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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/02/2026 has been entered.
Claims Status
Claims 1, 15-17, 56, 57, 61, 64, 66, & 72 filed on 03/02/2026 are pending. Claims 17, 64, & 72 are currently under examination directed to the elected species of detecting the presence of inflammatory gene mRNA in claim 17, of nivolumab in claim 47, of ipilimumab in claim 64, and of hepatocellular cancer in claim 72 (see response dated 05/27/2025). All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Information Disclosure Statement
Only the abstract of the reference in the IDS submitted on 03/02/2026 that are lined through, under the foreign patent documents section, was considered because an English copy of the full document was not provided.
Claim Rejections - 35 USC § 112
Claims 1, 15-17, 56, 57, 61, 64, 66, & 72 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitation of “wherein the inflammatory signature score is determined by measuring the expression of … CD274 (PD-L1), CD8A, LAG3, and STAT1” in lines 6-8 of the claim followed by the recitation of “wherein the method does not comprise measuring the expression of one or more genes selected from the group consisting of … CD274 …” in lines 14-18 of the claim is unclear how the inflammatory signature score requires measuring the expression of a panel of genes consisting of CD274 and further that the method comprises not measuring the expression of one or more genes consisting of CD274. It is unclear how the expression of CD274 is both required to be measured and to not be measured.
Claims 15-17, 56, 57, 61, 64, 66, 66, & 72 are rejected due to their dependence on claim 1.
Claim Rejections - 35 USC § 103
Claim(s) 1, 15-17, 56, 57, & 72 is/are rejected under 35 U.S.C. 103 as being unpatentable over Danaher (Danaher et al.; Journal for ImmunoTherapy of Cancer, Vol. 6, pages 1-17, June 2018), as cited on the IDS dated 05/27/2025, in view of Johnson (Johnson et al.; Cancer Immunology Research, Vol. 4, pages 959-967, November 2016), and Bi (Bi et al.; Annals of Oncology, Vol. 30, pages 644-651, February 2019), as cited on the IDS dated 05/27/2025, as evidenced by TCGA (TCGA Data Types Collected, March 6th, 2019).
Regarding amended claim 1, it is noted that claim 1 is a comprising (open) claim and that “consists of” in line 8 of the claim does not exclude the gene expression analysis of other genes.
Danaher teaches a method to assess an 18-gene Tumor Inflammation Signature (TIS) (inflammatory signature score) in various tumor types from The Cancer Genome Atlas (TCGA) and a method to measure tumor mutation load (tumor mutation burden) as a means to assess the clinical sensitivity and response to administering an anti-PD-1 antibody (abstract lines 1-16; pg. 2 2nd column 1st full paragraph lines 1-4 & 14-18; pg. 3 paragraph bridging column 1 & 2 lines 1-25; pg. 7 column 1 1st full paragraph lines 7-8 & 26-29). Danaher also teaches that the TIS (inflammatory signature score) comprises CD274, CD8A, LAG3, and STAT1 (Table 1) and that a TIS is determined by averaging the expression of the panel of the 18-gene inflammatory panel by tumor type (from a population of subjects afflicted with the tumor) and that TIS scores higher than the median TIS score (high TIS) for a tumor type (at least 25% higher) correlate to higher rates of response to anti-PD-1 antibodies (pg. 4 paragraph bridging column 1 & 2 lines 1-8; pg. 4 column 2 3rd full paragraph lines 1-5; pg. 5 paragraph bridging column 1 & 2 lines 1-10; Figure 1). Danaher also teaches that TIS (inflammatory signature score) does not comprise measuring the expression of CCL2 (the method does not comprise measuring the expression of one or more genes selected from the group consisting of CCL2) (Table 1).
Danaher does not teach that a tumor mutation burden of at least about 10 mutations per megabase of genes by whole exome sequencing and does not teach administering the anti-PD-1 antibody at a flat dose of about 240 mg once every two weeks or about 480 mg once every four weeks.
Johnson teaches a method of treating a tumor in a subject in need comprising administering an anti-PD-1 antibody in which this subject has a high tumor mutational burden (TMB) status, such as a TMB of at least 23.1 mutations/megabase of genome sequenced (at least about 10 mutations per megabase), as the patients were divided into high (>23.1 mutations/MB), intermediate (3.3-23.1 mutations/MB), and low (<3.3 mutations/MB) mutation loads, in which the high mutational load group observed superior objective response rates to the anti-PD-1 antibody (abstract lines 1-27; pg. 959-960 paragraph bridging pg. 959 & pg. 960 lines 1-19; pg. 960 column 1 2nd full paragraph lines 1-9; pg. 961 column 1 2nd full paragraph lines 1-15; pg. 961 paragraph bridging column 1 & 2 lines 1-6; Figure 1; Table 2). Johnson also teaches that TMB was determined using the next generation sequencing (NGS) platform, the FoundationOne® assay by whole exome sequencing (TMB status is determined by whole exome sequencing (WES)) (pg. 960 column 1 3rd full paragraph lines 1-11; pg. 960 paragraph bridging column 1 & 2 lines 1-4 & 19-32). Johnson teaches the anti-PD-1 antibody is nivolumab or pembrolizumab (pg. 960 column 1 1st full paragraph lines 4-7). Finally, Johnson teaches that this method effectively stratifies patients by likelihood of response and can be a clinically feasible predictor of response to anti-PD1 antibody (abstract lines 24-27).
