DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/22/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-2, 6, 8-11, 14-15, 17-18) in the reply filed on 04/03/2025 is acknowledged.
Claims 24-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 04/03/25.
Claims Status
Claims 1, 6, 8-11, 14-15, 17-18, and 24-32 are pending.
Claims 24-31 are withdrawn.
Claims 1, 6, 8-11, 14-15, 17-18, and 32 are currently under examination
Priority
This application is a U.S. National Phase Application filed under 35 U.S.C. § 371 claiming benefit to International Patent Application No. PCT/EP2020/070689, filed July 22, 2020, which claims the benefit of priority from United Kingdom Application No. GB 1910444.7, filed July 22, 2019. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of GB 1910444.7 has been filed on Jan. 21, 2022. The priority date of claim set filed on Nov. 7, 2025, is determined to be July 22, 2019.
Drawings
The drawings are objected to because Figure 6 contains sequences without a reference to the SEQ ID No. in the figure or description of the Figure 6. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 32 are objected to because of the following informalities: the preamble recites “A method of testing for, screening for or diagnosing cancer” (ln 1). The limitation of a treatment in step (b) is required, thus the preamble in claim 1 does not seem to adequately describe the method required by the limitations of claim 1 or claim 32.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6, 8-11, 14-15, 17-18 and 32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 32 are indefinite over the limitation “administering a cancer therapy to the patient” and “sample obtained from a patient”. It is unclear as to whether any patient in which a sample was obtained is administered a cancer therapy or if a particular population of patients are administered the cancer therapy. Furthermore, it’s unclear how the step of “administering a cancer therapy to the patient” relates back to the preamble “A method of testing for, screening for or diagnosing cancer”. Clams 6, 8-11, 14-15 and 17-18 depend on claim 1.
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 1, 6, 8-11, 14-15, 17-18 and 32 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards a natural phenomenon of gene expression in cancer and routine and conventional biomarkers for gene expression in cancer, without significantly more. The claim(s) recite(s) natural phenomena and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 1 is directed towards: A method of testing for, screening for or diagnosing cancer, comprising: a) determining the level of expression of: i) all of NEK2, FOXM1, TOP2A, MMP13, NR3C1, and S100A16; and at least 7 biomarkers selected from the group consisting of HOXA7, CENPA,DNMT1, INHBA, BIRC5, CXCL8, IVL, AND CBX7; or ii) all of HOXA7, CENPA, NEK2, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, IVL, CBX7, AND S100A16; and at least 1 of the biomarkers selected from the group consisting of DNMT1 and INHBA or iii) HOXA7, CENPA, NEK2, INHBA, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7, and S100A16; or iv) HOXA7, CENPA, NEK2, DNMT1, INHBA, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7, AND S100A16; in a sample obtained from a patient; and b) administering a cancer therapy to the patient, wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof.
The instant claim 32 is directed towards: A method of testing for, screening for or diagnosing cancer, comprising: a) determining the level of expression of HOXA7, CENPA, NEK2, DNMT1, 1NHBA, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7 and S100A16 in a sample obtained from a patient; and b) administering a cancer therapy to the patient, wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof.
The correlation of gene expression biomarkers to cancer is a natural phenomenon.
The determining the level of expression in step a) is considered to be an active step requiring the analysis of a sample. The active step is routine and conventional as demonstrated by Zhang et al. (“Zhang”; (2019). Co-Expression Network Analysis Identified Gene Signatures in Osteosarcoma as a Predictive Tool for Lung Metastasis and Survival. Journal of Cancer, 10(16), 3706–3716.).
