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 .
Election/Restrictions
Applicant’s election of Group I, Claims 1-14 and 19, drawn to a method of detecting lung cancer, and species of claim 1 in the reply filed on 03/13/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 15-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-IV (claims 15-18) and specie of claim 19, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/13/2026.
Claims Status
Claims 1-19 are pending.
Claims 15-19 are withdrawn.
Claims 1-14 are currently under examination.
Priority
This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63/319,425. Accordingly, the priority date of claim set filed on 03/11/2026, is determined to be 03/14/2022.
Claim Rejections - 35 USC § 112(b)
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 1-14 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.
Claim 1 is indefinite over the limitations “treating the subject with a cancer management program based on the determination in step (e)” (ln 16) and “cancer management program” (ln 16), and “determining whether the subject has lung cancer” (ln 11). It is unclear whether the subject being treated is free of lung cancer or has lung cancer. Claims 2-14 depend on claim 1.
Claim 5 is indefinite over the limitations “one or more miRNAs comprise miR-21 and miR-223” (ln 1-2) It is unclear whether the one or more miRNAs is intended to claim at least on miRNA, miR-21 or miR-21, or two miRNAs, miR-21 and or miR-223. Claims 6-10 depend on claim 5.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Steps (a-f) are required in the limitations of claim 1, thus removal of steps render the claim an improper dependent. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Steps (a-f) are required in the limitations of claim 1, thus removal of steps render the claim an improper dependent. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards abstract ideas/mental processes of comparing the expression level and metabolite concentration of a test sample to a control and assessing parameters and lung cancer treatment, assessing one or more parameters, and assessing the subject’s response; abstract ideas/mathematical relationship of statical analysis; natural phenomenon of difference in the expression level of the one or more miRNAs or concentration of metabolites relative to the normal control are indicative of lung cancer; and routine and conventional steps of determining the expression level and metabolite concentration and treating a subject with cancer management program, without significantly more. The claim(s) recite(s) abstract ideas, natural phenomenon and routine and conventional steps. 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 detecting lung cancer in a subject comprising the steps of: a) determining in a serum sample, the expression level of one or more miRNAs; b) determining in a urine sample, the concentration of one or more metabolites; c) comparing the expression level of the one or more miRNAs with the expression level of the one or more miRNAs in a normal control; d) comparing the concentration of the one or more metabolites with the concentration of the one or more metabolites in a normal control; e) determining whether the subject has lung cancer in accordance with the result of steps (c) and (d); wherein a difference in the expression level of the one or more miRNAs relative to the expression level of the normal control, and a difference in the concentration of the one or more metabolites relative to the concentration of the normal control, are indicative of lung cancer; and f) treating the subject with a cancer management program based on the determination in step (e).
The correlation of gene expression biomarkers to cancer is a natural phenomenon.
The determining the level of expression of one or more biomarkers is considered to be an active step requiring the analysis of a sample. The active step is routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about lung cancer, miRNA(s), expression detection, control(s), metabolites, metabolite detection, and analysis 12. (Original) The method of claim 11, wherein the steps (c) and (d) comprise a mathematical algorithm to express oncogenic and cancer-suppressive characteristics of the miRNAs, metabolites, or both based on their biological functional pathways.
The instant claim 12 is directed towards: The method of claim 11, wherein the steps (c) and (d) comprise a mathematical algorithm to express oncogenic and cancer-suppressive characteristics of the miRNAs, metabolites, or both based on their biological functional pathways. The “mathematical algorithm” is interpreted as an abstract idea relating to a mathematical relationship.
The instant claim 13 is directed towards: The method of claim 1, further comprising assessing one or more parameters selected from demographic data, clinical characteristics, functional status, social/occupational history, diagnostic imaging scans, pathology reports, pulmonary function test results, previous medical and surgical history, age, gender, history of smoking, and presence of chronic obstructive pulmonary disease. The “assessing” is interpreted as an abstract idea relating to a mental process.
