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 .
The amendment filed 02/17/2026 is acknowledged. Regarding the Office action mailed 10/17/2025:
The rejection of claims 3, 4, 10, 11, 17 and 18 under 35 USC 112(b) is withdrawn in view of the amendment to claims 3, 10 and 17 to remove “one or more serum tumor protein biomarkers”.
The rejection of claims 1-3 and 5-7 under 35 USC 103 over Iijima in view of Koeppel and Blackman is withdrawn in view of the amendment to claim 1 to recite comparing the baseline ctDNA level with two or more consecutive on-treatment ctDNA levels. While Iijima’s Table 4 represents a comparison of pre-treatment samples and multiple on-treatment samples, Iijima did not instruct comparison specifically with “two or more consecutive” on-treatment samples. For the same reason, the rejections of claims 8-10, 12-17, 19 and 20 are withdrawn. Claims 4, 11 and 18 were cancelled, rendering the rejections of those claims moot.
New grounds of rejection are set forth below in response to the amendment. Any of Applicant’s arguments that would still pertain to the new grounds of rejection will be addressed following the rejections.
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.
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.
Claim(s) 1-3 and 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iijima (European Journal of Cancer 86:349-357, Nov 5, 2017, previously cited) in view of Koeppel (PLoS ONE 12(11):e0188174, Nov 21, 2017, previously cited) and Hoos (J Natl Cancer Inst 102:1388-1397 (2010)).
Regarding claims 1, 2 and 7, Iijima disclosed a method for predicting efficacy of nivolumab (an immune checkpoint inhibitor) treatment in patients with non-small cell lung cancer (see title). The method comprised determining a baseline ctDNA level at a first timepoint prior to the patient beginning treatment and multiple “on-treatment” ctDNA levels at timepoints thereafter; page 351, section 2.4: “Peripheral blood samples were collected from the patients before and at 1, 2, 4, 6 and 8 weeks after initiation of nivolumab treatment.” See also figure 4, which shows non-responders (panel A) and responders (panel B), and table 4. Iijima determined the level of ctDNA as a variant allele fraction (AF) by targeted sequencing of specific genes in which tumor-specific mutations were located; page 351, section 2.5. Iijima notes (page 352, section 3.5): “ctDNAs of non-responders showed consistently high AF after treatment but those of responders showed a rapid decrease mostly within 2 weeks (Fig. 4).” It is noted that responders showed successive later timepoints where ctDNA level was below the baseline; see table 4.
The difference between Iijima and the claimed invention is that Iijima did not “capture” the target sequences from the sample (i.e. did not capture fragments using capture probes) as recited in claim 1, did not specifically instruct to compare the pre-treatment sample (i.e., “baseline”) to two or more consecutive on-treatment samples as recited in claim 1, did not specify the criteria for calling a prognosis or therapeutic response as “positive” as recited in claims 1 and 5, and did not determine the level of ctDNA based on “tumor mutation burden” as recited in claims 3 and 6.
Koeppel stated it was known in the art that patients having a high tumor mutation load (i.e. tumor mutation burden) tended to have better responses to immune checkpoint inhibitors (sentence spanning pages 1-2). Koeppel then demonstrated the feasibility of determining tumor mutation load using circulating tumor DNA; see Abstract and entire Results section. In particular, Koeppel concluded (Abstract): “When comparing cfDNA-WES to tDNA-WES, mutation detection sensitivity was 53%, consistent with previously published prospective study comparing cfDNA-TGS to tDNA-TGS. For samples in which presence of tumor DNA was confirmed in cfDNA, tumor mutation load from liquid biopsy was correlated with tumor biopsy. Taken together, this study demonstrated that liquid biopsy may be applied to determine tumor mutation load. Qualification of liquid biopsy for interpretation is a crucial point to use cfDNA for mutational load estimation.” It is noted that Koeppel’s protocol for using ctDNA to determine tumor mutation load involved capture of target sequences; see page 4, section “Whole exome sequencing (tDNA and cfDNA)”.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to either (1) modify the method of Iijima by substituting the determination of ctDNA level by targeted sequencing of tumor-specific mutations with the determination of ctDNA by whole-exome sequencing for tumor mutation burden (tumor mutation load) as disclosed by Koeppel, or (2) to implement the assessment of tumor mutation burden as suggested by Koeppel by assessing the tumor mutation in ctDNA at multiple time points before and during treatment as taught by Iijima, in either case arriving at the same set of steps as recited in the claims. One would have been motivated to do this because both Iijima and Koeppel taught their methods for the purpose of predicting responsiveness to immune checkpoint inhibitors, and Koeppel specifically advocated the use of tumor mutation burden (load) as a biomarker for efficacy of such cancer immunotherapy, the concept having been proposed “in several studies” (Abstract, first sentence). Koeppel provides a reasonable expectation of success that ctDNA could be used to determine tumor mutation burden.