Zhang teaches a method comprising “A metastasis signature was constructed according to the expression level and association with the metastasis status of genes” (Pg 3707, Lasso Cox Regression and Metastasis Signature, Para. 1). Zhang teaches a method comprising “a microarray dataset containing gene expression patterns of 19 OS cell lines and 6 normal samples (osteoblasts and bones). The platforms of these datasets are the GPL10295 Illumina human-6 v2.0 expression beadchip and GPL6102 Illumina human-6 v2.0 expression beadchip.” (Pg. 3707, Material and Methods, Para. 1). Zhang teaches a method comprising “In clinical circumstances, if we apply the signature to OS patients, we can detect the expression levels of specific genes from biopsies or surgically procured samples and predict metastasis progression. For patients with a high score or at a high risk, more frequent follow-ups and active treatment may greatly improve their survival and quality of life, corresponding with the concept of precision medicine.” (Pg. 3713, Last para.) “microarray dataset containing gene expression patterns … Illumina human-6 v2.0 expression beadchip” reads on step a). Thus, Zhang teaches a method wherein determining the level of expression of the claimed combinations of biomarkers in a sample obtained from a patient.
The “administering a cancer therapy to the patient, wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof” is considered not particular, as there is a list of particular and non-particular options, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2).
Dependent claims set forth further limitations about the reference markers, method of detecting and quantifying gene expression, sample, cancer, expression regulation of biomarker(s).
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, natural phenomena.
With regard to claim 1, the claim recites” A method of testing for, screening for or diagnosing cancer, comprising: a) determining the level of expression of: i) all of NEK2, FOXM1, TOP2A, MMP13, NR3C1, and S100A16; and at least 7 biomarkers selected from the group consisting of HOXA7, CENPA,DNMT1, INHBA, BIRC5, CXCL8, IVL, AND CBX7; or ii) all of HOXA7, CENPA, NEK2, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, IVL, CBX7, AND S100A16; and at least 1 of the biomarkers selected from the group consisting of DNMT1 and INHBA or iii) HOXA7, CENPA, NEK2, INHBA, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7, and S100A16; or iv) HOXA7, CENPA, NEK2, DNMT1, INHBA, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7, AND S100A16;in a sample obtained from a patient; and b) administering a cancer therapy to the patient.” The method of determining the level of expression of a cancer biomarker is routine and conventional. Cancer cells naturally express these genes that are considered biomarkers and is thus a natural phenomenon.
With regard to claim 32, the claim recites” A method of testing for, screening for or diagnosing cancer, comprising: a) determining the level of expression of HOXA7, CENPA, NEK2, DNMT1, 1NHBA, FOXM1, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7 and S100A16 in a sample obtained from a patient; and b) administering a cancer therapy to the patient.” The method of determining the level of expression of a cancer biomarker is routine and conventional. Cancer cells naturally express these genes that are considered biomarkers and is thus a natural phenomenon.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
The “administering a cancer therapy to the patient, wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof” is considered not particular, as there is a list of particular and non-particular options, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2).
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claims 1 and 32, the claim requires the routine and conventional active steps of determining the level of expression of a cancer biomarker to determine, test or screen for or diagnose cancer similar to that of Zhang et al. (“Zhang”; (2019). Co-Expression Network Analysis Identified Gene Signatures in Osteosarcoma as a Predictive Tool for Lung Metastasis and Survival. Journal of Cancer, 10(16), 3706–3716.).