The instant claim 14 is directed towards: The method of claim 1, further comprising assessing the subject's response to lung cancer treatment comprising determining the expression levels of the miRNAs and the concentrations of the metabolites prior to treatment and after treatment, comparing the expression levels of the miRNAs and the concentrations of the metabolites in a normal control, and predicting a response if there is a difference in the levels. The “assessing” is interpreted as an abstract idea relating to a mental process.
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, abstract ideas and natural phenomenon.
With regard to claim 1, the claim recites “A method of detecting lung cancer in a subject comprising the steps of: a) determining in a serum sample, the expression level of one or more miRNAs; b) determining in a urine sample, the concentration of one or more metabolites; c) comparing the expression level of the one or more miRNAs with the expression level of the one or more miRNAs in a normal control; d) comparing the concentration of the one or more metabolites with the concentration of the one or more metabolites in a normal control; e) determining whether the subject has lung cancer in accordance with the result of steps (c) and (d); wherein a difference in the expression level of the one or more miRNAs relative to the expression level of the normal control, and a difference in the concentration of the one or more metabolites relative to the concentration of the normal control, are indicative of lung cancer; and f) treating the subject with a cancer management program based on the determination in step (e). .” 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 12, the claim recites “The method of claim 11, wherein the steps (c) and (d) comprise a mathematical algorithm to express oncogenic and cancer-suppressive characteristics of the miRNAs, metabolites, or both based on their biological functional pathways.” The “mathematical algorithm” is interpreted as an abstract idea relating to a mathematical relationship.
With regard to claim 13, the claim recites “The method of claim 1, further comprising assessing one or more parameters selected from demographic data, clinical characteristics, functional status, social/occupational history, diagnostic imaging scans, pathology reports, pulmonary function test results, previous medical and surgical history, age, gender, history of smoking, and presence of chronic obstructive pulmonary disease.” The “assessing” is interpreted as an abstract idea relating to a mental process.
With regard to claim 14, the claim recites “The method of claim 1, further comprising assessing the subject's response to lung cancer treatment comprising determining the expression levels of the miRNAs and the concentrations of the metabolites prior to treatment and after treatment, comparing the expression levels of the miRNAs and the concentrations of the metabolites in a normal control, and predicting a response if there is a difference in the levels.” The “assessing” is interpreted as an abstract idea relating to a mental process.
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. Although the independent claim 1 step (c) recites administering neoadjuvant chemotherapy to the subject, which is of great generality being routine and conventional as demonstrated in the prior art rejections documented below and is not a particular treatment.
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 claim 1, the claim requires the routine and conventional active steps of determining and comparing the level of expression of cancer biomarker miRNA(s) and concentration of cancer biomarker metabolite(s) compared to controls to determine, test or screen for or diagnose cancer similar to that of Haznadar et al. (“Haznadar”; Patent App. Pub. US 20160169899 A1, June 16, 2016) as discussed in the 35 U.S.C. 103 rejection below.
Haznadar discloses “The present invention provides methods and materials for diagnosing cancer in an individual using a tissue, blood or urine sample from the patient. Specifically, the disclosed method comprises determining the level of one or more metabolite selected from the group consisting of creatine riboside, metabolite 561+, Cortisol sulfate and N-acetylneuraminic acid. The present invention also provides a method for determining the prognosis of a cancer patient by determining the level of one or more metabolite selected from the group consisting of creatine riboside, metabolite 561+, Cortisol sulfate and N-acetylneuraminic acid. Also provided are kits for detecting cancer or determining the prognosis of a cancer patient.” (Abstract).Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require further limitations upon lung cancer, miRNA(s), expression detection, control(s), metabolites, metabolite detection, and analysis which are all routine and conventional based on Haznadar et al. (“Haznadar”; Patent App. Pub. US 20160169899 A1, June 16, 2016) in view of Zhang et al. (“Zhang”; (2017). Plasma miR-145, miR-20a, miR-21 and miR-223 as novel biomarkers for screening early-stage non-small cell lung cancer. Oncology letters, 13(2), 669–676.) and Xiang et al. (“Xiang”; (2018). Cortisol, cortisone, and 4-methoxyphenylacetic acid as potential plasma biomarkers for early detection of non-small cell lung cancer. The International journal of biological markers, 33(3), 314–320.) as discussed in the 35 U.S.C. 103 rejection below.
