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 .
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, drawn to a method of treating a subject with a NSCLC tumor, in the reply filed on 06/24/2026 is acknowledged. Applicant further elects without traverse methods species (A) directed to a method of treating a subject afflicted with NSCLC comprising administering a flat dose of 240 or 480 mg of an anti-PD-1 antibody and an anti-CTLA4 antibody, that the anti-PD-1 species is nivolumab, and that the anti-CTLA4-species is ipilimumab.
Claims 12-14 and 19-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/24/2026.
Claims 1-7, 16-18, and 24-26 are examined on the merits in the present Office Action.
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.
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 1-7, 16-18, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Rizvi et al (Rizvi, Hira et al. Journal of clinical oncology: official journal of the American Society of Clinical Oncology vol. 36,7 (2018): 633-641. doi:10.1200/JCO.2017.75.3384), hereinafter Rizvi, Liu (US20170210806A1), Paraghamian et al (Paraghamian, Sarah E et al. Gynecologic oncology research and practice vol. 4 3. 2 Feb. 2017, doi:10.1186/s40661-017-0038-9), hereinafter Paraghamian, Frampton et al (Frampton, Garrett M et al. Nature biotechnology vol. 31,11 (2013): 1023-31. doi:10.1038/nbt.2696), hereinafter Frampton, Chmielecki et al (Chmielecki, Juliann et al. Cancer research vol. 77,2 (2017): 509-519. doi:10.1158/0008-5472.CAN-16-1106), hereinafter Chmielecki, and Pillai et al (Pillai, Rathi N., et al. Cancer Research 77.13_Supplement (2017): CT070-CT070), hereinafter Pillai.
Rizvi teaches that tumor mutation burden (TMB) is a predictive biomarker for response to immune checkpoint blockade in advanced non-small cell lung cancer (NSCLC), including anti-PD-1/PD-L1 therapy alone or in combination with anti-CTLA4 therapy (Abstract and Methods: Patients section). Using next-generation sequencing and whole-exome sequencing, Rizvi assessed TMB as single-nucleotide variants (SNVs) per megabase (Mb) and reported a median TMB of 7.4 SNVs/Mb, with a range of 0.8 to 91.8 SNVs/Mb (see Page 635, left column, under Results section). As such, the study included NSCLC patients having TMB of ≥10 mutations/Mb. Genes associated with response to immunotherapy included KRAS, STK11, EGFR, ALK, ERBB2, RET, ROS1, POLE, JAK2, JAK3, CD274, PTEN, MDM2, and ATR among others assessed in the genomic profiling (see Fig 2 and Table A1). High TMB was associated with durable clinical benefit and objective response to immune checkpoint inhibitor therapy (see Abstract). Importantly, TMB and PD-L1 expression are independent biomarkers, such that TMB provides predictive information independent of PD-L1 expression (see Abstract).
Rizvi does not teach that an NSCLC patient having less than 1% PD-L1 tumor expression nor that the TMB status is based on the genomic profile recited in claim 1, wherein the anti-PD-1 antibody is nivolumab administered at 240 mg every two weeks and the anti-CTLA-4 antibody is ipilimumab administered at 1 mg/kg every six weeks.
However, Liu teaches that anti-PD-1 antibodies can be used for the treatment of PD-L1 negative tumors, such as lung cancer (Abstract, Para. 0027 and 0028); and Paraghamian further provides evidence that PD-L1 negative tumors can respond to anti-PD-1 therapy, reporting a complete response to nivolumab in a patient with recurrent, metastatic PD-L1 negative small cell neuroendocrine carcinoma of the cervix (Abstract).
Frampton further teaches a comprehensive genomic profiling assay—which uses massively parallel next-generation sequencing (NGS) of tumor DNA from routine formalin-fixed paraffin-embedded (FFPE) tumor specimens and needle biopsies—to identify genomic alterations across numerous cancer-related genes. Multiple classes of genomic alterations are detected, including base substitutions, insertions and deletions (indels), copy number mutations (CNAs), and fusions (Abstract and last paragraph of Introduction on Page 1024). It is emphasized that essential to the successful delivery of personalized cancer therapy are diagnostic tests that comprehensively characterize the genomic alterations occurring within individual tumors. These diagnostic tests enable patients to be matched with targeted therapies (2nd and 3rd paragraphs of Introduction, pp 1023-1024). Thus, the comprehensive NGS-based genomic profiling assay can be used in clinical oncology as a diagnostic tool and to match patients with the appropriate targeted therapy (Introduction and Discussion, last paragraph). Frampton therefore teaches assessment of tumor mutations by genomic profiling as a diagnostic process prior to selection and administration of an appropriate therapeutic.
