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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Application Status
Claims 1, 3-4, 7-15, and 28-29 are pending.
Claim 15 is withdrawn.
Claims 1, 3-4, 7-14, and 28-29 are examined on the merits herein.
Grounds of Rejection Withdrawn
Previous rejection of claims 1, 3-4, 7-10, 13-14, and 28-29 under U.S.C. 103 are withdrawn in view of applicant’s common ownership exception statement under 35 U.S.C. 102(b)(2)(C).
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, 3-4, 7-10, 13-14, 16-17, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Kwak et al. (Oncotarget, 2016, 7:81778-81790; IDS entered on July 30, 2021), Basile (Expert Opin Biol Ther, 2017,17(6):709-721; cited in OA 04/14/2025) and Schönmeyer (Pan Stanford Publishing Pte. Ltd: Singapore, 2018; 101–130; PTO-892).
Regarding claims 1, 4, 16-17, and 28-29, Kwak teaches a method for obtaining an Immunoscore (IS) from a human tissue sample collected from an advanced CRC (p. 81787, col 2, para. 4 - p. 81788, col. 1 para 4; Fig.1A and 1B for CD3 and CD8 identification, respectively). Table 2 clearly denotes that testing was done on both pathological tumor stages (pT) 1-3, as well as pT stage 4 CRC patients. The method comprises:
the obtained tumor tissue included the area of tumor center (CT) and invasive margin (IM) of the primary tumor as well as its related distant metastasis (DM) (p. 81787, col 2, para. 4);
immunohistochemistry was performed using antibodies for CD3 and CD8 (the CT or tumor core is identified as the tumor center and region of interest) (p. 81787, last para - p. 81788, 1st para);
scanning slides and analyzing density of CD3 and CD8 positive cells normalized to nuclear stain (p. 81788, col 1, para. 2); and
using cutoff values for score normalization (Table 1).
Regarding claim 8, Kwak teaches that the ROI is identified automatically, by computerized analysis system, Image Scope™ (p. 81788, col. 1, para. 2).
Kwak does not teach that the CRC is previously diagnosed as having deficient MMR, selection of a treatment, using the ICS to determine whether an immune checkpoint therapy is indicated, the specific checkpoint therapy; or applying a non-continuous scoring function to a feature vector comprising the CD8+ density.
Regarding claims 1, 3, 9-10, 13, and 16-17, Basile teaches that it has been observed that CRC patients with a high infiltration of memory T cells and CD8+ T cells experienced a longer progression free survival (PFS) and overall survival (OS) (section 3.1, p. 712). Basile further teaches that the immunoscore is obtained by counting two lymphocyte populations identified by CD3/CD45RO, CD3/CD8 or CD8/ CD45RO positivity, in both the tumor core (TC) and invasive margin (IM) and has been used to help identify patient’s disease stage as well as patients that might benefit from specific treatments (section 3.1, p. 712). Basile further teaches that CRC is classified by MSI status, metabolic status and phenotype (section 3.2, p. 712). Basile further teaches that MSI cancers have higher immunoscores than MSS tumors and that this supports the treatment of MSI CRC patients with an anti-PD-1/ PD-L1 antibody (section 3.3, p. 713). Basile further teaches that the combination of different biomarkers (i.e. properly defined and documented PD-L1 expression, the presence of TILs, and molecular classification) may help identify responders to immunotherapy and that current evidence has suggested that patients with CRC tumors that exhibit the presence of TILs, MSI-H and high expression of neo-antigens are good candidates for checkpoint immunotherapy (section 3.3, p. 713).
Regarding claim 14, Basile teaches that the ESMO consensus guidelines recommend MSI testing because of its strong predictive value for the use of checkpoint inhibitors in the treatment of CRC patients, suggesting the potential use of pembrolizumab in patients with dMMR tumors and a small phase II trial results with improved objective response rate (ORR) and progression free survival (PFS) (p 714, col 1, para 1) and that the Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to pembrolizumab for the treatment of MSI-H CRC (p 718, col 2, para 2).
Regarding claims 1, 4, 8, and 28-29, Schönmeyer teaches that since the number of immunohistochemical markers in each tissue section is limited to three or four in bright-field microscopy, the method of serial sectioning has been used to combine several, sequentially cut tissue sections to one information block (page 105, para 3); consecutive tissue slices can be virtually aligned in a way that corresponding regions match to each other in a common coordinate system (page 109, para 1); and that image co-registration helps twofold: first, the pathologist annotation in H&E can be automatically transferred to the corresponding IHC sections, and second, the measurements in each ROI of each tissue section may be combined using arithmetical operations (page 105, para 4). Schönmeyer teaches that the pathologist may delineate tumor regions using a digital pathology workstation particularly in hematoxylin and eosin (H&E)-stained images, enabling the software to determine cell counts within the ROI, so that the density of the cells corresponding to a given class can be easily calculated, such as CD8(+) cells depicting cytotoxic T cells (page 104, last para). Schönmeyer further teaches that in most cases it is required to compose a score from various measurements to deliver predictive power, such as the Immunoscore® combines CD8(+) and CD3(+) cell density measurements in the tumor center and in the invasive margin to a final score predictive of colon cancer survival (page 112, para 1). Schönmeyer further teaches that image mining requires the aggregation of all measurements for a single patient into a single feature vector which comprises various numerical and categorical entries (page 104, para 2). Schönmeyer further teaches that the image content is frequently aggregated using statistical operations in specific regions of interest (ROIs) and that common aggregation methods are minimum, mean, quantiles, or maximum value of the measurements within the ROI (page 104, para 2).
