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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 18, 2026 has been entered.
DETAILED ACTION
The amendment filed March 18, 2026 in response to the Office Action of September 18, 2025 is acknowledged and has been entered.
Claims 9, 11, 17, 21, 22, 24, and 28-33 have been amended.
Claims 13 and 34 have been cancelled.
Claims 35 and 36 been added.
Claims 9-11, 16-22, 24, 28-33, 35 and 36 are pending and under consideration.
In view of the claim amendments, the 112(a) rejection on claim 24 is hereby withdrawn.
It is acknowledged that the amended claims 28, 29, 31, and 33 removed the limitation “indicative that the subject has colorectal cancer or a pre-cancerous stage of colorectal cancer”. However, with the amendment, the independent claim 9 and 28 newly added the limitation “determining a score value based on the level of Flt3L and CYFRA21-1”, claim 17 newly added the limitation “a score value based on the level of Flt3: and CYFRA21-1 in a biological sample from the subject has been determined”. These limitations are drawn to judicial exception, thus, new 101 rejections are made.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9, 10, 16-20, 28-31, 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., Clinical Epidemiology, 2017:9 517-526, with suppl. materials, included in this office action Publication Date: 10/31/2017, cited in IDS of 12/08/2021, of record) in view of Karl (Karl et al., WO 2006/066915 A1, Publication Date: 06/29/2006, cited in IDS of 12/08/2021, of record).
Given Broadest Reasonable Interpretation (BRI), any subject would read on “a subject at risk of developing colorectal cancer”, because all subjects are possible to develop colorectal cancer. Given the “comprising” language, step “a score value based on the level of Flt3L and CYFRA21-1” (see claims 9, 17, 28) requires using Flt3L and CYFRA21-1 to determine the score value, but it does not exclude using other markers in the score value determination. For instance, the additional proteins of claim 10 and 11 could be used in the score determination.
Regarding claim 9, Chen teaches that reliable noninvasive biomarkers for early detection of colorectal cancer (CRC) are highly desirable for efficient population-based screening with high adherence rates (page 517, § Objective).
Chen teaches that advanced adenoma is the most important precursor of CRC, which has a substantial risk of development into CRC in the long run (page 524, col. 1, para. 3).
Chen teaches that an algorithm based on growth differentiation factor 15 (GDF-15), amphiregulin (AREG), Fas antigen ligand (FasL), Fms-related tyrosine kinase 3 ligand (Flt3L) and TP53 autoantibody was constructed. In the validation set, the areas under the curves of this five-marker algorithm were 0.82 (95% CI, 0.74–0.90) for detecting CRC and 0.60 (95% CI, 0.52–0.69) for detecting advanced adenomas. At cutoffs yielding 90% specificity, the sensitivities (95% CI) for detecting CRC and advanced adenomas were 56.4% (38.4%–71.8%) and 22.0% (13.4%–35.4%), respectively. The five-marker panel showed similar diagnostic efficacy for the detection of early- and late-stage CRC (page 517, § Results).
Chen teaches that the five-marker algorithm showed comparable or even better diagnostic performance in detecting CRC and its precursors than plasma ethylated Septin 9 and FOBT in external validation (page 518, col. 1, para. 1).
Chen teaches method of protein profiling, data normalization and statistical analysis for the protein biomarkers (§ Laboratory Procedures). In particular, protein profiling were done with Proseek Multiplex Oncology I. The Proseek reagents are based on the proximity extension assay (PEA) technology, where oligonucleotide-labeled antibody probe pairs are allowed to bind to their respective target present in the sample (the bridging paragraph of page 519-520), which read on “an antibody capable of specifically binding Flt3L”.
Chen teaches blood samples were used (page 519-§ Laboratory Procedures – Sample preparation).
Chen teaches that a multi-marker algorithm was derived by applying logistic regression model based on significant biomarkers identified. The prediction algorithms were further validated using receiver operating characteristic (ROC) curves in the validation set. Areas under the cure (AUCs) and sensitivities at cutoffs yielding 80% and 90% specificity, respectively, and their 95% CIs of the multi-marker algorithms were calculated (page 520, col. 2, para. 3). This would read on determining a score value based on the level of biomarkers, as evidenced by paragraphs [0058] and [0059] of instant publication US 2022/0276249 A1 (“[0059] Scores used for deriving the ROC-AUCs and the rest of performance values were obtained using univariate logistic regression model for the individual proteins and multivariate logistic regression models for the different combination of proteins considered. 95% CI for the AUCs was obtained with the DeLong methodology both in individual markers and combination of them”), a similar method of determining a score value is used in the instant specification.
Chen teaches comparing of ROC of biomarkers (a score) in colorectal cancer and in controls (Figs. 2A and 2B).
Chen teaches that identification of supplementary markers that could further enhance the diagnostic performance of our algorithm to levels competitive with the best available stool tests in further research would be highly desirable (page 524, col. 2, para. 2).
Chen teaches as set forth above. However, Chen does not teach detecting CYFR21-1 for colorectal cancer or a pre-cancerous stage of colorectal cancer.
Karl teaches that early diagnosis of CRC translates to a much better prognosis. Most malignant tumors of the colorectum appear to arise from benign tumors, i.e. from adenoma (page 1, lines 23-25).
