (OS) potential of a triple negative (TN) treating breast cancer in a subject having a triple negative (TN) breast cancer, the method comprisingconsisting of the steps:
(a) quantifying mRNA expression levels of biomarkers STK3 and KLF6, and at least one biomarker selected from CD24 and KRAS in a test sample from a subject using a biological assay;
(b) comparing [[a]]said mRNA expression level of at least three said biomarkers chosen selected from STK3, KLF6, and at least one of CD24 andor KRAS quantified in step (a) using a biological assay in a test sample from a subject to the expression level of said the at least three biomarkers quantified using the biological assay in a standard sample indicative of a recurrent TN breast cancer; and
(c[[b]]) modifyingadministering an aggressive cancer treatment regimen ofto the subject based on the results of step (b[[a]]) wherein a difference an increase in the expression level of the biomarkers between the standard sample and the test sample is used to predict the OS potential of the TN breast cancer in the subject.
A notice of allowance was mailed on October 1, 2013.
