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 .
2. This action is in response to the papers filed March 11, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 1, 5-13, 20, 22-23, 33-34, and 36 are currently pending.
Claims 20 and 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 30, 2023.
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 1, 5-6, 8-13, 33-34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Goldberg (Clin Cancer Res 24(8) Epub 1/12/2018) in view of Anagnostou (Cancer Discovery 7(3) 264-276 March 2017) and Schvartsman (Lung Cancer 112 (2017) 90-95).
Regarding Claim 1 Goldberg teaches that they investigated whether the effectiveness of immunotherapy could be predicted based on early changes in ctDNA levels in patients with metastatic NSCLC (page 1872-1873). They compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non–small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. ctDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multi gene next-generation sequencing assay. Golberg teaches that strong agreement was observed between ctDNA response and radiographic response Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; P < 0.001). A ctDNA response was associated with superior progression-free survival and superior overall survival. Goldberg teaches that a drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC (abstract). Figure 1 shows plasma levels of ctDNA and measurements of radiographic tumor burden for two representative patients with metastatic NSCLC: a patient with treatment response (B) and a patient with progression disease. (C). Patient B was an 89-year-old woman who received anti–PD-1 immunotherapy as first-line treatment achieved undetectable ctDNA on day 42, and met radiographic response criteria on day 125. The patient received 27 cycles of immunotherapy, with treatment continuing as of the data cutoff date. Undetectable ctDNA is indicated by open diamonds. Patient C was a 73-year-old woman who received first-line anti–PD-1 immunotherapy who failed to meet criteria for radiographic or ctDNA response. Radiographic progression was noted on day 38 and therapy was stopped on day 73 (date of death). Radiographic and ctDNA measurements for the remaining 26 patients in the study are presented in Supplementary Fig. S1 (page 1875).
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Thus Goldberg teaches a method comprising: obtaining a first biological sample from the subject at a first time point (baseline), detecting a first level of circulating tumor DNA (cfDNA) in the first biological sample; obtaining a second biological sample from the subject at a second time point; detecting a second level of cfDNA in the second biological sample, wherein the subject has received an immunotherapy between the first time point and the second time point; identifying the subject as not be responsive to the immunotherapy, based on the second level of cfDNA not being lower than the first level of cfDNA.
Regarding Claim 5 Goldberg teaches a method wherein the biological sample obtained from the subject at the first time point, the second time point, or both comprises plasma (page 1873, col 1).
Regarding Claim 6 Goldberg teaches a method wherein the detecting includes a next generation sequencing method (abstract, 1873).
Regarding Claim 8 Goldberg teaches that the level of ctDNA increased following immunotherapy in a non-responder (Fig 1 C).
Regarding Claims 10-13 Goldberg teaches that they enrolled metastatic NSCLC patient who were receiving immune checkpoint inhibitor therapy. Goldberg teaches that among 28 patients, 22 were treated with a single agent anti-PD-1 or anti-PD-L1 therapy and 6 received combination immunotherapy (page 1874, col 1). Goldberg teaches patient 020 was treated with anti-PD-1/anti-CTLA-4 immunotherapy (Fig S1). Thus Goldberg teaches a method wherein the immunotherapy is a checkpoint inhibitor, wherein the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor.
Regarding Claims 33 and 34 Goldberg teaches they analysis of plasma samples that were obtained at baseline, during treatment, or up to 2 weeks after termination of immunotherapy (page 1874). As shown in Fig S1 the second time point for several of the patients was 2-6 weeks after the first time point (baseline) As shown in Fig S1 the second time point for several of the patients was 4 weeks after the first time point (baseline).
Regarding Claim 36 Goldberg teaches a method wherein the patient has NSCLC (page 1873).
Goldberg does not teach a method further comprising detecting a first level of at least one TCR clonotype in the first biological sample; detecting a second level of the at least one TCR clonotype in a second biological sample, wherein the subject has received an immunotherapy between the first time point and the second time point; and identifying the subject as not being responsive to the immunotherapy when the second level of the at least one TCR clonotype is not higher than the first level of the at least one TCR clonotype (clm 1). Finally Goldberg does not teach a method wherein the second level of the at least one TCR clonotype is lower than the first level of the at least one TCR clonotype (clm 9).
However Anagnostou teaches that to examine mechanisms of resistance to immunotherapy they performed T-cell receptor (TCR) clonotype analysis (page 265, col 2). Anagnostou teaches that they studied a population of patients with NSCLC that initially responded to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies but then later developed resistance (abstract). Anagnostou teaches that they analyzed serially collected PBMCs prior to immunotherapy initiation, at clinical response, and at resistance for patients CGLU117 and CGLU127, and at response and disease progression for patient CGLU161 (Supplementary Table S15). We hypothesized that loss of neoantigens would lead to a decrease in clonality of cytotoxic TCR clonotypes, thus reflecting tumor immune evasion at the time of emergence of resistance. For patients CGLU127 and CGLU117, we observed peripheral T-cell expansion of a subset of the top 100 most frequent intratumoral clones, with the most frequent clones reaching a 44- and 25-fold increase in abundance in the blood at the time of response, respectively, followed by a decrease to pretreatment levels at the time of resistance (Fig. 3C and Supplementary Fig. S11). (page 269). Further Anagnostou teaches detecting TCR clonotypes by next generation sequencing methods (page 274, col 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Goldberg by further considering the levels of at least one TCR clonotype before and after immunotherapy when trying to determine efficacy of an immunotherapy treatment. In the instant case, both Goldberg and Anagnostou researched methods that can be used to predict whether a lung cancer patient will respond to treatment with immunotherapy. Goldberg teaches that a drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC (abstract). Thus Goldberg teaches that elevated/increased cfDNA levels after immunotherapy treatment are correlated with being non-response to treatment. Anagnostou teaches for patients CGLU127 and CGLU117, they observed peripheral T-cell expansion of a subset of the top 100 most frequent intratumoral clones, with the most frequent clones reaching a 44- and 25-fold increase in abundance in the blood at the time of response respectively, followed by a decrease to pretreatment levels at the time of resistance (Fig. 3C and Supplementary Fig. S11). (page 269). Thus Anagnostou teaches that decreased TCR clonotype levels after immunotherapy treatment are correlated with being non-responsive to treatment. In view of these teachings it would have been obvious to try predicting immunotherapy efficacy by considering both the levels of cfDNA and TCR clonotypes. The claims would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is like the product not of innovation but of ordinary skill and common sense.