Zhang teaches a method comprising “A metastasis signature was constructed according to the expression level and association with the metastasis status of genes” (Pg 3707, Lasso Cox Regression and Metastasis Signature, Para. 1). Zhang teaches a method comprising “a microarray dataset containing gene expression patterns of 19 OS cell lines and 6 normal samples (osteoblasts and bones). The platforms of these datasets are the GPL10295 Illumina human-6 v2.0 expression beadchip and GPL6102 Illumina human-6 v2.0 expression beadchip.” (Pg. 3707, Material and Methods, Para. 1). Zhang teaches a method comprising “In clinical circumstances, if we apply the signature to OS patients, we can detect the expression levels of specific genes from biopsies or surgically procured samples and predict metastasis progression. For patients with a high score or at a high risk, more frequent follow-ups and active treatment may greatly improve their survival and quality of life, corresponding with the concept of precision medicine.” (Pg. 3713, Last para.) “microarray dataset containing gene expression patterns … Illumina human-6 v2.0 expression beadchip” reads on step a). Thus, Zhang suggests a method comprising determining the level of expression of the claimed combinations of biomarkers in a sample obtained from a patient. Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require reference marker(s), methods of detecting and quantifying gene expression, sample distinction, cancer type, expression regulation of biomarker(s) which are all routine and conventional based on Teh, Muy, Teck ("Teh", Patent App. Pub. No. WO 2012013931 A1, Feb. 2, 2012) in view of Zhang et al. (“Zhang”; (2019). Co-Expression Network Analysis Identified Gene Signatures in Osteosarcoma as a Predictive Tool for Lung Metastasis and Survival. Journal of Cancer, 10(16), 3706–3716.), Spetzler et al. (“Spetzler”, Patent App. Pub. No. WO 2016141169 A1, Sept. 09, 2016), Mongan et al. (“Mongan”, Patent App. Pub. No. WO 2018057971 A1, March 29, 2018), Kim et al. (“Kim”, (2012). Biomarker detection for the diagnosis of lymph node metastasis from oral squamous cell carcinoma. Oral oncology, 48(4), 311-319), Wang et al. (“Wang”, (2015). An eleven gene molecular signature for extracapsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases. Oral oncology, 51(4), 355-362) and Sapkota et al. (“Sapkota”, S100A16 promotes differentiation and contributes to a less aggressive tumor phenotype in oral squamous cell carcinoma. BMC cancer, 15, 1-14.).
Response to Arguments
Applicant’s arguments filed 05/22/2026 (Pg. 6-8) with respect to claim 1, 6, 8-11, 14-15, 17-18 and 32 have been considered but are not persuasive. To clarify some instances argued in the response filed 05/22/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Applicant submits amended claim I requires the additional step of treating the subject with particular therapies and is therefore not directed towards a natural product or phenomenon.” (Pg. 7)
Response: Applicant's argument filed 05/22/2026 has been fully considered but is not persuasive. As stated above in the non-final office action, The “administering a cancer therapy to the patient, wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof” is considered not particular, as there is a list of particular and non-particular options, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2).
Applicants’ argument: “None of the cited prior art documents discloses a method of testing for, screening for or diagnosing cancer comprising assessing the claimed combinations of biomarkers.” (Pg. 8)
Response: Applicant's argument filed 05/22/2026 has been fully considered but is not persuasive. As stated above in the non-final office action, “microarray dataset containing gene expression patterns … Illumina human-6 v2.0 expression beadchip” reads on step a). Human genome arrays such as Illumina human-6 v2.0 expression beadchip are known for comprising more than 48,000 transcript probes per sample to genes in the human genome.
Applicants’ argument: “Claim 1 therefore recites additional elements that provide an inventive concept and amount to significantly more than an alleged law or nature and natural phenomena. Accordingly, claim 1 is clearly patent eligible” (Pg. 8)
Response: Applicant’s arguments have been fully considered and found unpersuasive because applicants amendments do not overcome the lack of patentably matter under U.S.C. 35 101. The previously presented and amended claims recite a natural phenomenon of gene expression in cancer and routine and conventional biomarkers for gene expression in cancer. The judicial exceptions are not integrated into a practical application because the claim limitations do not appear to improve the current technology or technical field beyond well-understood, routine, conventional activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no specific limitations that provide significantly more.