Like Iijima and Koeppel, Hoos discussed assessment of response to immunotherapeutic treatment of cancer. Hoos noted (page 1388, left column, middle paragraph, citations omitted): “Adjusting the clinical development paradigm from chemotherapy to immunotherapy requires addressing the unique characteristics of immunotherapeutic agents in clinical trials to provide more adequate tools for evaluation, including the adjustment of clinical trial endpoints.” Hoos also noted (immediately following that text): “The continuum of biological events following administration of immunotherapy to a cancer patient can be divided into three steps: 1) immune activation and T-cell proliferation starting early after administration, 2) clinically measurable antitumor effects mediated by activated immune cells over weeks to months, and 3) potential delayed effect on patient survival several months after first administration compared with agents not requiring immune activation (Table 1).”
The endpoint relevant to this discussion is the antitumor response.
For assessment of antitumor response, Hoos discussed a physical assessment of tumor size (looking at increase or decrease in size of lesions, and the appearance, or not, of new lesions) using radiographic assessment (page 1391, first two paragraphs under “Measurement of Antitumor Response: irRC”. Hoos noted that because of the “delay” of response for immunotherapy, as opposed to conventional chemotherapy, the patterns of response were more complex: “For example, some reported clinical experiences with cancer vaccines demonstrated that patients with stable disease or progressive disease may have subsequent tumor regression, whereas others may show initial mixed responses, with regression in some lesions while other lesions remain stable, progress, or first appear” (citations omitted). Hoos disclosed (page 1391, last sentence of last full paragraph): “To create a process, which systematically captures all observed response patterns, irRC were proposed”. irRC stands for immune-related response criteria; see footnote for Table 1.
These criteria are outlined in Table 3. A complete response (irCR) is a 100% decrease in total measurable tumor burden, while a partial response (irPR) is a ≥50% decrease in total measurable tumor burden. Thus, the concept of a positive response to immunotherapy for cancer correlating with a ≥50% decrease in total measurable tumor burden (which encompasses a ≥80% decrease in total measurable tumor burden) had been proposed in the prior art. In addition, the determination of any of the categories of response (irCR, irPR, irSD (stable disease) and irPD (progressive disease)) requires a second assessment at least 4 weeks apart (see footnotes for Table 3), which Hoos noted was “two consecutive time points”, noting “Overall, immune-related response based on two or more tumor assessments is derived as shown in Table 3” (page 1392, right column). Thus, Hoos suggested comparing baseline tumor burden to two or more consecutive time points, and suggested reduction in tumor burden by ≥50% in those consecutive time points as correlating with a positive response (i.e. being at least a “partial response”). This means that a reduction by ≥80% would also represent a positive response.
Iijima established ctDNA levels as a surrogate for tumor volume; section 3.3: “There was a statistically significant correlation between TV and ctDNA level”. Therefore, it would have been prima facie obvious to modify the method suggested by the combined teachings of Iijima and Koeppel by comparing baseline levels of ctDNA with two or more consecutive on-treatment samples to determine whether the patient was experiencing a partial or complete response in order to make an informed decision whether to continue, terminate, or change treatment. In fact, Iijima made mention of the irRC system of categorization; section 2.2: “Thus, response to immunotherapy was evaluated at the second radiological examination. This is based on immune-related response criteria (irRC) for immunotherapy.” It is noted that where the claims recite “≥80%” or “≥90%”, Hoos teaches that tumor burden reduction of ≥50% correlated with partial response, while 100% correlated with complete response. The range recited by the claims falls within the range disclosed in the prior art. As noted in MPEP 2144.05, where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Claim(s) 8-10, 12-14, 15-17 and 19-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iijima (European Journal of Cancer 86:349-357, Nov 5, 2017, previously cited) in view of Koeppel (PLoS ONE 12(11):e0188174, Nov 21, 2017, previously cited) and Hoos (J Natl Cancer Inst 102:1388-1397 (2010)) as applied to claims 1-3 and 5-7 above, and further in view of El-Helali (US 2019/0127805, previously cited).
The teachings of Iijima, Koeppel, and Hoos have been discussed. These references did not teach “systems” comprising processors and memory for carrying out the method.
It was known in the art to automate methods using systems with processors, in particular for analyzing biomarkers and predicting responsiveness to therapy based thereon. See El-Helali paragraph [0217].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to automate the method suggested by the combined teachings of Iijima, Koeppel and Hoos, as it is obvious to automate a manual utility (MPEP 2144.04 (III)), and since El-Helali demonstrates it was known in the art to automate methods for predicting treatment response based on biomarkers using systems with processors configured to carry out the analysis.
Response to Arguments
Applicant's arguments filed 02/17/2026 have been fully considered but they are not persuasive. Applicant argues:
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This argument is not persuasive in view of the new grounds of rejection, relying on Hoos, which suggests considering a response as positive (either a partial or complete response to immunotherapy) based on ≥50% reduction or 100% reduction, respectively, in tumor burden at two or more consecutive time points following treatment (compared to baseline levels).
Applicant argues:
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This argument is not persuasive. Hoos taught a 100% reduction in tumor burden in two or more consecutive samples would be considered a complete response, and Iijima established that levels of ctDNA correlate with tumor volume (i.e. tumor burden). It would therefore have been obvious to consider a 100% reduction in levels of ctDNA in two or more consecutive samples as also indicative of a positive response to treatment.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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