Karl teaches that marker CYFRA 21-1 (cytokeratin fragment marker 21-1) can be used for assessing colorectal cancer from a liquid sample. Measurement of CYFRA 21-1 can be used in the early detection of colorectal cancer or in the surveillance of patients who undergo therapy (page 1, para. 1).
Karl teaches that in the sense of the present invention early diagnosis of CRC refers to a diagnosis at a pre-malignant state (adenoma) or at a tumor stage where no metastasis at all (page 2, para. 1).
Karl teaches kits for performing the method according to the present invention (page 4, lines 19-26).
Karl teaches that the preferred test samples include blood, serum, and plasma (page 6, lines 12-13, 20).
Karl teaches that measurement of CYFRA 21-1 is typically based upon two monoclonal antibodies (KS19.1 and BM 19.21) specifically for CYFRA 21-1 (page 6, lines 25-31).
Karl teaches that the marker CYFRA 21-1 in a significant percentage of samples derived from patients with CRC (page 8, lines 14-18).
Karl teaches in a preferred embodiment the assessment of CRC according to the present invention is performed in a method comprising measuring in a sample the concentration of a) CYFRA 21-1, b) optionally one or more other marker of CRC, and c) using the concentration determined in step (a) and optionally step (b) in the assessment of CRC (page 9, lines 14-26).
Karl teaches that CYFRA 21-1 alone will not suffice to allow for a general screening e.g. of the risk population for CRC. Most likely no single biochemical marker in the circulation will ever meet the sensitivity and specificity criteria required for screening purposes. Rather it has to be expected that a marker panel will have to be used in CRC screening. The data established in the present invention indicate that the marker CYFRA 21-1 will form an integral part of a marker panel appropriate for screening purpose (page 10, lines 11-24; page 13, lines 10-15).
Karl teaches that combining measurements of CYFRA 21-1 with other recently discovered markers, or with other markers of CRC yet to be discovered, leads and will leads, respectively, to further improvements in assessment of CRC (page 25, lines 16-19).
Karl teaches that sensitivity for multiple markers has been calculated at a common specificity level of 90% for each individual marker tested. The marker CYFRA 21-1 has be found to have the highest sensitivity for CRC as compared to all the other markers investigated (Example 2, and Table 3).
Karl teaches various therapy for CRC, including surgery, chemotherapy or radiotherapy (page 6, lines 3-9).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to measure a panel of protein biomarkers including amphiregulin (AREG), Fms-related tyrosine kinase 3 ligand (Flt3L) and determining a score value of the biomarkers for early diagnosis of CRC as taught by Chen, and to add the marker CYFRA 21-1 into the panel and to calculate a score including AREG, Flt3L and CYFRA21-1, as taught by Karl and Chen, because CYFRA 21-1 has been found to be a good marker for diagnosis of CRC. Both Chen and Karl teach that combine with additional markers would be able to enhance sensitivity and specificity for CRC diagnosis. Based on the references, one of ordinary skilled in the art would have recognized that combination of biomarkers such as Flt3L, AREG, GDF-15, FasL, TP53 (taught by Chen) and CYFRA 21-1 (taught by Karl) would be able to improve CRC early diagnosis. Given that the method of measuring the protein markers (e.g. antibody based detection) and determining a score value of multiple biomarkers have been well-known in the art, as evidenced by Chan and Karl, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to improve the diagnosis and treatment for CRC.
Regarding claims 10 and 30, Chen teaches that the five-marker panel includes growth differentiation factor 15 (GDF-15), amphiregulin (AREG), Fas antigen ligand (FasL), Fms-related tyrosine kinase 3 ligand (Flt3L) and TP53 (page 517, § Results).
Regarding claims 16, 17 and 28, Chen teaches that high quality of screening colonoscopy leads to high adenoma detection rate (page 518, col. 2, para. 2). Chen teaches the large cohort of participants attending screening colonoscopy, therefore representing the target population for CRC screening (page 524, col. 2, para. 3). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to further include colonoscopy to the subject with a score over the cutoff compared to control (e.g. a cutoff of 90% sensitivity, taught by Chen) in the process to further improve diagnostic performance of the method, because the method is widely used in CRC screening and showed efficacy in CRC diagnosis and treating the patient after diagnosis.
In addition, as set forth above, Chen and Karl teach method of diagnosis of CRC based on detection of deviation or a variation in the level of protein biomarkers including amphiregulin (AREG), Fms-related tyrosine kinase 3 ligand (Flt3L), and CYFRA 21-1 as compared to a control sample from healthy subjects (the bridging paragraph of pages 23-24 of Karl).
Regarding claims 18 and 29, Chen teaches that Flt3L level is decreased in CRC population compared to control population (Table S2). Karl teaches that the inventors of the present invention have surprisingly been able to detect the marker CYFRA 21-1 in a significant percentage of samples derived from patients with CRC. Even more surprising they have been able to demonstrate that the presence of CYFRA 21-1 in such liquid sample obtained from an individual can be used in the assessment of colorectal cancer. One of ordinary skill in the art would have recognized that CYFRA 21-1 level is increased in CRC patients, because it is absent in health controls.