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 1, 6, 8-11, 14-15, 17-18 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Teh, Muy, Teck ("Teh", Patent App. Pub. No. WO 2012013931 A1, Feb. 2, 2012) in view of Spetzler et al. (“Spetzler”, Patent App. Pub. No. WO 2016141169 A1, Sept. 09, 2016), Mongan et al. (“Mongan”, Patent App. Pub. No. WO 2018057971 A1, March 29, 2018), Kim et al. (“Kim”, (2012). Biomarker detection for the diagnosis of lymph node metastasis from oral squamous cell carcinoma. Oral oncology, 48(4), 311-319), Wang et al. (“Wang”, (2015). An eleven gene molecular signature for extracapsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases. Oral oncology, 51(4), 355-362) and Sapkota et al. (“Sapkota”, S100A16 promotes differentiation and contributes to a less aggressive tumor phenotype in oral squamous cell carcinoma. BMC cancer, 15, 1-14.).
Claim interpretations: The limitation(s) reciting “optionally” in claims 6, 9, 11 and 15, is interpreted as rendering the phrase thereafter as an optional limitation to the claim.
Teh discloses methods for diagnosing cancer in a patient or for identifying a patient at risk of developing cancer. The methods comprise determining the amount of five or more biomarkers selected from HOXA7, AURKA, NEK2, FOXMIB, CCNBI, CEP55, CENPA, DNMT3B, DNMTI, HELLS, MAPKS, BMII, ITGBl, IVL and CTNNBI in a sample obtained from a patient and comparing the amount of the determined biomarkers in the sample from the patient to the amount of the biomarkers in or of a normal control (Abstract).
Regarding claims 1 and 32, Teh teaches a method comprising, determining the amount of one or more, … biomarkers selected from HOXA7, AURKA, NEK2, FOXM1B, CCNBl, CEP55, CENPA, DNMT3B, DNMT1 , HELLS, MAPK8, BMIl, ITGBl , IVL and CTNNB in a sample obtained from a patient (e.g., Pg. 1, Para 4. -Pg. 2. Para. 1, Summary of Invention). FOXM1B is interpreted as FOXM1 isoform B. Teh teaches a method “comprising Prognosis and choice of treatment are dependent upon the stage of the cancer and the patient's general state of health.” (Pg. 5, Para. 6) Thus, Teh suggests a method of testing for, screening for or diagnosing cancer, comprising: a) determining the level of expression of HOXA7, CENPA, NEK2, DNMT1, and FOXM1 in a sample obtained from a patient; and b) administering a cancer therapy to the patient.
However, Teh does not explicitly teach INHBA, TOP2A, BIRC5, MMP13, CXCL8, NR3C1, IVL, CBX7, and S100A16; or wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof.
Spetzler discloses methods and systems of molecular profiling of diseases, such as cancer (Abstract).
Regarding claims 1 and 32, Spetzler teaches a method comprising “the cancer comprises…, head and neck squamous cell carcinoma (HNSCC), … (Para. 55). Table 2 provides a listing of gene and corresponding protein symbols and names of many of the molecular profiling targets that are analyzed according to the methods of the invention (Para. 271, Table 2). Spetzler teaches BIRC5 and TOP2A in Table 2. Spetzler teaches “Genes and gene products that are known to play a role in cancer and can be assayed by any of the molecular profiling techniques of the invention include without limitation … MMP13...” (Para. 273). Spetzler teaches “the panel of genes assessed as part of the MI molecular profiling is expanded to include additional biomarkers... INHBA…” (Para. 471). Furthermore, Spetzler teaches “Cancer therapies that can be identified as candidate treatments by the methods of the invention include without limitation: … Gemcitabine… ” (Para. 286). Thus, Spetzler suggests a method comprising, determining the level of expression of one or more biomarkers selected from the group consisting of BIRC5, TOP2A, MMP13 INHBA; and wherein the cancer therapy is selected from the group consisting of: resecting the tumor, radiotherapy, chemotherapy, immunotherapy, gemcitabine, and Folfirinox, and a combination thereof.
Mongan discloses methods and compositions that are useful for assessing gene expression for tumor immune response profile of a sample.
