DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election of species,
(immune markers): a. determining and quantifying the density of an immune marker;
(scoring system): non-continuous scoring system; and
(pathological response assessment): ypTNM scoring system in the reply filed on December 10, 2025 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)).
3. Claims 1-19, 21 and 25-28 are pending.
Claims 11-14, 16 and 21, drawn to non-elected species are withdrawn from examination.
Claims 20 and 22-24 have been cancelled.
Claims 1, 5, 6, 8, 9, 11-13, 15-19, 21 and 25-28 have been amended.
Claims 1-10, 15, 17-19 and 25-28 are examined on the merits reading on species, (immune markers): a. determining and quantifying the density of an immune marker;
(scoring system): non-continuous scoring system; and
(pathological response assessment): ypTNM scoring system.
Claim Objections
4. Claims 25 and 26 are objected to because of the following informalities:
(a) claim 25 recites “a” twice after the preposition, with on line 2; and (b) claim 26 recites steps b) and c), however fail to recite a step a).
Correction is required.
Claim Rejections - 35 USC § 112
5. 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.
6. Claim 8 recites the limitation "the density of CD3+ cells" and “the density of CD8+ cells” in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
7. 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.
8. Claim(s) 1-10, 15, 17-19 and 25-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galon et al., US 2019/0309369 A1 (published October 10, 2019), and further in view of Liang et al. (Cancer Immunology, Immunotherapy 69: 2623-2634, published online 29 June 2020/ IDS reference #1 submitted December 30, 2022), Sauer et al. (N. Engl. J. Med 351: 1731-1740, October 21, 2004) and Li et al. (Gastric Cancer 21(6): 977-987, 10 May 2018/ IDS reference #3 submitted December 30, 2022). Galon teaches quantifying two or more immune response markers or biological markers from a patient with a solid cancer in methods for the prognosis of survival time, assessing the responsiveness of a patient to antitumoral treatment and status of the immune response of said patient against a solid cancer, see abstract; and page 1, sections 0005 and 0006. It is within the Examiner’s purview the said prognosis reads on predicting risks such as cancer recurrence and/or death, as a survival prognosis is art known to read on expected outcome of a disease and/or the likelihood of survival or death. An organ with cancer is rectum, see page 2, section 0030.
Galon teaches “…each biological marker is indicative of the status of the immune response… quantified in a tumor sample obtained from said patient”, as well as from a reference group, determining values for the biological markers and calculating the arithmetic mean value or the median value of percentile, see page 1, sections 0006-0010. These values are compared with a reference values and correlated with survival time, see page 1, sections 0010-0018.
Patients may receive “… radiotherapy, chemotherapy or immunotherapy. The treatment may consist of an adjuvant therapy (i.e. treatment after chirurgical resection of the primary tumor) [or] a neoadjuvant therapy (i.e. treatment before chirurgical resection of the primary tumor) deemed as postoperative therapy or preoperative therapy, respectively.”, see page 14, section 0169.
The biomarkers are considered as immune biomarkers or adaptive immune biomarkers, which “…are associated with the time of recurrence, with the time before death, with the time before the response to treatment, with the amplitude of response to treatment, and with the prolonged time during which the patient is responding to treatment. The said biomarkers are “…associated with the length, with the time of survival, with the prolonged survival, and the prolonged response to the treatment.”, see page 2, sections 0023 and 0024.
A ”“tumor tissue sample” means any tissue tumor sample derived from the patient… the tumor sample may result from a biopsy performed in the primary tumour of the patient or performed in metastatic sample distant from the primary tumor of the patient. For example an endoscopical biopsy performed in the bowel of the patient affected by a colorectal cancer. Typically the tumor tissue sample is fixed in formalin and embedded in a rigid fixative, such as paraffin (wax) or epoxy, which is placed in a mould and later hardened to produce a block which is readily cut.”, see page 2, section 0033; page 3, section 0035.
“Biological markers include the presence of, or the number or density of, cells from the immune system at the tumor site”, wherein “surface antigens of interest used as biological markers include CD3, CD4, CD8 and CD45RO that are expressed by T cells or T cell subsets.”, see page 3, sections 0042, 0043, 0045 and 0046; and page 4, section 0057.
Galon does not explicitly teach the method, wherein the immune response is assessed before preoperative adjuvant therapy that is a combination of radiotherapy and chemotherapy in a patient with locally advanced rectal cancer and pathological response is determined by a ypTNM scoring system. Galon also does not teach the postoperative adjuvant therapy is administered to a patient determined to have ypTNM=II-IV score.
However, Sauer teaches preoperative chemoradiotherapy for locally advanced rectal cancer, as well as postoperative chemoradiotherapy, see Abstract. And Liang teaches a method of predicting the risk of recurrence and/or death of a patient suffering from a solid cancer (colorectal liver metastasis) after preoperative adjuvant therapy (preoperative chemotherapy) and radical surgery (resection of the primary tumor and liver metastases) comprising the step of assessing at least two parameters, wherein the first parameter is the immune response determined before the preoperative adjuvant therapy (Immunoscore) and the second parameter is the pathological response determined after radical surgery (histopathological growth patterns (HGPs) determined in FFPE tissue samples of metastatic liver) and wherein the combination of said parameters indicates the risk of recurrence and/or death, see Abstract on page 2623; and "Pathological…segment bridging pages 2624 and 2625. Liang also teaches after hepatectomy “…immunoscore was calculated according to the densities of immunostained CD3+ and CD8+ cells” of the CRLM patients, see abstract on page 2623. Utilizing immunohistochemical (IHC) staining on [formalin-fixed paraffin-embedded] FFPE tissue samples immune densities were assessed, see page 2625, Immunoscore…segment. It is art known, biopsy specimens are preserved and prepared to create FFPE tissue samples.
