Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 43-64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/10/2026.
Applicant’s election without traverse of Group I, claims 32-42, in the reply filed on 02/10/2026 is acknowledged.
Specification
The use of the terms “RNeasy Mini Kit” (p43), “Qubit RNA BR Assay Kit” (p43), “Proteome Profiler Mouse XL Cytokine Array” (p44), “Agilent TapeStation” (p44), “Illumina Novoseq 6000” (p44), “Qiagen Mini-purification kit” (p45), “Qiagen EB elution buffer” (p45), “GraphPad Prism 7 software” (p48), and “Fiji ImageJ” (p48), which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 32-42 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and an abstract idea without significantly more.
Subject Matter Eligibility Test (see MPEP § 2106):
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed towards “a method of estimating a likelihood of cancer relapse for a subject following cancer treatment” (a process).
Step 2A: Are the claims directed to a judicial exception?
Prong 1: Do the claims recite an abstract idea, law of nature, or a natural phenomenon?
Yes, the claims describe the consequence of a natural phenomenon, e.g. the naturally-occurring relationship between the expression of SOX9 in cancer cells and the likelihood of cancer relapse as a result. This could also be considered an abstract idea (e.g., mental process) involving nothing more than manipulating data to reach a conclusion. An example of a claim that recites a mental process is “a claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016)” see MPEP 2106.04(a)(2).III.A.
Prong 2: Do the claims recite additional elements that integrate the judicial exception into a practical application?
Claim 32 recites the limitations of (1) “introducing ex vivo a nucleic acid molecule comprising a reporter gene…”, (2) “exposing ex vivo the cancer cells to a cancer treatment”, (3) “determining the amount of SOX9 positive cancer cells following cancer treatment based on expression of the reporter gene” which can all be considered insignificant extra-solution activity.
Limitation (1) relates to a method of detecting gene expression which is well known in the art and thus does not represent an improvement in existing technology. Per MPEP 2106.05(a).II: “Using well-known standard laboratory techniques to detect enzyme levels in a bodily sample such as blood or plasma, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1355, 1362, 123 USPQ2d 1081, 1082-83, 1088 (Fed. Cir. 2017).”
Limitation (2) represents mere data gathering in that a test is being performed to “obtain the input for an equation”, wherein the cells are subjected to a cancer treatment so that the resulting expression of SOX9 positive cells can be measured. see In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989).
Limitation (3) similarly involves determining the amount of positive SOX9 cells in a sample and thus represents nothing more than mere data gathering. see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012)
The additional limitations of claims 33-41 include, but are not limited to, determining the amount of SOX9 positive cells before/after treatment, using a viral vector to introduce a nucleic acid molecule ex vivo, cancer treatment options, and type of brain cancer. These can also be considered to be insignificant extra-solution activity.
Claim 42 recites “determining a subject to be likely to suffer from relapse based on the estimated likelihood” which is in-and-of-itself an abstract idea relating to a mental process with no additional limitations that would integrate it into a practical application.
Therefore, the addition of any of these limitations do not integrate the recited exception into a practical application.
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception?
The additional limitations of claims 32-42 are considered either insignificant extra-solution activity, or a judicial exception on its own, and thus do not amount to significantly more than the judicial exception either individually or when taken together.
In summary, claims 32-42 do not contain eligible subject matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 32-42 are rejected under 35 U.S.C. 103 as being unpatentable over Espersen (Espersen ML et al. Human pathology. 2016 Jun 1;52:38-4; IDS reference) in view of Lee (Lee SC et al. Pharmacogenetics and genomics. 2009 Nov 1;19(11):833-42), Yu (Yu M et al. Science. 2014 Jul 11;345(6193):216-20), and Hiraoka (Hiraoka K et al. Biochemical and biophysical research communications. 2015 May 1;460(2):216-21).
Espersen teaches a method for predicting the likelihood of colon cancer relapse based upon the expression of SOX9 in tumors (abstract). To develop this method, Espersen obtained primary tumor samples from colon cancer patients who had undergone treatment (primarily surgical resection) and performed immunohistochemistry targeting SOX9 on the samples (p39). Espersen found that there was a significant association between SOX9 expression and cancer relapse, indicating its potential importance in evaluating risk of relapse for personalized treatment (abstract).