Regarding claims 1 and 32, Mongan teaches a method directed to a plurality of target sequences to measure the expression levels of the targets in the sample wherein the target genes are selected from immune response genes… In some embodiments, the target genes are selected from immune response genes consisting of one or more function of Table A” ( Para. 56) “CXCL8” (Pg. 27, Table A). Thus, Mongan suggests a method comprising determining the level of expression of CXCL8.
Kim discloses the gene set detected from the combined dataset classified the lymph node status more accurately in the validation dataset and clear expression patterns classifying the lymph node status based on chromosomal location were observed. The combined dataset holds promise for use as a more accurate candidate gene set for the diagnosis of lymph node metastasis and the selected gene set could be used for biological validation in further studies (Summary).
Regarding claims 1 and 32, Kim teaches a method comprising, “the selected genes from the combined dataset are summarized in Table 3” (e.g., Pg. 316) and “NR3C1” (e.g., Pg. 314, Table 3, 43rd symbol). Kim teaches a method wherein, “examined the expression patterns of genes selected from the combined dataset” and “NR3C1 on chromosome 5 was up regulated” (Pg. 319, Expression patterns of the selected genes on the chromosomal location). Thus, Kim suggests a method comprising determining the level of expression of NR3C1.
Wang discloses an 11 gene signature (GGH, MTFR1, CDKN3, PSRC1, SMIM3, CA9, IRX4, CPA3, ZSCAN16, CBX7 and ZFP3) which was robust in segregating tumors by ECS status. In node negative patients, patients harboring this ECS signature had a significantly worse overall survival (Summary-Results).
Regarding claims 1 and 32, Wang teaches a method comprising “gene expression profiling was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform” (e.g., Pg. 356, Gene expression profiling data). Wang teaches a method comprising “identify a set of genes consistently differentially expressed between node-positive patients with ECS and those without” and “the 11 gene set included … CBX7…” (e.g., Pg. 356, Results). Thus, Wang suggests a method comprising determining the level of expression of CBX7.
Sapkota discloses both S100A16 mRNA and protein levels were found to be progressively down-regulated from normal human oral mucosa (NHOM) to oral dysplastic lesions (ODL) and oral squamous cell carcinoma (OSCC) (Abstract-Results).
Regarding claims 1 and 32, Sapkota teaches a method wherein “in the current study for the expression analysis of S100A16 by immunohistochemistry (IHC) and/or quantitative RT-PCR (qRT-PCR).” (e.g., Pg. 2, Human tissue specimens, col 2 ). Thus, Sapkota suggests a method comprising determining the level of expression of S100A16.
Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest the limitations of claims 1 and 32.
Teh, Spetzler, Mongan, Kim, Wang and Sapkota are all considered to be analogous to the claimed invention because they are in the same field of molecular profiling of cancer with implications in SCC. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising determining the level of expression of one or more biomarkers selected from the group consisting of HOXA7, CENPA, NEK2, DNMT1, FOXM1, IVL, … in a sample obtained from a patient and treatment of cancer as suggested by Teh to incorporate the method comprising BIRC5, TOP2A, MMP13, and/or INHBA as suggested by Spetzler, CXCL8 as suggested by Mongan, NR3C1 as suggested by Kim, CBX7 as suggested by Wang, and S100A16 as suggested by Sapkota and provide a method for testing screening or diagnosing cancer. Teh suggests that “there is an imperative need for a cost-effective, fast, reproducible, objective and quantitative molecular method to alleviate cancer classification dilemmas shrouding clinicians and scientists” (Pg. 1, Para. 2) and suggests that “it should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. (Pg. 42, Para. 2). Furthermore, a skilled artisan would understand that a customizable molecular mechanism-based multi biomarker diagnostic system, based on FOXM I-orchestrated transcriptional signatures, for objective quantification of malignancy status in human SCCs as suggested by Teh is meant to be customized.(Pg. 41) In addition, Spetzler suggests that “patients with refractory or metastatic cancer are of particular concern for treating physicians because the majority of patients with metastatic or refractory cancer eventually run out of treatment options or may suffer a cancer type with no real treatment options…For these patients, molecular profiling of their cancer may provide the only viable option for prolonging life” Para. 3), Thus, one of ordinary skill in the art would be motivated to further optimize the multi-biomarker expression profile with other known cancer biomarkers. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 32. A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating the other biomarkers because determining the expression of the biomarkers in cancers such as SCC in a patient and treating the patient is already known in the art. Doing so would provide an improved method for the testing, screening, or diagnosing the classification of cancer harboring of the characteristic biomarkers of a more aggressive form of SCC.