Chmielecki further teaches the use of the genomic profiling assay FoundationOne to characterize tumor genomic alterations (see Materials and Methods). For samples assayed on FoundationOne, DNA was adaptor ligated, and hybrid capture was performed for all coding exons of 395 cancer-related genes plus select introns from 31 genes frequently rearranged in cancer using version 5 (v5) of the assay (Materials and Methods). In particular, Table S5 identifies the genes assessed by FoundationOne Version 5, including each of the genes recited in claim 1 (see Supplementatry Data, Table S5, OA.appendix). Thus, Chmielecki teaches a genomic profiling assay that assesses the genes recited in claim 1.
Pillai teaches the use of flat-dose nivolumab in combination with weight-based ipilimumab for the treatment of advanced NSCLC, specifically 240 mg nivolumab every 2 weeks with 1 mg/kg ipilimumab every 6 weeks (see entire Abstract).
It would have been obvious to administer a combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) to an NSCLC patient having less than 1% PD-L1 tumor expression and a TMB of at least 10 mutations/Mb, wherein (1) nivolumab is administered at a flat dose and ipilimumab is administered at a weight-based dose, and (2) TMB is determined in a biological sample using genomic profiling comprising the genes recited in claim 1 prior to administering the combination therapy. One of ordinary skill in the art would have been motivated to do so since Rizvi teaches that high TMB is a predictive biomarker for immune checkpoint blockade in NSCLC independent of PD-L1 expression; and PD-L1 negative tumors can be treated by anti-PD-1 antibodies as taught by Liu and demonstrated by Paraghamian. Further, the combination of a 240 mg flat dose nivolumab every two weeks and 1 mg/kg ipilimumab every six weeks is effective for the treatment of advanced NSCLC in patients as taught by Pillai. Lastly, a comprehensive genomic profiling assay can be used to identify genomic alterations in tumor DNA obtained from tumor tissue sample as a diagnostic test prior to selection and, therefore, administration of a targeted therapy as taught by Frampton, with Chmielecki specifically disclosing a type of genomic profiling assay—FoundationOne assay (v5)— that assesses the genes recited in claim 1 (see OA.Appendix). Thus, one of ordinary skill in the art would reasonably expect that anti-PD-1 in combination with anti-CTLA-4 can effectively treat NSCLC in patients having PD-L1 negative tumors and a high TMB as determined via genomic profiling using the FoundationOne v5 assay.
Claims 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Rizvi in view of Liu, Paraghamian, Frampton, Chmielecki, and Pillai, as applied to claims 1-7, 16-18, and 24, and further in view of Manekas et al (WO2017011666A1), Manekas et al.
The teachings of Rizvi in view of Liu, Paraghamian, Frampton, Chmielecki, and Pillai have been discussed above and differ from the instantly claimed invention in that it is not specifically taught the anti-PD-1 antibody is administered at 360 mg every three weeks or 480 mg every four weeks.
However, Manekas teaches that an anti-PD-1 antibody such as nivolumab can be administered at 360 mg every three weeks or 480 mg every four weeks to treat polyomavirus-positive cancers such as non-small cell lung carcinoma (NSCLC) (Para. 0058, Para. 0066, and Para. 0110).
It would have been obvious to one of ordinary skill in the art to modify the method of treating NSCLC patients with less than 1% PD-L1 tumor and high TMB of at least 10 mutations/Mb as taught by Rizvi in view of Liu, Paraghamian, Frampton, Chmielecki, and Pillai such that the anti-PD-1 antibody nivolumab is administered a at 360 mg every three weeks or 480 mg every four weeks. One of ordinary skill in the art would have been motivated to do so since anti-PD-1 antibody nivolumab is administered a at 360 mg every three weeks or 480 mg every four weeks are dosage regiments that can be used to treat polyomavirus-positive cancers such as non-small cell lung carcinoma (NSCLC) as taught by Manekas. Therefore, one of ordinary skill in the art would reasonably expect that the anti-PD-1 antibody nivolumab administered at 360 mg every three week or 480 mg every four weeks in combination with 1 mg/kg ipilimumab every six weeks can effectively treat NSCLC patients with less than 1% PD-L1 tumor and high TMB of at least 10 mutations/Mb.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
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