Regarding claims 19, 30 and 31, Chen teaches that AREG level is increased (fold change 1.34, p-value < 0.001) in CRC population compared to control population (Table 2).
Regarding claim 35, Karl teaches various therapy for CRC, including surgery, chemotherapy or radiotherapy (page 6, lines 3-9). It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to add a step of removing colorectal cancer (e.g. by surgery), if cancer is detected by colonoscopy. The motivation would have been to treat the cancer promptly without delay.
Regarding claim 36, although the claim recites “the biomarker signature consists of Flt3L and CYFRA21-1”, the claim also recites “said method comprising…”. Given the “comprising” language, the claim does not exclude other proteins to be measured. Thus, measuring the expression of the 6-gene panel comprising Flt3L, and CYFRA 21-1 would read the claim.
Claims 11, 21, 22, 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., Clinical Epidemiology, 2017:9 517-526, Publication Date: 10/31/2017, cited in IDS of 12/08/2021, of record) in view of Karl (Karl et al., WO 2006/066915 A1, Publication Date: 06/29/2006, of record), as applied to claims 9, 10, 16-20, 28-31, 35 and 36 above, and further in view of Chen2015 (Chen et al., Clinical Cancer Research, 21(14), 3318-3326, Publication Date: 07/15/2015, cited in IDS of 12/08/2021, of record).
Chen and Karl teach methods of claims 9, 17 and 28 as set forth above. However, Chen and Karl do not teach further comprising measuring level of ErbB4, HGFR or CLEC2C, or have a decreased level of ErbB4, an increased level of HGFR or an increased level of CLEC2C as compared to control.
Chen2015 teaches among 92 biomarkers, AREG shows the best diagnostic performance for CRC detection (page 3323, col. 1, para. 3).
Chen2015 teaches that AREG has been shown to compete with EGF to bind to the EGFR, which belongs to the ERBB/human epidermoid receptor (HER) family, including ERBB1, ERBB2, ERBB3 and ERBB4. All of these four members were tested in plasma samples and were found to be downregulated in colorectal cancer cases compared with controls. However, differences were statistically significant for ERBB4 only (the bridging paragraph of pages 3323-3324).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to measure a protein panel including amphiregulin (AREG), Fms-related tyrosine kinase 3 ligand (Flt3L) CYFRA 21-1 for early diagnosis of CRC and to add ERBB4 in the protein panel, because ERBB4 are statistically significantly downregulated in CRC population, ERBB4 downregulation may associated with biomarker AREG in the protein panel, one of ordinary skill in the art would have expected to improve CRC diagnosis by combining additional CRC associated biomarkers, as suggested by both Chen and Karl. Because the method of measuring ERBB4 has been well known in the art, as evidenced by Chen 2015, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention. The motivation would have been to further improve CRC diagnosis by combining known biomarkers associated with CRC.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., Clinical Epidemiology, 2017:9 517-526, with suppl. materials, included in this office action Publication Date: 10/31/2017, cited in IDS of 12/08/2021, of record) in view of Karl (Karl et al., WO 2006/066915 A1, Publication Date: 06/29/2006, cited in IDS of 12/08/2021, of record), as applied to claims 9, 10, 13, 16-20, 28-31, 35 and 36 above, and further in view of Abitbol (Abitbol et al., US 2018/0160885 A1, Publication Date: 06/14/2018).
Chen and Karl teach methods of claim 17 as set forth above. However, Chen and Karl do not teach wherein colonoscopy comprises removing a polyp.
Abitbol teaches that a colonoscope can provide a visual diagnosis (e.g. ulceration, polyps) and grants the opportunity for biopsy or removal of suspected colorectal cancer lesions. Colonoscopy can remove polyps as small as one millimeter or less ([0008]). Snare-type devices may be extended out of the end of the endoscope to lasso the polyps, and a heated wire may be used to cauterize the polyps ([0009]).
Abitbol teaches the equipment for performing the procedure (Fig. 2), and snare device for remove polyps ([0120]).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings from Chen, Karl and Abitbol and to modify the method of claim 17 taught by Chen and Karl, and to have a colonoscopy comprising removing a polyp, because Abitbol teaches that colonoscope can provide the opportunity for removal of suspected colorectal cancer lesions and small polyps, and the equipment to do this. One of ordinary skill in the art would have had recognized that removing colorectal cancer lesions or small polyps during colonoscopy would provide additional benefits to patients under colonoscopy. Given that the procedure is well known in the art, as evidenced by Abitbol, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention. The motivation would have been to get additional benefits for colonoscopy.
Response to Arguments
For the 103 rejection, Applicant argues:
Applicant has identified the combination of Flt3L and CYFRA21-1 as a signature that can distinguish a subject with colorectal cancer from normal healthy subjects with high sensitivity and specificity (see Tables 10 and 12, and lines 3-6 at page 36 stating that "all the best signatures comprise [Flt3L and CYFRA21-l]"). Specifically, Applicant has determined that the combination of Flt3L and CYFRA21-1 is characterized by an AUC of 0.865, with positive predictive value of 0.952 and negative predictive value of 0.72 for distinguishing a subject with colorectal cancer from normal healthy subjects (see Table 10).