The teachings of Teh, Spetzler, Mongan, Kim, Wang and Sapkota, are documented above in the rejection of claims 1 and 32 under 35 U.S.C. 103. Claims 8-11, 14-15 and 17-18 depend on claim 1.
Regarding claim 6, Teh teaches a method comprising “the expression level of the one or more reference genes, for example YAP1 and/or POLR2A” (e.g., Pg. 3, para. 3, Summary of Invention). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest comprising determining the level of expression of one or more reference biomarkers, optionally wherein the one or more reference biomarkers are selected form the group consisting of YAP1, POLR2A, ACTB, GAPDH, and HPRT 1.
Regarding claim 8, Teh teaches a method wherein “The mRNA expression levels of each of the 128 genes in the transduced cells were measured” (e.g., Pg. 18, Detailed description of the invention, Figure 1). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein determining the level of expression of one or more biomarkers comprises determining the amount of mRNA or protein corresponding to each of the biomarkers in the sample.
Regarding claim 9, Teh teaches a method wherein “the cancer is a squamous cell carcinoma (SCC)” (e.g., Pg. 5, SUMMARY OF THE INVENTION). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein the cancer is squamous cell carcinoma (SCC), optionally wherein the SCC is head and neck SCC (HNSCC).
Regarding claim 10, Teh teaches a method wherein “the sample comprises biological … tissue obtained from the patient” (e.g., Pg. 8, para. 3-4). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein the sample is a tissue sample.
Regarding claim 11, Teh teaches a method wherein “(b) comparing the amount of the determined biomarkers in the sample from the patient to the amount of the biomarkers in or of a normal control” (e.g., Pg. 2, para. 2). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein the method further comprises comparing the level of expression of the one or more biomarkers to one or more control biomarkers, optionally wherein the level of expression of the one or more control biomarkers is represented by the level of expression of one or more biomarkers selected from the group consisting of YAPI, POLR2A, ACTB, GAPDH, and HPRTQ, further optionally wherein the level of expression of the one or more control biomarkers is the level of expression of the corresponding biomarkers from a sample obtained from a healthy patient.
Regarding claim 14, Teh, M.T., Spetzler et al., Mongan et al., Kim et al., Wang et al. and Sapkota et al. is documented above. Teh teaches a “method for diagnosing cancer in a patient or for identifying a patient at risk of developing cancer” ( Pg. 1, para. 3, Summary of Invention). Teh teaches method wherein “(HOXA7, … NEK2, FOXM1B, …, CENPA, …, DNMTI, …) show progressive upregulation and … IVL) showed progressive downregulation across the cell panel (Figure 2C)” (Pg., 32, para. 1). Teh teaches a method wherein “qPCR for each of the target genes and 2 reference genes across a training panel of 8 independent primary NHOKs (isolated from oral mucosa tissues donated by healthy disease-free individuals), 5 oral premalignant and 11 malignant oral SCC cell types” The up- or downregulation regulation of expression of target genes in cancer cells compared to normal cell is interpreted as indicative or predictive of cancer. Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein upregulation of any of HOXA7, CENPA, NEK2, DNMT1, and FOXM1 and downregulation of IVL is indicative or predictive of cancer.