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, 4-6 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Haznadar et al. (“Haznadar”; Patent App. Pub. US 20160169899 A1, June 16, 2016).
Haznadar discloses “The present invention provides methods and materials for diagnosing cancer in an individual using a tissue, blood or urine sample from the patient. Specifically, the disclosed method comprises determining the level of one or more metabolite selected from the group consisting of creatine riboside, metabolite 561+, Cortisol sulfate and N-acetylneuraminic acid. The present invention also provides a method for determining the prognosis of a cancer patient by determining the level of one or more metabolite selected from the group consisting of creatine riboside, metabolite 561+, Cortisol sulfate and N-acetylneuraminic acid. Also provided are kits for detecting cancer or determining the prognosis of a cancer patient.” (Abstract).
Regarding claim 1 steps (a) – (e), Haznadar teaches a method comprising “in one embodiment the presence of cancer is detected by measuring the level of one or more biomarkers in conjunction with the level of one or more microRNAs” (Para. 83). Thus, Haznadar suggests a method of detecting lung cancer in a subject comprising steps (a) through (e).
Regarding claim 1 steps (a) and (c), Haznadar teaches a method comprising “the level of one or more biomarkers is determined from a... serum sample” (Para. 60). Haznadar teaches a method comprising “the diagnostic and prognostic accuracy of biomarkers of the present invention may be improved when the levels of such biomarkers are measured in combination with the level or presence of other, known cancer biomarkers… One type of known biomarker to measure in combination with one or more biomarker of the present invention is a microRNA (miRNA)... Since their discovery, miR-mediated post-transcriptional modulation of gene expression has been found to be associated with a number of diseases, including cancer...The association of microRNA expression with prognosis and progression in early-stage, non-small cell lung adenocarcinoma: a retrospective analysis of three cohorts… For example, mir-21 has been found to be up-regulated in most cancer sites, including lung...The association of microRNA expression with prognosis and progression in early-stage, non-small cell lung adenocarcinoma” (Para. 92). Haznadar teaches a method comprising “Once the level of a biomarker has been determined, the level may be compared to the normal level of the same biomarker and a determination of whether or not the individual has cancer can be made” (Para. 79). Thus, Haznadar suggests a method of detecting lung cancer in a subject comprising the step: a) determining in a serum sample, the expression level of one or more miRNAs; and c) comparing the expression level of the one or more miRNAs with the expression level of the one or more miRNAs in a normal control.
Regarding claim 1 steps (b) and (d), Haznadar teaches a method comprising “the level of one or more biomarkers is determined from a urine sample” (Para. 60). Haznadar teaches a method comprising “detection of cancer comprising determining the level of one or more compounds” (Para. 4). Haznadar teaches a method comprising “the cancer is lung cancer.” (Para. 4). Haznadar teaches a method comprising “Once the level of a biomarker has been determined, the level may be compared to the normal level of the same biomarker and a determination of whether or not the individual has cancer can be made” (Para. 79) and “compared to matched population controls” (Para. 131). Thus, Haznadar suggests a method comprising step b) determining in a urine sample, the concentration of one or more metabolites; and d) comparing the concentration of the one or more metabolites with the concentration of the one or more metabolites in a normal control.
Regarding claim 1 step (e), Haznadar teaches a method comprising “wherein elevated levels of … metabolite … indicate the presence of cancer” (Para. 4). Thus, Haznadar suggests a method comprising step e) determining whether the subject has lung cancer in accordance with the result of steps (c) and (d); wherein a difference in the expression level of the one or more miRNAs relative to the expression level of the normal control, and a difference in the concentration of the one or more metabolites relative to the concentration of the normal control, are indicative of lung cancer.