Applicant submits that the cited references, each alone or in combination, fail to teach or suggest that it is possible to effectively distinguish subjects with colorectal cancer from normal healthy subjects based on the level of Flt3L and CYFRA21-1. … Specifically, Chen teaches a panel of four biomarkers including Flt3L that has an AUC of 0.81 for distinguishing between colorectal cancer (CRC) and healthy controls, and a panel of five biomarkers including Flt3L that has an AUC of 0.82 for distinguishing between CRC and healthy controls (see Chen at Abstract and table 3 at page 522). Chen also teaches that additional biomarkers to the five-biomarker panel may be required to achieve improved discrimination. Specifically, Chen reports that the
diagnostic performance of the five-marker panel described therein was "inferior to diagnostic performance of the most widely used" tests" (see page 524, right column, second paragraph of Chen). Chen states that identifying "supplementary biomarkers that could further enhance the diagnostic performance of [the] algorithm" would be highly desirable (see page 524, right
column, second paragraph of Chen).
In contrast, Applicant's invention relies on a different set of biomarkers, Flt3L and CYFRA21-l, to achieve an AUC of 0.865, which is significantly higher than the AUC of 0.82
achieved by the five-marker panel of Chen. This AUC of a two-marker panel which includes
Flt3L and CYFRA21-1 surprisingly exceeds the AUC of 0.82 of the five-marker panel disclosed
in Chen, despite relying on substantially fewer biomarkers. Given that Chen teaches that
additional biomarkers to the five-biomarkers panel are required to achieve improved discrimination, one of ordinary skill in the art would not have expected that a two-biomarker
panel, let alone a panel comprising Flt3L and CYFRA21-1, would outperform the five biomarker
panel disclosed in Chen. Thus, Applicant's invention is unexpected in view of the cited references.
Applicant’s arguments have been fully considered but they are not persuasive. Applicants argue that Flt3L and CYFRA21-1 achieve an AUC of 0.865 (cite data in Table 10) which is significantly better than the AUC of 0.82 achieved by the 5-gene panel taught by Chen.
First, given the “comprising” language, step “a score value based on the level of Flt3L and CYFRA21-1” (see claims 9, 17, 28) requires using Flt3L and CYFRA21-1 to determine the score value, but it does not exclude using other markers in the score value determination. For instance, the additional proteins of claim 10 and 11 could be used in the score determination.
Secondly, the data present in the specification was based on one small population (32 CRC and 32 health controls) which are used for both discovery of the biomarkers and validation of the biomarkers. Thus, it is not surprising if the biomarkers performing well in the discovery process will perform well in the validation analysis (same population). However, Chen’s study used two different populations: discovery population (226 CRC + 118 health controls) and validation population (41 CRC and 107 health controls), see Table 1 of Chen. Both populations are significantly larger than the population used in the instant specification. Importantly, the biomarker was identified based on the discovery population and the AUC of 0.82 was achieved in the validation population. Given that the population size is larger and the validation has been done in a completely different population, the results of Chen would have more statistical power and is not inferior to the data shown in the instant specification.
Thirdly, based on the teachings of Chen and Karl, combining the five-gene panel with CYFRA21-1 would further improve the performance of the screening, e.g. increasing AUC value.
Applicants further argues that Chen’s five-marker panel assay is “inferior to diagnostic performance of the most widely used stool test…”. However, Chen teaches the five-marker panel has higher sensitivity than other reported blood test (page 524, col. 2, para. 1). Chen teaches: “our panel exhibited comparable diagnostic performance compared to the plasma methylated Septin 9, the only US FDA approved blood based
test for CRC screening. Chen’s method is a blood test which provides many advantages (such as simplicity, and non-invasive) compared with a stool test. In addition, Chen teaches that combine other markers that could further enhance the diagnostic performance (page 524, col. 2, para. 2). Thus “major efforts should be made to identify blood-based tests with higher diagnostic accuracy for detecting advanced adenomas” provides motivation to combine markers taught by Chen and marker taught by Karl.
Applicant submits that the present claims require determining a score value based on the level of Flt3L and CYFRA21-1, or performing colonoscopy based on the deviation or a variation in the score value determined based on the level of Flt3L and CYFRA21-1, or detecting a biomarker signature consisting of Flt3L and CYFRA21-1. Thus, contrary to the Examiner's assertion, the present claims do not read on the combination of the five-marker panel of Chen and CYFRA21-1 of Karl.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, given the “comprising” language, step “a score value based on the level of Flt3L and CYFRA21-1” (see claims 9, 17, 28, and 36) requires using Flt3L and CYFRA21-1 to determine the score value, but it does not exclude using other markers in the score value determination. For instance, the additional proteins of claim 10 and 11 could be used in the score determination. Thus, the rejection is maintained for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 9-11, 16-22, 28-33, 35 and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 1, 14-21 of copending Application No. 17/906,597 (hereinafter Appl. 597, US 2023/0204584 A1 ), as applied to claim 27 above, further in view of Chen (Chen et al., Clinical Epidemiology, 2017:9 517-526, Publication Date: 10/31/2017, cited in IDS of 12/08/2021), Karl (Karl et al., WO 2006/066915 A1, Publication Date: 06/29/2006, cited in IDS of 12/08/2021) and Chen2015 (Chen et al., Clinical Cancer Research, 21(14), 3318-3326, Publication Date: 07/15/2015, cited in IDS of 12/08/2021).