It would have obvious to one of ordinary skill of the art prior to the effective filing date of the claimed invention to classify CRC tumors by MMR/ MSI status in addition to Immunoscore to select immune checkpoint therapy as taught by Basile to the method of obtaining an Immunoscore as taught by Kwak and to integrate the density of CD8+ cells in the ROI to H&E staining as taught by Schönmeyer. The ordinary artisan would have been motivated to do so as Basile teaches that MSI cancers have higher immunoscores than MSS tumors and that this supports the treatment of MSI CRC patients with an anti-PD-1/ PD-L1 antibody and that the ESMO consensus guidelines recommend MSI testing because of its strong predictive value for the use of checkpoint inhibitors in the treatment of CRC patients. Schönmeyer teaches that the image content is frequently aggregated using statistical operations in specific regions of interest (ROIs) and that common aggregation methods are minimum, mean, quantiles, or maximum value of the measurements within the ROI and that image mining requires the aggregation of all measurements for a single patient into a single feature vector which comprises various numerical and categorical entries, such as the Immunoscore® combines CD8(+) and CD3(+) cell density measurements in the tumor center and in the invasive margin to a final score predictive of colon cancer survival. The ordinary artisan would have a reasonable expectation of success to combine MMR/ MSI status with Immunoscore into a feature vector to select CRC patients for therapy and more specifically checkpoint inhibitor therapy as these are analogous arts and previous data indicates that MSI status correlates with Immunoscore and has demonstrated improved clinical outcomes with checkpoint therapy in advanced CRC patients.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Kwak et al. (Oncotarget, 2016, 7:81778-81790; IDS entered on July 30, 2021) and Basile (Expert Opin Biol Ther, 2017,17(6):709-721; cited in OA 04/14/2025) and Schönmeyer (Pan Stanford Publishing Pte. Ltd: Singapore, 2018; 101–130; PTO-892) as applied to claims 1, 3-4, 7-10, 13-14, 16-17, and 28-29 above, and further in view of Kareva (Int J Mol Sci, 2017, 18(10):2134; cited in OA 04/14/2025).
The teachings of Kwak, Basile, and Schönmeyer as applied to claims 1, 3-4, 7-10, 13-14, 16-17, and 28-29 are detailed above.
Kwak, Basile, and Schönmeyer do not teach that the treatment comprises a reduced course of chemotherapy, wherein the reduced course of chemotherapy is a reduction of the number, dose and or duration of agents.
Kareva teaches that standard chemotherapy is done at the maximum tolerated dose , but metronomic chemotherapy that is administered more frequently at a lower dose has the advantages of decreased tumor vascularization, lower therapeutic resistance, and augmented anti-tumor response (section 2, page 2). Kareva further teaches that the combination of metronomic chemotherapy and checkpoint inhibitors would be expected to have synergistic effect because both increase immune cell activation, facilitated tumor infiltration by cytotoxic immune cells, and experimental evidence (figure 3). Kareva further teaches that the combination of immune checkpoint inhibitors and metronomic chemotherapy would provide an avenue to target therapy resistant cells without inflicting unacceptable toxicity resulting in high treatment compliance and improved outcomes for difficult to treat cancers (page 8).
It would have obvious to one of ordinary skill of the art prior to the effective filing date of the claimed invention to reduce the dose of chemotherapy to metronomic chemotherapy as taught by Kareva in combination with the method of treatment with a checkpoint inhibitor after patient selection by MMR/MSI and Immunoscore into a feature vector as taught by Kwak, Basile, and Schönmeyer. The ordinary artisan would have been motivated to do so as Kareva teaches that there would be an expected synergistic effect between checkpoint inhibitor therapy and metronomic chemotherapy because both increase immune cell activation, facilitated tumor infiltration by cytotoxic immune cells, and experimental evidence. Kareva further teaches that the combination of immune checkpoint inhibitors and metronomic chemotherapy would provide an avenue to target therapy resistant cells without inflicting unacceptable toxicity resulting in high treatment compliance and improved outcomes for difficult to treat cancers. The combination therapy with reduced chemotherapy and immune checkpoint therapy would provide a therapeutic benefit to advanced CRC patients.
Response to Arguments
Applicant’s arguments filed 12/23/2025 with respect to claim(s) 1, 3-4, 7-10, 13-14, and 28-29 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant's arguments filed 07/11/2025 have been fully considered but they are not persuasive.
Applicant submits: Kwak does not disclose that a non-continuous scoring function ( claim 1) or a continuous scoring function ( claim 29) may be applied to a feature vector including an obtained CD8+ cell density to determine an immune context score. Moreover, Kwak does not teach the use of first and second serial sections as required by claims 1 or 29. For instance, Kwak does not disclose or suggest that annotations from a digital image of a serial section stained with hematoxylin and eosin may be automatically registered to a digital image of a different serial section stained for the presence of the CD8+ biomarker; or that a region of interest may be automatically registered from one digital image to the other for use in determining CD8+ cells. As such, Kwak cannot teach all of the recitations of the claimed invention.
In response: The deficiencies noted above for Kwak are remedied by newly cited art Schönmeyer detailed above, that teaches serial sectioning and staining with biomarkers that then have ROI delineated by a pathologist and the images are quantified as well as combined into an information block that further facilitates aggregation of all measurements for a single patient into a single feature vector which comprises various numerical and categorical entries.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643