Regarding claim 1 step (f), Haznadar teaches a method wherein “metabolites are prospectively associated with lung cancer development in smokers. …and customized treatment” (Para.18). Haznadar teaches a method comprising “administering a cancer treatment to the patient; c) determining the level of the one or more biomarkers of the present invention in the patient to obtain a post-treatment level of the one or more biomarkers; and d) comparing the pre-treatment and post-treatment biomarker levels to determine the efficacy of the treatment” (Para. 9-11). Thus, Haznadar suggests a method comprising step f) treating the subject with a cancer management program based on the determination in step (e).
Therefore, the invention as recited in claim 1 is prima facie obvious over the prior art Haznadar et al. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claim limitations. It would have been obvious to provide a method of detecting lung cancer in a subject according to the limitations of the instant application claim 1 based on Haznadar et al. (Patent App. Pub. No. US 20160169899 A1).
The teachings of Haznadar are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 4, 11, and 13-14 depend on claim 1. Claim 6 depend on claim 5, which depends on claim 4, which depends on claim 1. Claim 12 depends on claim 11, which depends on claim 1.
Regarding claim 4, Haznadar teaches a method wherein “non-small cell lung cancer ” (Para. 92). Thus, Haznadar suggests a method wherein the lung cancer comprises non- small cell lung carcinoma.
Regarding claim 5-6, “the one or more miRNAs comprise miR-21 and miR-223” is interpreted as at least one miRNA comprise miR-21 and/or miR-223. Haznadar teaches a method wherein “microRNA-21… overexpression in non-small cell lung cancer by quantitative real-time R T-PCR.” (Para. 92). Thus, Haznadar suggests a method wherein the one or more miRNAs comprise miR-21 and miR-223; and wherein the step of determining the expression level of the one or more miRNAs comprises a real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay.
Regarding claim 11, Haznadar teaches a method wherein “A) Logistic regression results... B) ROC analysis of individual metabolites” (Para. 26; Para. 121;Fig. 8). ROC reads on receiver operating characteristic curve. Thus, Haznadar suggests a method wherein the steps (c) and (d) comprise statistical analysis selected from binary logistic regression, receiver operating characteristic curve, or both.
Regarding claim 12, Haznadar teaches a method wherein “a normalization algorithm” (Para. 101). Thus, Haznadar f suggests a method wherein the steps (c) and (d) comprise a mathematical algorithm to express oncogenic and cancer-suppressive characteristics of the miRNAs, metabolites, or both based on their biological functional pathways.
Regarding claim 13, Haznadar teaches a method wherein “we performed logistic regression in all and in early stage I-II cases (FIG. 8A), adjusting for race, gender, interview year, smoking status, pack years and urine collection” (Para. 121). Haznadar teaches a method wherein “In some embodiments of the present invention, such characteristics may be significant. In such cases, the significant characteristic(s) (e.g., age, sex, race, etc.) will be indicated.” (Para. 45). Thus, Haznadar suggests a method further comprising assessing one or more parameters selected from demographic data, clinical characteristics, functional status, social/occupational history, diagnostic imaging scans, pathology reports, pulmonary function test results, previous medical and surgical history, age, gender, history of smoking, and presence of chronic obstructive pulmonary disease.
Regarding claim 14, Haznadar teaches a method wherein “The present invention relates to the use of specific biomarkers in the detection of cancer and the prediction of the prognosis of cancer patients.” (Para. 1). Haznadar teaches a method wherein “One embodiment of the present invention is a method for monitoring the efficacy of a cancer treatment, the method comprising: a) determining the level of one or more biomarkers selected from the group consisting of creatine riboside, metabolite 561+, cortisol sulfate and N-acetylneuraminic acid in a sample patient having cancer to obtain a pre-treatment level of the one or more biomarkers; b) administering a cancer treatment to the patient; c) determining the level of the one or more biomarkers of the present invention in the patient to obtain a post-treatment level of the one or more biomarkers; and d) comparing the pre-treatment and post-treatment biomarker levels to determine the efficacy of the treatment” (Para. 7-11;Para. 12; Para. 13). Thus, Haznadar suggests a method further comprising assessing the subject's response to lung cancer treatment comprising determining the expression levels of the miRNAs and the concentrations of the metabolites prior to treatment and after treatment, comparing the expression levels of the miRNAs and the concentrations of the metabolites in a normal control, and predicting a response if there is a difference in the levels.
