Response to Amendment
The amendment filed 8 July 2026 is acknowledged. The amendment incorporated the limitations of claim 42 and 43 into claim 32. Additionally, claim 42 has been cancelled. Therefore, claims 32-41 and 43-64 remaining pending with claims 43-64 having been previously withdrawn.
In regards to the office action mailed 8 April 2026 and in view of Applicant’s amendment:
The objections to the specification have been withdrawn.
All rejections of claim 42 have been rendered moot as the claim has been canceled.
The rejection of claims 32-41 under 35 USC § 101 is withdrawn.
The rejection of claims 32-41 under 35 USC § 103 is withdrawn as the amendment introduces previously unconsidered limitations to claim 32 (from which the remainder depend). However, a new ground of rejection is made in view of Harrington.
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 32-41 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; previously cited) in view of Lee (Lee SC et al. Pharmacogenetics and genomics. 2009 Nov 1;19(11):833-42; previously cited), Yu (Yu M et al. Science. 2014 Jul 11;345(6193):216-20; previously cited), Hiraoka (Hiraoka K et al. Biochemical and biophysical research communications. 2015 May 1;460(2):216-21; previously cited), and Harrington [Harrington KJ et al. Advanced drug delivery reviews. 2000 Nov 15;44(2-3):167-84.].
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 SOX9-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 a 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, Espersen 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.
None of the aforementioned sources teach the administration of a viral vector comprising a suicidal gene based upon the determination that an individual is likely to suffer from relapse.
Harrington discusses the development of gene therapy, particularly as it relates to suicide gene strategies, for the treatment of cancer and the need for safeguards to prevent the unnecessary death of non-cancer cells. One such safeguard involves taking advantage of the transcriptional framework that already exists, a framework which is mediated by the interaction between enhancer/promoter elements in the DNA and specific proteins (p168). Certain genes are upregulated in a range of tumors in a tissue non-specific manner, like SOX9 as previously discussed. By using the promoters of these genes to transcriptionally control the expression of a suicide gene, a variety of malignant tissues can be targeted without the need to tailor design of the promoters used on an individual, patient-by-patient, basis (p171).
Therefore, a person of ordinary skill in the art prior to the effective filing date of the claimed invention, would have been motivated to administer a viral vector comprised of a suicide gene and under the transcriptional control of SOX9 because this form of gene therapy is well known in the art. The combined method of Espersen, Yu, Hiraoka, and Lee identifies the presence of SOX9 positive cells in a sample after ex vivo treatment, demonstrating the ineffectiveness of the treatment and identifying the individuals who would most benefit from treatment by more complex treatments, such as the described gene therapy. This would have the added benefit of preserving quality of life of the individuals who may have undergone unnecessary and intense treatment regimes.
Response to Arguments
Applicant's arguments filed 8 July 2026 have been fully considered but they are not persuasive.
Applicant additionally argues the rejection does not account for the following elements which will be responded to in kind:
Element 1: Exposing ex vivo the cancer cells to a cancer treatment
Yu performed ex vivo culturing of several circulating tumor cell lines and performed anti-cancer drug sensitivity testing on these lines at a range of concentrations (abstract, Fig. 2) in order to determine which drug was likely to be most effective at treating the individual tumors. Therefore, Yu explicitly discloses exposing cancer cells to a cancer treatment ex vivo.
Element 2: Determining the amount of SOX9 positive cancer cells following cancer treatment based on expression of the reporter gene
Hiraoka found that SOX9 directly upregulates the transcription of LGR5, suggesting that its upregulation is important for the proliferation and tumorigenicity of glioblastoma (p216). First, Hiraoka used luciferase-reporter plasmids to first identify regions where promoter activity may be occurring. By placing Then, Hiraoka used siRNA to investigate the most likely transcription factor candidates are found that SOX9 resulted in the most significant reduction of LGR5 transcription. A second luciferase assay was then performed in which a mutant SOX9 binding site was included in the plasmid constructs, thereby silencing the effects of SOX9, mimicking biological conditions in which SOX9 is not present and confirming its role in the upregulation of LGR5 (p218). Additional studies performed by Hiraoka further showed that SOX9 plays a key role in the tumorigenicity of glioblastoma cells (p219).
Hiraoka clearly describes performing assays in which reporter genes are used to evaluate the transcription of genes within a biological system through the use of custom designed plasmids. While Hiraoka designed the plasmid of the second assay to include a mutant SOX9 promoter, a skilled artisan would recognize that using the wild-type SOX9 promoter would similarly be possible. Therefore, Hiraoka shows the routine nature of these assays, as well as their adaptability to answer any number of expression-based questions. A skilled artisan would be able to create a plasmid in which a wild type SOX9 promoter and a reporter gene were present in order to inform on the presence or absence of SOX9 within a biological system.
While Hiraoka alone does not teach first administering a cancer treatment to cancer cells, the combination of Yu and Hiraoka does. Yu discloses performing ex vivo drug susceptibility testing on cancer cells. Yu determined the efficacy of the treatment by comparing the amount of viable cells present before and after treatment administration (Fig. 2) and the skilled artisan would recognized reporter-plasmid assays as one possible method of detection as Hiraoka teaches them to be routine in the art.
Element 3: Estimating a likelihood of cancer relapse following cancer treatment for the subject based on SOX9 positive cancer cells.
Applicant argues that Espersen discloses estimating a likelihood of cancer relapse following treatment based upon the expression level of SOX9 protein and is not based on SOX9 positive cells. However, Espersen determined expression level by calculating the percent of tumor nuclei that were positive and negative and assigning a score based upon the percent positive (p39). As discussed in the above 35 USC § 103 rejection, performing this percent calculation would require knowing both the number of positive cells, the number of negative cells, and the total number of cells. Therefore, while additional factors are taken into consideration (i.e., intensity of staining), the number of SOX9 positive cells present in a sample serves as a basis for Espersen’s likelihood calculation.
Therefore, each of the claim elements are taught by the cited references, either individually or in combination.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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