The claims of Appl. 597 teach:
1. An in vitro method for screening for colorectal cancer or a precancerous stage thereof comprising:
a) measuring the concentration level of at least protein TFF3 (Trefoil factor 3), in a plasma sample obtained from a subject,
b) determining if the concentration level of TFF3 is statistically higher than a reference concentration level of TFF3 measured in healthy control subjects, and
c) identifying said subject as one having colorectal cancer or a precancerous stage thereof when the measured concentration level of TFF3 is statistically higher than said measured reference concentration level.
14. The in vitro method according to claim 1, comprising:
a) measuring the concentration levels of at least proteins TFF3 and Flt3L (Fms-related tyrosine kinase 3 ligand), in plasma sample obtained from the subject,
b) determining if the concentration levels of TFF3 and Flt3L are statistically higher than the concentration levels of TFF3 and Flt3L measured in healthy control subjects, and
c) identifying said subject as one having colorectal cancer or a precancerous stage thereof when the measured concentration levels of TFF3 and Flt3L are statistically higher than said measured reference concentration levels.
15. The in vitro method, according to claim 1, comprising:
a) measuring the concentration level of the proteins from at least one of the following groups of proteins: TFF3, Flt3L and HGFR; TFF3, Flt3L and IGFBP2; TFF3, Flt3L and CD147; TFF3, Flt3L and CD163; TFF3, Flt3L and CYFRA21-1; TFF3, Flt3L and ADAMDEC1; TFF3, Flt3L and FASL; TFF3, Flt3L, HGFR and IGFBP2; TFF3, Flt3L, HGFR and CD147; TFF3, Flt3L, IGFBP2 and CD147; TFF3, Flt3L, CD163 and IGFBP2; TFF3, Flt3L, CD163 and HGFR; TFF3, Flt3L, CD163 and CD147; TFF3, Flt3L, CYFRA21-1 and CD147; TFF3, Flt3L, CYFRA21-1 and IGFBP2; TFF3, Flt3L, CD163, and CYFRA21-1; TFF3, Flt3L, HGFR, and CYFRA21-1; or TFF3, Flt3L, CYFRA21-1, and CEA in a plasma sample obtained from the subject;
b) determining if the concentration levels of the proteins in any one or more of the groups of proteins in a) is statistically higher than the concentration levels of the same groups of proteins measured in healthy control subjects; and
c) identifying said subject as one having colorectal cancer or a precancerous stage thereof when the concentration levels of the proteins measured in any one or more of the groups of proteins in a) are statistically higher than said measured reference concentration levels.
16. The in vitro method further comprising processing the measured concentration values of the proteins to obtain a risk score and identifying said subject as one having colorectal cancer or a precancerous stage thereof when concentration level of the protein measured are statistically higher than said measured reference concentration levels. This reads on determining a score value based on the level of biomarkers.
17. The in vitro method according to claim 1, wherein the pre-cancerous stage of colorectal cancer is advanced colorectal adenoma.
18. The in vitro method according to claim 1, further comprising confirming the identification of said subject as one having colorectal cancer or a precancerous stage thereof by an imaging technique.
19. A kit for screening for colorectal cancer or a pre-cancerous stage thereof comprising:
a) reagents or tools suitable for obtaining a plasma sample from a subject, and
b) reagents or tools suitable for determining the concentration level of TFF3 (Trefoil factor 3) in said plasma sample.
20. The kit according to claim 19, further comprising reagents or tools suitable for determining the concentration level of Flt3L (Fms-related tyrosine kinase 3 ligand) in said plasma sample.
21. The kit according to claim 19, comprising reagents or tools for determining the concentration levels of the proteins from at least one of the following groups of proteins: TFF3, Flt3L and HGFR; TFF3, Flt3L and IGFBP2; TFF3, Flt3L and CD147; TFF3, Flt3L and CD163; TFF3, Flt3L and CYFRA21-1; TFF3, Flt3L and ADAMDEC1; TFF3, Flt3L and FASL; TFF3, Flt3L, HGFR and IGFBP2; TFF3, Flt3L, HGFR and CD147; TFF3, Flt3L, IGFBP2 and CD147; TFF3, Flt3L, CD163 and IGFBP2; TFF3, Flt3L, CD163 and HGFR; TFF3, Flt3L, CD163 and CD147; TFF3, Flt3L, CYFRA21-1 and CD147; TFF3, Flt3L, CYFRA21-1 and IGFBP2; TFF3, Flt3L, CD163, and CYFRA21-1; TFF3, Flt3L, HGFR, and CYFRA21-1; or TFF3, Flt3L, CYFRA21-1, and CEA in a plasma sample obtained from the subject.
Thus, the claims of Appl. 597 teach screening or identifying subjects having colorectal cancer or a precancerous stage thereof by measuring gene combinations comprising Flt3L and CYFRA21-1 in a plasma sample. However, the claims of Appl. 597 do not teach using an antibody capable of specifically binding Flt3L and an antibody capable of specifically binding CYFRA21-1; or further comprising measuring AREG; or treating a subject a therapy for CRC or pre-cancerous stage of CRC.
