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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 20, 2025 has been entered.
Claim Status
Claim listing filed on August 20, 2025 is pending. Claims 2-4 and 6 are canceled. Claims 1, 5, 7, and 19-20 are amended. Claims 21-24 are new. Claims 14 and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species. Claims 1, 5, 7-13, 15-18, and 21-24 are examined upon their merits.
Withdrawn Claim Objections and Rejections
Applicant’s amendments overcome the claim objections of record, and the claim objections are withdrawn.
The rejection of Claims 1, 5, and 7-11 under 35 U.S.C. 103 as being unpatentable over Lei WO 2020/198676 in view of Liao et al, Cancer Cell. March 2019 is withdrawn in view of Applicant’s arguments filed August 20, 2025. Upon further consideration, it is persuasive that because PD-L1 and IRF2 are inversely correlated, methods of generating a single score by combining PD-L1 and IRF2 expression levels would most likely misidentify the subject.
The rejection of Claims 12-13 under 35 U.S.C. 103 as being unpatentable over Lei WO 2020/198676 in view of Liao et al Cancer Cell. March 2019, and further in view of Mimura et al, Cancer Sci. 2017 is withdrawn in view of Applicant’s arguments filed August 20, 2025. Mimura does not overcome the deficiencies of Lei and Liao.
The rejection of Claims 15-18 under 35 U.S.C. 103 as being unpatentable over Lei WO 2020/198676 in view of Liao et al Cancer Cell. March 2019 (of record), and further in view of Lai et al, Oncogene. 2018 and Hicks et al, Oncoimmunology. 2018 is withdrawn in view of Applicant’s arguments filed August 20, 2025. Lai and Hicks do not overcome the deficiencies of Lei and Liao.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 1, 5, 7-13, 15-18, and 21-23 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 is maintained. Note, the previous rejection applied to Claims 1, 5, 7-13, and 15-18 and now applies to Claims 1, 5, 7-13, 15-18, and 21-23 due to Applicant’s amendments.
The amended claims recite “wherein the reference level for IRF2 is a level of IRF2 in a subject who is expected to respond to checkpoint inhibitors without additional intervention” and “wherein the reference level for PD-L1 is a level of PD-L1 in a subject who is expected to respond to checkpoint inhibitors without additional intervention.” These amendments do not overcome the indefinites of “reference level.” The reference levels of IRF2 and PD-L1 in a subject who is expected to respond to checkpoint inhibitors are not defined in the specification. The expression levels of IRF2 in a subject expected to respond to checkpoint inhibitors is not taught in the art prior to the time of filing. Shukuya et al. J Thorac Oncol. 2016 teaches PD-L1 expression as a predictive biomarker for PD-1/PD-L1 blockade, but the threshold of PD-L1 expression varies from 1%, 5%, 10%, or 50% depending on the study (Table 2). Therefore, the art teaches a range of possible PD-L1 levels in subjects expected to respond to checkpoint inhibitors without additional intervention, and the metes and bounds of the reference level cannot be determined.
Applicant's arguments filed August 20, 2025 have been fully considered but they are not persuasive. Applicant argues that methods of identifying subjects expected to respond to checkpoint inhibitors were well known in the art and one skilled in the art would readily understand how to perform such methods. This argument is interpreted to mean that one of ordinary skill is expected to (1) identify subjects expected to respond to checkpoint inhibitors using diagnostics and (2) measure the IRF2 and PD-L1 levels in the identified patients to determine the reference level as described by the claims. However, MPEP § 2173.05(b) states that “the claims, when read in light of the specification and the prosecution history, must provide objective boundaries for those of skill in the art” (emphasis added). Requiring one of ordinary skill to perform experiments to determine the appropriate reference levels demonstrates that the claims do not provide objective boundaries.