Bi teaches a dose regimen for nivolumab (an anti-PD-1 antibody) at a flat dose of 240 mg once every two weeks (abstract conclusion lines 1-4; pg. 644 & 645 paragraph bridging pg. 644 & pg. 645 lines 10-14; pg. 645 column 1 2nd full paragraph lines 1-7). Bi also teaches a dose regimen for nivolumab (an anti-PD-1 antibody) at a flat dose of 480 mg once every four weeks (abstract conclusion lines 1-4; pg. 645 column 1 1st full paragraph lines 1-3; pg. 645 column 1 2nd full paragraph lines 1-7). Finally, Bi teaches increasing the flat dose and decreasing the frequency administered maintains efficacy and safety of the anti-PD-1 antibody (pg. 650 paragraph bridging column 1 & 2 lines 1-10).
Danaher, Johnson, and Bi are considered to be analogous to the claimed invention because they are all in the same field of administering anti-PD-1 antibodies for treatment in cancer patients. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining TMB in Danaher to incorporate determining the TMB in 315 genes as assessed by whole exome sequencing and stratifying the TMB by mutations/megabase as taught in Johnson because Johnson teaches that doing so would provide a clinically feasible predictor of response to anti-PD-1 antibody in cancer and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of administering an anti-PD-1 antibody in Danaher and Johnson to incorporate the flat dose regimens of 240 mg once 2 weeks and 480 mg once 4 weeks as taught in Bi because Bi teaches that these flat dose regimens allowed for a decreased frequency in administering the anti-PD-1 antibody without compromising the safety or efficacy of the anti-PD-1 antibody.
Regarding claim 15, Danaher teaches the gene expression data from TCGA database of primary tumors (tumor tissue biopsy) was used for calculating TIS and TMB (pg. 3 paragraph bridging column 1 & 2 lines 1-10). Johnson also teaches that the tumor sample is a tumor tissue biopsy (pg. 960 column 1 2nd full paragraph lines 1-4).
Regarding claim 16, Johnson teaches that the tumor sample is a formalin-fixed paraffin-embedded tumor tissue sample (pg. 960 column 1 2nd full paragraph lines 1-4).
Regarding claim 17, Danaher teaches assessing the gene expression data from TCGA database of primary tumors which includes mRNA expression (detecting the presence of inflammatory gene mRNA), as evidenced by TCGA (pg. 5 of TCGA).
Regarding claim 56, Bi teaches a dose regimen for nivolumab (an anti-PD-1 antibody) at a flat dose of 240 mg once every two weeks (abstract conclusion lines 1-4; pg. 644 & 645 paragraph bridging pg. 644 & pg. 645 lines 10-14; pg. 645 column 1 2nd full paragraph lines 1-7).
Regarding claim 57, Bi teaches a dose regimen for nivolumab (an anti-PD-1 antibody) at a flat dose of 480 mg once every four weeks (abstract conclusion lines 1-4; pg. 645 column 1 1st full paragraph lines 1-3; pg. 645 column 1 2nd full paragraph lines 1-7).
Regarding claim 72, Danaher teaches the tumor is derived from liver hepatocellular cancer (pg. 3 paragraph bridging column 1 & 2 lines 1-10; Table 2).
Claim(s) 61, 64, & 66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Danaher (Danaher et al.; Journal for ImmunoTherapy of Cancer, Vol. 6, pages 1-17, June 2018), as cited on the IDS dated 05/27/2025, Johnson (Johnson et al.; Cancer Immunology Research, Vol. 4, pages 959-967, November 2016), and Bi (Bi et al.; Annals of Oncology, Vol. 30, pages 644-651, February 2019), as cited on the IDS dated 05/27/2025, as applied to claims 1, 15-17, 56, 57, & 72 above, and further in view of Cogswell (WO 2013/173223 A1), as cited on the IDS dated 05/27/2025.
The teachings of Danaher, Johnson, and Bi with respect to claim 1 is discussed above.
Regarding claims 61, 64, & 66, Danaher, Johnson, and Bi does not teach further administering an antibody or antigen binding fragments that binds specifically to cytotoxic T-lymphocyte associated protein (CTLA-4) (and anti-CTLA-4 antibody).