Espersen does not teach exposing cancer cells ex vivo to a cancer treatment, nor the detection of SOX9 expression following said treatment through the use of a reporter gene, to assess a patient’s likelihood of relapse.
Lee describes the heterogeneity of cancer and the inherent issues with performing pre-treatment testing for prognosis purposes, theorizing that treatment outcomes may depend not only on a tumor’s intrinsic biology, but also a tumor’s cellular response to drug exposure (p833). Lee showed that postchemotherapy signatures were more prognostic than prechemotherapy signatures in predicting treatment outcomes and enables an assessment of resistance to, and effectiveness of, the treatment for the tumor (p839).
Yu discloses a method of performing ex vivo culturing of breast tumor cells in order to conduct individualized testing of drug susceptibility (abstract). Yu showed that tumor cells could be harvested from the peripheral blood of patients and successfully cultured long term (>6 months), thus providing a non-invasive way to monitor and optimize a patient’s treatment plan over the course of their disease (p217).
Hiraoka investigated the mechanism underlying increased expression of LGR5 in glioblastoma cells ultimately finding that it is directly upregulated by SOX9, with both LGR5 and SOX9 having been previously shown to play a major role in the poor prognosis of patients with a variety of different cancers, including glioblastoma (p216). One way in which this relationship was examined was through the use of a luciferase assay in which cells were transfected with a luciferase-reporter plasmid having a SOX9-binding site which served as a promoter for LGR5 (p217). Subsequent suppression of SOX9 showed decreased LGR5 expression and cell proliferation, highlighting the importance of the SOX9-LGR5 pathway to the tumorigenicity of glioblastoma cells (p219-220).
Taken together, these references collectively teach each feature of the claimed invention. Espersen establishes SOX9 as a meaningful biomarker for assessing treatment-related prognosis; Lee and Yu each teach the value of ex vivo culturing and post-treatment expression profiling; and Hiraoka establishes that reporter-based detection methods are known and routine when used for the assessment of SOX0-related gene expression pathways.
The skilled artisan would have been motivated to modify the method of Espersen to assess post-treatment SOX9 expression signatures as the information would have more prognostic value than pre-treatment signatures. The same artisan would have seen the value of performing this testing/treatment ex vivo to reduce potential harm from mismanaged therapies and non-invasively optimize the patient’s treatment plan and would have recognized that reporter-based detection methods are known in the art and thus suitable for assessing SOX9 gene expression. Finally, the skilled artisan would have reason to apply the method of Espersen to a variety of cancer types as Hiraoka teaches that SOX9 plays an ubiquitous role in tumorigenicity.
Therefore, while no single reference teaches all features combined, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention, that the features of the references could be combined with a reasonable expectation of success, thereby arriving at the claimed invention. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.).
Regarding claims 33-35, Lee assessed the gene signatures in prechemotheraphy (T1) samples and postchemotheraphy (T2) samples, and also determined the chemotherapy-induced relative changes in the gene signatures (TΔ). The goal was to determine which assessment method (T1 vs T2 vs TΔ) was better suited for predicting pathological response and progression-free survival (p833), finding that both T2 and TΔ were superior to T1 signatures (abstract). Therefore, a skilled artisan would expect that posttreatment signatures or the change in signatures pre and posttreatment to be suitable methods for determining the likelihood of cancer relapse.
Furthermore, with regards to the distinction of determining “amount” vs “proportion” of SOX9 positive cancer cells in claims 32-35, for each examined area, Esperson determined the percent of tumor nuclei that were positive and negative as a first step in their scoring method (p39). Calculating these percentages would require knowing both the number of positive cells, the number of negative cells, and thus knowing the total number of cells. Using this information, a skilled artisan would be able to report the results as either a percentage or as a count, based off which best suited their data presentation needs. As Hiraoka determined that SOX9 suppression resulted in decreased LGR5 expression and cell proliferation (Fig. 4), its apparent that a similar method of data manipulation is possible with reporter-based detection method.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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/K.N.K./ Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681
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