The combined references do not teach administering a second therapy that is different from the immunotherapy, thereby treating the subject that is identified as not being responsive (clm 1). The combined references do not teach that the second therapy comprises adoptive T cell therapy, radiation therapy, surgery, chemotherapy, immune checkpoint inhibitors, targeted therapy, signal transduction inhibitors, bispecific antibodies, monoclonal antibodies, or any combination thereof (clm 1).
However Schvartsman teaches investigation of the efficacy of chemotherapy in the setting of post-immune checkpoint inhibitor therapy failure, and suggests that anti-PD1 may confer delayed synergism to subsequent cytotoxic therapy (page 92, col 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Goldberg and Anagnostou by administering a second therapy that it different from the immunotherapy when the subject is identified as not being responsive to the immunotherapy. In the instant case, both Goldberg and Anagnostou researched methods that can be used to predict whether a cancer patient will respond to treatment with immunotherapy. The prior art of Schvartsman discloses chemotherapy as a treatment option for lung cancer when immunotherapy has failed. One of skill in the art would have been motivated to stop administering an immunotherapy drug when it is determined that the patient is not responding and then administer a different treatment such a chemotherapy for the benefit be providing a treatment that is more effective and to avoid wasting time, money, etc. on a treatment that does not work. Further one of skill in the art would be motivated to switch to chemotherapy after progression on immunotherapy since Schvartsman teaches that the overall response rate to single-agent chemotherapy after anti-PD1 failure was 39%.
6. Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Goldberg (Clin Cancer Res 24(8) Epub 1/12/2018) in view of Anagnostou (Cancer Discovery 7(3) 264-276 March 2017) and Schvartsman (Lung Cancer 112 (2017) 90-95) as applied above to claim 1 and in further view of Phallen (Sci Transl Med 9 eaan2415 August 16, 2017 pages 1-12).
The teachings of Goldberg, Anagnostou, and Schvartsman are presented above.
The combined references do not teach a method wherein the step of detecting the first level of cfDNA, the step of detecting the second level of cfDNA, or both comprises:
extracting cell-free DNA from blood; ligating a low complexity pool of dual index barcode adapters to the cell-free DNA to generate a plurality of barcode adapter-ligated cell-free DNA segments; capturing the plurality of barcode adapter-ligated cell-free DNA segments; sequencing the plurality of captured barcode adapter-ligated cell-free DNA segments; aligning the sequenced plurality of captured barcode adapter-ligated cell-free DNA segments to a reference genome; and
identifying sequence alterations using aligned sequences of multiple distinct molecules containing identical redundant changes.
However Phallen teaches a method comprising extracting cell-free DNA from blood (page 9, col 1); ligating a low complexity pool of dual index barcode adapters to the cell-free DNA to generate a plurality of barcode adapter-ligated cell-free DNA segments (page 9, col 2); capturing the plurality of barcode adapter-ligated cell-free DNA segments (page 9 col 2); sequencing the plurality of captured barcode adapter-ligated cell-free DNA segments (page 9, col 2); aligning the sequenced plurality of captured barcode adapter-ligated cell-free DNA segments to a reference genome (page 10, col 1); and identifying sequence alterations using aligned sequences of multiple distinct molecules containing identical redundant changes (page 10, col 1). See also Fig 1.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Goldberg, Anagnostou, and Schvartsman by performing TEC-Seq to detect the level of cfDNA as suggested by Phallen. In the instant case Lee teaches performing digital droplet PCR to detect cfDNA (see Supplementary Methods). Phallen teaches that they used digital droplet PCR to confirm the results of TEC-Seq (page 5, col 2). The claim would have been obvious because the substitution of one known method (digital droplet PCR) for another known method (TEC-Seq) would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Further the skilled artisan would have been motivated to use TEC-Seq to determine cfDNA levels since Phallen teaches that this method allows ultrasensitive direct evaluation of sequence changes in circulating cell free DNA using massively parallel sequencing (abstract).
Response To Arguments
7. In the response the Applicants traversed the rejections under 35 USC 103. The Applicants point out that claim 1 has been amended to recite that the subject has lung cancer. They argue that the prior arts previously cited do not teach or suggest a method of treating a subject that is identified as not being responsive to an immunotherapy, wherein the subject has a lung cancer.
The amendment has been considered. The rejections have been modified to address the claims as amended.
8. 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 extension fee 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 date of this final action.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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