Cogswell teaches a method of providing immunotherapy to a cancer patient through administering an anti-PD-1 antibody and an anti-CTLA-4 antibody (see claim 61) in which the anti-CTLA-4 antibody is ipilimumab (see claim 64) and is administered at dose regimens adjusted to provide the optimum desired therapeutic response or minimal adverse effects including a dose ranging from 0.1-20.0 mg/kg body weight once every 2, 3, or 4 weeks (abstract lines 1-7; pg. 36 lines 28-33; pg. 53 lines 1-8; pg. 56 lines 29-33; pg. 57 lines 1-3). In addition, Cogswell teaches that the administration of anti-PD-1 and anti-CTLA-4 antibodies had a stronger anti-tumor effect (pg. 54 lines 4-6).
Danaher, Johnson, Bi, and Cogswell are considered to be analogous to the claimed invention because they are all in the same field of administering anti-PD-1 antibodies for treatment in cancer patients. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of administering an anti-PD-1 antibody in Danaher and Johnson to incorporate administering anti-PD-1 and anti-CTLA-4 antibodies and administering the anti-CTLA-4 antibody at a dose regimen of 0.1-20.0 mg/kg body weight once every 2, 3, or 4 weeks as taught in Cogswell because Cogswell teaches that the administration of the combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody provided a stronger anti-tumor effect.
Response to Arguments
The response traverses the rejection. The response asserts that no combination of the references cited teaches every element of claim 1 as claim 1 recites a method that comprises, in part, identifying a subject based an inflammatory signature score that consists of CD274 (PD-L1), CD8A, LAG3, and STAT1 and further amended claim 1 clearly recites that the method does not comprise measuring the expression of one or more genes selected from a group listed in lines 15-19 of amended claim 1. Further, the response asserts that nothing in Danaher, Johnson, or Bi teaches or suggests that a subject having an inflammatory signature score based on the expression of CD274 (PD-L1), CD8A, LAG3, and STAT1 alone would be sufficient to identify a subject afflicted with a tumor as being likely to respond to treatment with an anti-PD-1 antibody or antigen binding portion thereof and that Danaher discloses an 18-gene inflammatory panel that includes CD274 (PD-L1), CD8A, LAG3, and STAT1, however that 14 other genes disclosed in the Danaher panel are excluded from the method of amended claim 1. Further, the response asserts that none of Danaher, Johnson, and Bi specifically calls out CD274 (PD-L1), CD8A, LAG3, and STAT1 as having any particular importance on their own relative to the other 14 genes listed, while excluding one or more of the other recited genes. This argument has been thoroughly reviewed but was not found persuasive as the prior art of Danaher, Johnson, and Bi, as evidenced by TCGA, as applied to amended independent claim 1, teaches every element of claim 1 as discussed above. Specifically, Danaher teaches the newly added limitation to amended claim 1 as Danaher teaches that TIS (inflammatory signature score) does not comprise measuring the expression of CCL2 (the method does not comprise measuring the expression of one or more genes selected from the group consisting of CCL2) (Table 1). Further, as discussed previously and above, it is noted that claim 1 is a comprising (open) claim and that “consists of” in line 8 of the claim does not exclude the gene expression analysis of other genes. Therefore, claim 1 as currently amended does not require an inflammatory signature score consisting of CD274 (PD-L1), CD8A, LAG3, and STAT1 alone and may include the gene expression analysis of other genes as well. In addition, it is noted that the newly added limitation to amended claim 1 does not exclude measuring the 14 other genes disclosed in the Danaher panel as recited in amended claim 1. Further, amended claim 1 requires not measuring the expression of one or more genes selected from the group listed in lines 15-19 of amended claim 1, in which Danaher teaches that TIS (inflammatory signature score) does not comprise measuring the expression of CCL2 (the method does not comprise measuring the expression of one or more genes selected from the group consisting of CCL2) (Table 1) as discussed above.
The response also asserts that neither Johnson nor Bi discloses an inflammatory gene panel or use thereof and therefore these references do not overcome the deficiencies of Danaher. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
The response also asserts that for at least these reasons a person of ordinary skill in the art would not have arrived at the claimed anti-PD-1 antibody in view of any combination of the alleged disclosures of Danaher, Johnson, and Bi with any reasonable expectation of success. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
The response also asserts that claims 15-17, 56, 57, 61, 64, 66, and 72 depends directly or indirectly from amended claim 1 and thus includes every element of amended claim 1 and therefore, claims 15-17, 56, 57, 61, 64, 66, and 72 would also not have been obvious in view of any combination of Danaher, Johnson, and Bi. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1, 15-17, 56, 57, 61, 64, 66, & 72 are rejected.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682
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