Applicant submits Exhibit A (Patel et al. J Immunother Cancer 2019) to teach that at the time of filing, FDA approval of checkpoint inhibitor therapies could be tied to at least three different companion diagnostics. However, Patel was published on October 26, 2019, and the effective filing date of Claims 1, 5, 7-13, and 21-23 is May 10, 2019. Therefore, the Patel reference was published after the effective filing date and is not considered prior art. Further, Patel teaches that “PD-L1 thresholds were variable both within and across tumor types using several different assays, including approvals at the following PD-L1 thresholds: 1, 5, and 50%. PD-L1 expression was also measured in a variable fashion either on tumor cells, tumor-infiltrating immune cells, or both” (abstract). Patel teaches variability in the level of PD-L1 in a subject who is expected to respond to checkpoint inhibitors even after the effective filing date which supports the indefiniteness of “reference level” in the instant claims. The rejection is maintained.
Claim Rejections - 35 USC § 112 (New)
Claims 13 and 17 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.
Claim 13 recites “interferon gamma (e.g., IFN-gamma 1b). The phrase "e.g." renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of compact prosecution “e.g.” is interpreted as “optionally.”
Claim 17 encompasses the trademarked HDAC inhibitors ZolinzaTM and IstodaxTM as essential claimed elements. Applicant should note that a trademark or tradename does not denote a particular and fixed element. For example, the tradename “Coca-Cola” has been used on different formulations over the years. MPEP 2173.05(u) states: “If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b). Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982)….The claim scope is uncertain since the trademark or trade name cannot be used properly to describe any particular material or product. In fact, the value of a trademark would be lost to the extent that it became the generic name of a product, rather than used as an identification of a source or origin of a product. Thus, the use of a trademark or trade name in a claim to describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name.” Claim 17 is rejected for indefiniteness by claiming trademarked products. To overcome the rejection, Applicant could identify the HDAC inhibitors by their generic names only. Applicant is urged to carefully review the claims for additional trademarked products.
Claim Rejections - 35 USC § 103 (New)
Claims 1, 5, 7-13, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Higgs J Clin Oncol 34, 2016, Wu et al. EMBO J. 2018, and Liao et al. Cancer Cell March 2019 (of record), in view of Mimura et al. Cancer Sci. 2017 (of record).
Claims 1, 5, and 23 are directed to a method of treating a subject who has cancer comprising (a) providing a sample comprising cells from the cancer, (b) detecting a level of IRF2 in the sample, (c) detecting a level of PD-L1 in the sample, and (d) identifying a subject as having: (i) IRF2 and PD-L1 levels above a reference level, and treating the subject with a checkpoint inhibitor or (ii) IRF2 levels below an IRF2 reference level and PD-L1 levels above a PD-L1 reference level, and treating the subject with a checkpoint inhibitor and an interferon inducer or epigenetic modifier or (iii) IRF2 and PD-L1 levels below the reference levels and treating the subject with a treatment that does not include a checkpoint inhibitor. Because the definitions of the reference levels are indefinite (see 112(b) rejection above), the broadest reasonable interpretation is that the reference levels can comprise any threshold. Claim 24 recites comparing IRF2 levels to PD-L1 levels wherein IRF2 levels are below the PD-L1 levels, the subject is treated with a checkpoint inhibitor and an interferon inducer or epigenetic modifier.
Higgs teaches that biomarkers may help identify non-small cell lung cancer patients more likely to have improved outcomes to anti-PD-L1 therapy (background). Pre-treatment tumor biopsies were analyzed for levels of PD-L1 wherein samples with ≥25% tumor cells stained for PD-L1 were scored PD-L1+ (methods). Pre-treatment tumor biopsies were also analyzed for levels of IFNγ mRNA expression wherein samples with detectable levels of IFNγ were considered IFNγ+ (methods). Patients who were IFNγ+/PD-L1+ had longer overall survival compared to those who were IFNγ-/PD-L1-, even after adjusting for other contributing factors (results). Therefore, Higgs teaches that PD-L1 and IFNγ expression are biomarkers for anti-PD-L1 checkpoint inhibitor therapy.