Claims 1 and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Haznadar et al. (“Haznadar”; Patent App. Pub. US 20160169899 A1, June 16, 2016), in view of Zhang et al. (“Zhang”; (2017). Plasma miR-145, miR-20a, miR-21 and miR-223 as novel biomarkers for screening early-stage non-small cell lung cancer. Oncology letters, 13(2), 669–676.).
The teachings of Haznadar are documented above in the rejection of claims 1, 4-6 and 11-14 under 35 U.S.C. 103. Claim 7 depends on claim 6, which depends on claim 5, which depends on claim 4, which depends on claim 1. Furthermore, Haznadar teaches “internal standards” (Para. 33) and “A normal level may also be referred to as a base level, control level or reference level” (Para. 52). Haznadar does not explicitly teach the limitations of claim 7.
Zhang discloses “Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the world. Late diagnosis is one of the most significant reasons for the high mortality rate of lung cancer. The identification of microRNAs (miRNAs) has opened a new field for molecular diagnosis of cancer. The purpose of the present study was to investigate whether plasma miRNAs may be used as biomarkers for early-stage NSCLC. A total of 232 participants, including 149 NSCLC patients and 83 healthy controls, were recruited between July 2012 and May 2014. We measured the levels of 10 miRNAs (miR-30d, miR-383, miR-20a, miR-145, miR-221, miR-25, miR-223, miR-21, miR-126 and miR-210) in plasma samples of 40 individuals (20 patients and 20 matched healthy controls) at the point of identification of disease, and 129 NSCLC patients and 83 healthy controls at the validation stage using reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristics (ROC) curves were generated for each possible combination of the miRNAs. We observed that the expression of plasma miR-145, miR-20a, miR-21 and miR-223 was significantly increased in the early-stage NSCLC samples compared with controls. miRNAs have significant diagnostic value for early-stage NSCLC. Combined ROC analyses using these four miRNAs revealed an elevated area under the ROC curve (AUC) of 0.897, with a sensitivity and specificity of 81.8 and 90.1%, respectively. This AUC helped in distinguishing early-stage NSCLC. Furthermore, the levels of the four plasma miRNAs were significantly decreased following surgery (P<0.05). Altered expression of miR-145, miR-20a, miR-21 and miR-223 in plasma are of tumor origin, and the four miRNAs may represent potential novel non-invasive biomarkers for early-stage NSCLC.” (Abstract).
Regarding claim 7, Zhang teaches a method wherein “we added cel-miR-39 to each sample as a control.” (Pg. 670, Col. 2, Evaluation of internal controls for quantification of plasma miRNAs. Para. 1). Thus, Haznadar and Zhang suggest a method further comprising using Caenorhabditis elegans miR-39-5p as a control.
Haznadar and Zhang are both considered to be analogous to the claimed invention because they are in the same field of detecting lung cancer. 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 of detecting lung cancer in a subject according to the limitations of the instant application claims 1 and 4-6 as taught by Haznadar to incorporate the method of including C. elegans miR-39 as a control as taught by Zhang and provide a method for detecting NSCLC in a subject by comparing the levels of one or more miRNA and one or more metabolites, wherein the determining the expression level of the one or more miRNAs (mir-21 or mir-223) step utilizes a RT-qPCR assay and miR-39 as a control. One of skill in the art would have been motivated to use the universal spike-in control mir-39 to help determine variations in the RT-qPCR assay. 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 4-7. Doing so would allow for improved diagnostic and prognostic detection of lung cancer (e.g. NSCLC) in a subject.
Claims 1, 4-5 and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Haznadar et al. (“Haznadar”; Patent App. Pub. US 20160169899 A1, June 16, 2016), in view of Xiang et al. (“Xiang”; (2018). Cortisol, cortisone, and 4-methoxyphenylacetic acid as potential plasma biomarkers for early detection of non-small cell lung cancer. The International journal of biological markers, 33(3), 314–320.).