Moreover, Li teaches “[p]athologic regression grade is one indicator to evaluate the efficacy of neoadjuvant chemotherapy. … Therefore, a few studies have proposed that the ypN stage, combined with pathologic regression grade, may be helpful in stratifying the prognosis of esophageal cancer patients who undergo preoperative chemotherapy or chemoradiotherapy”, see page 983, 2nd column. This ypTNM=II-IV scoring system was implemented in combination with a tumor regression grading system.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of all the references and apply to rectal cancer to assess the immune responses to glean differences in clinicopathological characteristics before and after treatments, as well manage the data collected from the different measures to correlate with survival and/or responsiveness to treatments and administer the best postoperative adjuvant therapy, see all references in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Galon, Liang and Li to extrapolate the teachings to the locally advanced rectal cancer of Sauer to assay the immunoscore at any time point, given it is routine in the art to execute this assay and “the Immunoscore system… based on [these] densities is widely regarded as a reliable prognostic predictor for stage I-III colon cancer patients”, as well as aids in predicting a patient’s prognosis after a curative surgery, see all references and in particular, Galon, Example bridging pages 17 and 18; Liang, para. bridging pages 2623 and page 2624. And one of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all the references to collect the data and assign to an algorithm output and implement statistical analysis once a patient is determined to have a pathological response of ypTNM=II-IV in order to arrive at the best postoperative treatment to increase overall survival for the patient, see all references in their entirety, particularly Sauer, Liang and Li.
Double Patenting
9. 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.
10. Claims 1-10, 15, 17-19 and 25-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 10 and 11 of copending Application No. 18/557,140 (filed October 25, 2023) in view of Liang et al. (Cancer Immunology, Immunotherapy 69: 2623-2634, published online 29 June 2020/ IDS reference #1 submitted December 30, 2022) and Li et al. (Gastric Cancer 21(6): 977-987, 10 May 2018/ IDS reference #3 submitted December 30, 2022). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims read on predicting recurrence of a gastrointestinal cancer comprising quantifying the density of immune markers, a non-continuous scoring system and treating the patient with radical surgery. While the copending application does not teach the patient has had preoperative adjuvant therapy and an ypTNM scoring system with a tumor regression grading system.
Liang teaches a method of predicting the risk of recurrence and/or death of a patient suffering from a solid cancer (colorectal liver metastasis) after preoperative adjuvant therapy (preoperative chemotherapy) and radical surgery (resection of the primary tumor and liver metastases) comprising the step of assessing at least two parameters, wherein the first parameter is the immune response determined before the preoperative adjuvant therapy (Immunoscore) and the second parameter is the pathological response determined after radical surgery (histopathological growth patterns (HGPs) determined in FFPE tissue samples of metastatic liver) and wherein the combination of said parameters indicates the risk of recurrence and/or death, see Abstract on page 2623; "Pathological…segment bridging pages 2624 and 2625.
Li teaches “[p]athologic regression grade is one indicator to evaluate the efficacy of neoadjuvant chemotherapy. … Therefore, a few studies have proposed that the ypN stage, combined with pathologic regression grade, may be helpful in stratifying the prognosis of esophageal cancer patients who undergo preoperative chemotherapy or chemoradiotherapy”, see page 983, 2nd column. This ypTNM=II-IV scoring system was implemented in combination with a tumor regression grading system.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of all the references and apply to rectal cancer to assess the immune responses to glean differences in clinicopathological characteristics before and after treatments, as well manage the data collected from the different measures to correlate with survival and/or responsiveness to treatments and administer the best postoperative adjuvant therapy, see all references in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Li to assay the immunoscore at any time point, given it is routine in the art to execute this assay and “the Immunoscore system… based on [these] densities is widely regarded as a reliable prognostic predictor for stage I-III colon cancer patients”, as well as aids in predicting a patient’s prognosis after a curative surgery, see all references and in particular, Liang, para. bridging pages 2623 and page 2624. And one of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all the references to collect the data and assign to an algorithm output and implement statistical analysis once a patient is determined to have a pathological response of ypTNM=II-IV in order to arrive at the best postoperative treatment to increase overall survival for the patient, see all references in their entirety, particularly Liang and Li.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 1-10, 15, 17-19 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 15, 17, 18 and 23 of copending Application No. 18/003,535 (filed December 28, 2022). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims read on predicting recurrence of a gastrointestinal cancer comprising quantifying the density of immune markers, a non-continuous scoring system and treating the patient with radical surgery.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
12. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
-El Sissy et al. A diagnostic biopsy-adapted immunoscore predicts response to neoadjuvant treatment and selects patients with rectal cancer eligible for a watch-and-wait strategy. Clinical Cancer Research 26 (19): 5198-5207, October 1, 2020.
13. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
January 6, 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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