Regarding claim 15, Teh teaches a method wherein “All qPCR primers … associated with each biomarker panel used in this study for oral SCC (14 biomarkers plus 2 reference genes) and skin SCC (6 biomarkers and 2 reference genes) are listed in Table 1 and 2” (e.g., Pg. 26, Real-time absolute quantitative RT-PCR; Table 1-2). Primers are interpreted as a binding molecule. Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein the step of determining the level of expression of the one or more biomarkers comprises the use of a binding molecule or binding molecules specific for the biomarker or biomarkers whose level of expression is being determined, optionally wherein the binding molecule or binding molecules are oligonucleotides or antibodies.
Regarding claim 17, Teh teaches a method wherein the sample is “primary human oral cells” (e.g., Pg. 26, Real-time absolute quantitative RT-PCR, last sentence). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein the sample is from a human.
Regarding claim 18, Teh teaches a method wherein “samples obtained from a patient
suffering from or suspected of suffering from cancer” (e.g., Pg. 13, para. 3). Thus, Teh, Spetzler, Mongan, Kim, Wang and Sapkota suggest a method wherein the sample is from a patient having or suspected of having cancer.
Response to Arguments
Applicant’s arguments filed 05/22/2026 (Pg.8-15) with respect to claim 1, 6, 8-11, 14-15, 17-18 and 32 have been considered but are not persuasive. To clarify some instances argued in the response filed 05/22/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “there is nothing in any of the cited references that would motivate one of ordinary skill in the art to combine the teachings of these references to produce the presently claimed invention. Moreover, there is nothing in any of the cited references that would provide one of ordinary skill in the art with a reasonable expectation of success in making the combination in the presently claimed invention.” (Pg. 9-10)
Response: Applicant's argument filed 05/22/2026 has been fully considered but is not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as stated in the revised rejection under 35 U.S.C. 103 (documented above) towards claim 1, Teh, Spetzler, Mongan, Kim, Wang and Sapkota are all considered to be analogous to the claimed invention because they are in the same field of molecular profiling of cancer with implications in SCC. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising determining the level of expression of one or more biomarkers selected from the group consisting of HOXA7, CENPA, NEK2, DNMT1, FOXM1, IVL, … in a sample obtained from a patient and treatment of cancer as suggested by Teh to incorporate the method comprising BIRC5, TOP2A, MMP13, and/or INHBA as suggested by Spetzler, CXCL8 as suggested by Mongan, NR3C1 as suggested by Kim, CBX7 as suggested by Wang, and S100A16 as suggested by Sapkota and provide a method for testing screening or diagnosing cancer. Teh suggests that “there is an imperative need for a cost-effective, fast, reproducible, objective and quantitative molecular method to alleviate cancer classification dilemmas shrouding clinicians and scientists” (Pg. 1, Para. 2) and suggests that “it should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. (Pg. 42, Para. 2). Furthermore, a skilled artisan would understand that a customizable molecular mechanism-based multi biomarker diagnostic system, based on FOXM I-orchestrated transcriptional signatures, for objective quantification of malignancy status in human SCCs as suggested by Teh is meant to be customized.(Pg. 41) In addition, Spetzler suggests that “patients with refractory or metastatic cancer are of particular concern for treating physicians because the majority of patients with metastatic or refractory cancer eventually run out of treatment options or may suffer a cancer type with no real treatment options…For these patients, molecular profiling of their cancer may provide the only viable option for prolonging life” (Para. 3) Thus, one of ordinary skill in the art would be motivated to further optimize the multi-biomarker expression profile with other known cancer biomarkers. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 32. A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating the other biomarkers because determining the expression of the biomarkers in cancers such as SCC in a patient and treating the patient is already known in the art. Doing so would provide an improved method for the testing, screening, or diagnosing the classification of cancer harboring of the characteristic biomarkers of a more aggressive form of SCC.
Conclusion
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682 17/628,951
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