Chen, and Karl teach as set forth above. In particular, Chen teaches using antibody to detect five-marker panel which includes Flt3L for detecting colorectal cancer or advanced adenoma. Karl teaches detecting CTFRA21-1 by antibody for diagnosing colorectal cancer or early stage (adenoma) of colorectal.
Regarding claims 9, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to measure a panel of protein biomarkers including Flt3L and CYFRA21-1 and determining a score value based on the level of Flt3L and CYFRA21-1 for diagnosis of CRC as taught by the claims of Appl. 597, Chen and Karl, and to use an antibody capable of specifically binding Flt3L and CYFRA21-1 as taught by Chen and Karl because the antibodies have been tested and proven by Chen and Karl for CRC diagnosis. In addition, Chen and Karl also taught the method of using these reagents, as set forth above. One of ordinary skilled in the art would have had a reasonable expectation of success for reaching the claimed method. The motivation would have been to develop a CRC diagnosis method with well-tested and proven reagents and method.
Regarding claims 16, 17 and 28, Chen teaches that high quality of screening colonoscopy leads to high adenoma detection rate (page 518, col. 2, para. 2). Chen teaches the large cohort of participants attending screening colonoscopy, therefore representing the target population for CRC screening (page 524, col. 2, para. 3). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to further include colonoscopy in the process to further improve diagnostic performance of the method, because the method is widely used in CRC screening and showed efficacy in CRC diagnosis.
In addition, as set forth above, Chen and Karl teach method of diagnosis of CRC based on detection of deviation or a variation in the level of protein biomarkers including amphiregulin (AREG), Fms-related tyrosine kinase 3 ligand (Flt3L), and CYFRA 21-1 as compared to a control sample.
Regarding claims further reciting AREG and ErbB4, Chen2015 teaches among 92 biomarkers, AREG shows the best diagnostic performance for CRC detection (page 3323, col. 1, para. 3).
Chen2015 teaches that AREG has been shown to compete with EGF to bind to the EGFR, which belongs to the ERBB/human epidermoid receptor (HER) family, including ERBB1, ERBB2, ERBB3 and ERBB4. All of these four members were tested in plasma samples and were found to be down-regulated in colorectal cancer cases compared with controls. However, differences were statistically significant for ERBB4 only (the bridging paragraph of pages 3323-3324).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to measure a protein panel including Fms-related tyrosine kinase 3 ligand (Flt3L) CYFRA 21-1 for early diagnosis of CRC as taught by the claims of Appl. 597, Chen and Karl, and to add AREG and ERBB4 in the protein panel, because AREG shows the best diagnostic performance for CRC detection and ERBB4 are statistically significantly downregulated in CRC population, ERBB4 downregulation may associated with biomarker AREG in the protein panel, one of ordinary skill in the art would have expected to improve CRC diagnosis by combining additional CRC associated biomarkers, as suggested by both Chen and Karl. Because the method of measuring AREG and ERBB4 has been well known in the art, as evidenced by Chen and Chen2015, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention. The motivation would have been to further improve CRC diagnosis by combining known biomarkers associated with CRC.
Regarding claim 36, although the claim recites “the biomarker signature consists of Flt3L and CYFRA21-1”, the claim also recites “said method comprising…”. Given the “comprising” language, the claim does not exclude other proteins to be measured. Thus, measuring the expression of the 3-gene panel comprising TFF3, Flt3L, and CYFRA 21-1 would read the claim.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejection, Applicant argues:
Applicant submits that upon finalization of the claims and indication of allowable subject matter, Applicant may consider filing a terminal disclaimer, if appropriate.
Applicant’s arguments have been fully considered but they are not persuasive because the claims of the instant application are still obvious in view of the co-pending claims and a terminal disclaimer has not been filed. MPEP 804 I-B states: “The “provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in at least one of the applications.” Therefore, the rejections above are maintained for the reasons of record.
NEW GROUNDS OF REJECTIONS
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 17-22, and 24 is 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 17 is drawn to a method for treating a subject at risk of having colorectal cancer. However, no treating step is recited by the claim. It is unclear how performing colonoscopy can treat colorectal cancer. Incorporate the step of claim 35 to claim 17 would overcome the 112(b) rejection.
Claims 18-22 and 24 are also rejected because these claims depend on claim 17 directly or indirectly.
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 9-11, 16-22, 24, 28-33, and 35 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea and law of nature without significantly more. The claims recite “determining a score value based on the level of Flt3L and CYFRA21-1…” See claim 9 (c) and claim 28 (b); and “a score value based on the level of Flt3L and CYFRA21-1 in a biological sample from the subject has been determined to have a deviation or a variation as compared to a reference value” See claim 17. These judicial exceptions are not integrated into a practical application because the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions.
Under the broadest reasonable interpretation (BRI), the terms of the claims are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art. See MPEP 2111.01.
The claims are to processes, which fall in one of the statutory categories of invention. See MPEP 2106.03.
As explained in MPEP 2106.04(11) and the October 2019 Update, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim. The eligibility analysis comprises three-step tests: Step 1 determines whether the claim is directed to a process, machine, manufacture, or composition of matter. If the claim is directed to a statutory category, proceed to Step 2.