The teachings of Haznadar are documented above in the rejection of claims 1, 4-6 and 11-14 under 35 U.S.C. 103. Claim 10 depends on claim 9, which depends on claim 8, which depends on claim 5, which depends on claim 4, which depends on claim 1. Furthermore, Haznadar teaches that ”It should be appreciated that the diagnostic and prognostic accuracy of biomarkers of the present invention may be improved when the levels of such biomarkers are measured in combination with the level or presence of other, known cancer biomarkers. The known biomarker may be any molecule for which an association between the level or presence of the molecule and a diagnosis of cancer (or a prognosis related thereto) has been established. Examples of known biomarkers to measure include, but are not limited to, proteins, nucleic acid molecules, lipids, carbohydrates and combinations thereof. One type of known biomarker to measure in combination with one or more biomarker of the present invention is a microRNA (miRNA).” Haznadar does not explicitly teach the limitations of claim 8.
Xiang discloses “A total of 254 metabolites were detected and validated in plasma. Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) modeling indicated that 28 endogenous metabolites were present at significantly different levels in patients with NSCLC than healthy controls (variable importance in projection (VIP)>1 and P<0.001 (independent samples t-test) in both the screening group and the validation group). Further analysis revealed that cortisol, cortisone, and 4-methoxyphenylacetic acid had high sensitivity and specificity values as biomarkers for discriminating between NSCLC and healthy controls. Significant associations between specific plasma metabolites and the pathological type or stage of NSCLC were also observed.” (Abstract-Results).
Regarding claim 8, Xiang teaches a method wherein “To further investigate the potential of the selected metabolites for screening patients with NSCLC, metabolites with a fold-change < 0.4 or > 2.5 between patients with NSCLC and healthy controls were selected for further analysis. Three small plasma metabolites met these criteria: cortisol, cortisone and 4-methoxyphenylacetic acid (Table 2). The receiver operating control curves; the area under the curve values; the sensitivity and specificity of each of these metabolites alone and in combination for differentiating patients with NSCLC; and the healthy controls” (Pg. 318, Identification and validation of selected differentially expressed metabolites in patients with NSCLC and healthy controls, Para. 2). Thus, Haznadar and Xiang suggest a method wherein the one or more metabolites comprise 4-methoxyphenylacetic acid.
Haznadar and Xiang are both considered to be analogous to the claimed invention because they are in same field of detecting lung cancer. 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 of detecting lung cancer in a subject according to the limitations of the instant application claims 1 and 4-5 as taught by Haznadar to incorporate the method of wherein the one or more metabolites comprise 4-methoxyphenylacetic acid as taught by Xiang and provide a method for detecting NSCLC in a subject by comparing the levels of one or more miRNA and one or more metabolites, wherein the determining the expression level of the one or more miRNAs is mir-21 or mir-223 and wherein the determining the concentration of the one or more metabolites is 4-methoxyphenylacetic acid. One of skill in the art would have been motivated to determine the concentration of the metabolite 4-methoxyphenylacetic acid to detect NSCLC from a urine sample due to its increased sensitivity in detecting the disease (Table 3). 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, 4-5 and 8. Doing so would allow for improved diagnostic and prognostic detection of lung cancer (e.g. NSCLC) in a subject.
Regarding claim 9, Haznadar teaches a method wherein “various methods of detecting and/or determining the level of a biomarker include, but are not limited to… nuclear magnetic resonance spectroscopy (NMR)” (Para.78). Thus, Haznadar and Xiang suggest a method wherein the step of determining the concentration of the one or more metabolites comprises 1H-nuclear magnetic resonance spectroscopy.
Regarding claim 10, Haznadar teaches a method wherein “a biomarker present in a sample may be normalized to another compound present in the sample, such as, for example, hemoglobin level, packed red cell volume or creatinine” (Para. 61). The “normalized to another compound such as … Creatine” reads on control. Thus, Haznadar and Xiang suggest a method further comprising using one or more of 4-methoxyphenylacetic acid, citrate, creatine ribosome, creatinine, choline, and n- acetyl-neuraminic acid as quantified in normal urine as a control.
Conclusion
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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