1) Step 2A Prong one: evaluating whether the claim recites a judicial exception (MPEP 2106.3); 2) Step 2A Prong two: evaluating whether the claim as a whole integrates the recited judicial exception into a practical application of the exception (MPEP 2106.4); 3) Step 2B: evaluating whether the claim as a whole amounts to significantly more than the recited exception (MPEP 2106.5).
The present claims are directed to a process so Step 1 is satisfied.
Step 2A, Prong 1 – does the claim recite a judicial exception? Yes, in dependent claims 9, 17 and 28 recite an abstract idea (e.g. mathematical concepts and mental process).
Regarding the instant claims and with respect to Step 2A, 1st prong, at least preliminarily these claims recite judicial exceptions in the form of abstract ideas as follows.
Mental process recited: “determining a score value based on…” (or a score has been determined). The process of determining involves evaluating and analyzing data that could be practically performed in the human mind and/or with pen and paper.
Mathematical concept recited: “determining a score value based on the level of Flt3L and CYFRA21-1” (or a score value based on the level of Flt3L and CYFRA21-1 in a biological sample from the subject has been determined). Paragraphs [0058] and [0059] of instant publication US 2022/0276249 A1 state:
“[0058] Diagnostic performance for the individual proteins and some of their combinations has been assessed by their receiver operating characteristic (ROC) curves, and the area under the ROC curves (AUC). Moreover, sensitivities, specificities, positive predictive and negative predictive values (PPV and NPV) for the different tests were calculated at the optimal cutoff point defined by the best Youden's Index (or equivalently, the point of the ROC that maximizes the sum of sensitivity and specificity).
[0059] Scores used for deriving the ROC-AUCs and the rest of performance values were obtained using univariate logistic regression model for the individual proteins and multivariate logistic regression models for the different combination of proteins considered. 95% CI for the AUCs was obtained with the DeLong methodology both in individual markers and combination of them”,
Thus, determining a score value based on the level of Flt3L and CYFRA21-1 involves mathematical concepts and formulas. A series of calculations are required to determine the score value.
Claims 9, 17 and 28 recite a judicial exception, as set forth above, and the analysis must therefore proceed to Step 2A Prong Two.
Step 2A Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. 2019 PEG Section III(A)(2), 84 Fed. Reg. at 54-55.
Besides the abstract idea, the claims recite the additional element of:
For claim 9 the additional elements are:
“for detecting a protein biomarker in a biological sample from a subject at risk of developing colorectal cancer”;
“contacting the biological sample with an antibody capable of specifically binding Flt3L and an antibody capable of specifically binding CYFRA21-1”;
“measuring level of F1t3L and CYFRA21-1 in the biological sample”;
“wherein the biological sample is a blood sample, a serum sample or a plasma sample”.
For claim 17 the additional elements are:
“for treating a subject at risk of having colorectal cancer”;
“performing colonoscopy”;
“wherein the biological sample is a blood sample, a serum sample or a plasma sample”.
For claim 28 the additional elements are:
“for identifying a subject at risk of developing or having colorectal cancer (claim 28);
“measuring level of F1t3L and CYFRA21-1 in the biological sample”;
“performing colonoscopy on the subject if a deviation or a variation in the score value, as compared to a reference value, is found”
“wherein the biological sample is a blood sample, a serum sample or a plasma sample”.
As evidenced by Chen, Karl and Chen2015 (see 103 rejections above), these are routine and conventional steps in the art. Thus, the additional elements do not add an inventive concept to the instant claims.
Under Step 2A, Prong 2, these additional elements serve merely to gather data that is utilized as input to the recited judicial exception. Therefore, these steps equate to insignificant extra-solution activity and are insufficient to integrate into a practical application. (Step 2A: YES).
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. The previous considerations from Step 2A, Prong 2 are carried over and we re-evaluate the additional elements for their conventionality, both individually and in combination. In looking at the additional elements, they appear to be conventional both individually and in combination in light of prior art. Measuring Flt3L and CYFRA2-1 in a biological sample, such as blood sample, were well-known in the art at the time of the effective filing date, as evidenced by Chen, Karl and Chen2015, see 103 rejections above.
In addition, MPEP 2106.05(d) II teaches that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Thus, these routine measuring methods do not add an inventive concept to the instant claim.
Claim 10, 11 and 16, which depend on claim 9, recite the additional elements: “further comprising measuring level of AREG” (claim 10); “further comprising measuring level of ErbB4, HGFR or CLEC2C” (claim 11); “further comprising performing colonoscopy on the subject” (claim 16). However, as evidenced by Chen, Karl and Chen2015 (see 103 rejections above), these are well known in the art. Thus, the additional elements do not add an inventive concept to the instant claims.
Claim 18-22, 24 and 35, which depend on claim 17, recite the additional elements: “wherein the biological sample from the subject has been determined to have a decreased level of Flt3L as compared to the reference level of Flt3L in healthy control subjects and an increased level of CYFRA21-1 as compared to the reference level of CYFRA21-1 in healthy control subjects” (claim 18); “wherein the biological sample has been further determined to have a deviation or a variation in the level of AREG as compared to the reference level of AREG in healthy control subjects” (claim 19); “wherein the biological sample has been further determined to have an increased level of AREG as compared to the reference level of AREG in healthy control subjects” (claim 20); “wherein the biological sample has been further determined to have a deviation or a variation in the level of ErbB4, HGFR or CLEC2C as compared to the reference level of ErbB4, HGFR or CLEC2C in healthy control subjects” (claim 21); “wherein the biological sample has been further determined to have a decreased level of ErbB4 as compared to the reference level of ErbB4 in healthy control subjects, an increased level of HGFR as compared to the reference level of HGFR in healthy subjects, or an increased level of CLEC2C as compared to the reference level of CLEC2C in healthy control subjects” (claim 22); “wherein said colonoscopy comprises removing a polyp” (claim 24); and further comprising removing colorectal cancer following colonoscopy (claim 35). However, as evidenced by Chen, Karl and Chen2015 (see 103 rejections above), these are well known in the art. Thus, the additional elements do not add an inventive concept to the instant claims.
Claims 29-33, which depend on claim 28, recite the additional elements: “wherein a decreased level of F1t3L as compared to the reference level of Flt3L in healthy control subjects and an increased level of CYFRA21-1 as compared to the reference level of CYFRA21-1 in healthy control subjects is found” (claim 29); “further comprises measuring level of AREG” (claim 30); “wherein an increased level of AREG as compared to the reference level of AREG in healthy control subjects is found” (claim 31); “further comprises measuring level of ErbB4, HGFR or CLEC2C” (claim 32); “wherein a decreased level of ErbB4 as compared to the reference level of ErbB4 in healthy control subjects, an increased level of HGFR as compared to the reference level of HGFR in healthy control subjects, or an increased level of CLEC2C as compared to the reference level of CLEC2C in healthy control subjects is found” (claim 33). However, as evidenced by Chen, Karl and Chen2015 (see 103 rejections above), these are well known in the art. Thus, the additional elements do not add an inventive concept to the instant claims.
Thus, claims 9-11, 16-22, 24, 28-33, and 35 are properly rejected.
Response to Arguments
For the 101 rejection, Applicant first argues:
The next step (Step 2A) of the subject matter eligibility analysis requires a determination of whether the claims are directed a judicially recognized exception, i.e., to a law of nature, a natural phenomenon, or an abstract idea. Here, claim 28 requires performing colonoscopy on the subject if a deviation or variation in the score value, as compared to a reference value, is found. Thus, claim 28 does not claim the relationship between the risk of developing colorectal cancer and the level of Flt3L and CYFRA21-1 in a biological sample from the subject. Instead, claim 28 claims an application of that relationship, and, as such, does not recite or describe any recognized exception. Thus, it is not necessary to perform the markedly different characteristics analysis as described in subsections 3a and 3b on pages 7 4622-7 4624 of the Guidance. Accordingly, claim 28 is not directed to a judicial exception (Step 2A: NO), and is, therefore, patent eligible. Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, the amended independent claims 9, 17 and 28, recite mental process: determining a score value. The process of determining involves evaluating and analyzing data that could be practically performed in the human mind and/or with pen and paper. In addition, based on paragraphs [0058] and [0059] of the instant specification, determining a score value based on the level of Flt3L and CYFRA21-1 involves mathematical concepts and formulas. A series of calculations are required to determine the score value. Accordingly, claims 9, 17 and 28 directed to a judicial exception.
Applicants further argue:
Applicant respectfully submits that, just like in Vanda, the present inventors have recognized the relationship between the risk of developing colorectal cancer and the level of Flt3L and CYFRA21-1 in a biological sample from the subject and have claimed an application of this relationship. Just like the claims at issue in Vanda and unlike the claims at issue in Mayo, the claims here require performing a colonoscopy on the subject if a deviation or variation in the score value, as compared to a reference value, is found. Thus, the present claims are patent eligible under the first step of the Guidance. Reconsideration and withdrawal of the present rejection is respectfully requested.
The Office asserted that steps directed to measuring Flt3L and CYFRA21-1 in a biological sample, such as a blood sample, were well-known in the art at the time of the effective filing date, as evidenced by Chen, Karl, and Chen2015. Applicant respectfully traverses the above assertion. As discussed above, claim 28 and claims dependent therefrom are novel and inventive in view of the cited references.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, the additional elements of the claims are routine and conventional steps in the art. Thus, these elements do not add an inventive concept to the instant claims. For example, the claims 9, 17 and 28 have claimed an application: performing colonoscopy based on the determined score. However, performing colonoscopy is a conventional and routine application in the art as evidenced by the references cited in 103 rejection. The application does not add an inventive concept to the claims.
Applicant argues that measuring the Flt3L and CYFRA21-1 in a biological sample is novel and inventive. As set forth in the 103 rejection, Chen, Karl and Chen2015 that teach Flt3L, AREG, GDF-15, FasL, TP53 (taught by Chen) and CYFRA 21-1 (taught by Karl) would be able to improve CRC early diagnosis. Given that the method of measuring the protein markers (e.g. antibody based detection) and determining a score value of multiple biomarkers have been well-known in the art, as evidenced by Chan and Karl, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed method. Accordingly, measuring the Flt3L and CYFRA21-1 in a biological sample to detect early colorectal cancer is not novel and inventive. Thus, the 101 rejection is proper for the reasons of record.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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