Wu teaches that IRF2 is a transcriptional repressor of PD-L1 (abstract). Because of this relationship, levels of PD-L1 and IRF2 are inversely correlated as exemplified by the mRNA expression levels in A549 human lung carcinoma cells in Figure 5B. PD-L1 expression is decreased when IRF2 is expressed, and knockdown of IRF2 restores PD-L1 expression (Fig. 5B). Note, mRNA expression levels of PD-L1 and IRF2 were analyzed by quantitative PCR (Fig. 5B caption) which reads on Claims 7-8 and 21-22. Further, Wu teaches that PD-L1 expression can be induced by IFNγ (introduction paragraph 2). Figure 7E as pictured below summarizes the pathway connecting IRF2, IFNγ, and PD-L1 in tumor cells:
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Briefly, IRF2 represses PD-L1 (mediated through IRF1) and IFNγ promotes PD-L1 (mediated through IRF1). Together, the teachings of Higgs and Wu demonstrate that high PD-L1 expression is a known biomarker for anti-PD-L1 treatment efficacy, and IRF2 and PD-L1 expression levels are inversely correlated which reads on Claim 24. Higgs and Wu fail to teach IRF2 as a biomarker of checkpoint inhibitor therapy and the relationship between IRF2 and IFNγ.
Liao teaches that high IRF2 expression correlated positively with anti-PD-1 therapy response in patients with colorectal cancer (page 567, col. 1, par. 1 and Fig. 7D) demonstrating that IRF2 is a known biomarker for checkpoint inhibitor therapy. Further, Liao teaches the relationship between IRF2 and IFNγ. IRF2 is a transcription factor that binds to the IFN-stimulated response element and the IFN consensus sequence (page 563, col. 2, par. 4). Consequentially, IRF2 has importance in regulating IFN, and when IRF2 expression was enforced, genes in the IRF2-mediated IFNγ signatures showed upregulation (page 563, col. 1, par. 4). Further, cancer cells with IFNγ downregulation had mutually exclusive IRF2 deletion (page 562, col. 1, par. 2 to page 563, col. 1, par. 2). Therefore, it is well understood from Liao that IRF2 and IFNγ are positively correlated, meaning that when IRF2 is upregulated, the IFNγ pathway is upregulated and when IRF2 is downregulated, the IFNγ pathway is downregulated. From the teachings of Liao, the signaling pathway can be expanded to include an arrow from IRF2 to IFNγ indicating that IRF2 is known to promote IFNγ:
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From the teachings of Higgs, Wu, and Liao, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to administer a checkpoint inhibitor to a subject with cancer wherein a sample of the subject’s cancer expresses high levels of PD-L1 and IRF2 (Claim 1(d)(i)) as both PD-L1 and IRF2 were known to be positively correlated with immune checkpoint treatment response (Higgs and Liao respectively). One of ordinary skill would have understood the inverse to also be true wherein a patient sample that does not express the IRF2 or PD-L1 biomarkers should not be administered a checkpoint inhibitor as the patient is less likely to respond well to the treatment (Claim 1(d)(iii)). The motivation to identify patients by PD-L1 and IRF2 biomarkers is to administer checkpoint inhibitor therapy to cancer patients more likely to have improved outcomes (Higgs background).
In regard to Claims 1(d)(ii), 5, and 23-24, if the cancer sample expresses PD-L1 and does not express IRF2 (or wherein PD-L1 expression is higher than IRF2 expression as in Claim 24), the expression of PD-L1 indicates that the subject will likely respond to an immune checkpoint inhibitor. However, the downregulation of IRF2 indicates that IFNγ is also downregulated (see signaling cascade as taught by Wu and Liao). Mimura teaches that IFNγ benefits anti-PD-L1 therapy by upregulating PD-L1 (section 3.5). Tumor cells pre-treated with IFNγ in vitro followed by anti-PD-L1 treatment had higher cytotoxicity as compared to cells without IFNγ treatment (Mimura section 3.5 and Fig. 4).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cancer with biomarker-driven checkpoint inhibitor therapy as taught by Higgs and Liao to include combination therapy comprising a checkpoint inhibitor and the interferon inducer IFNγ as taught in Mimura. Wu and Liao mechanistically teach that IRF2 expression is positively correlated with IFNγ expression, and IFNγ promotes PD-L1. It would be obvious to treat patients with both anti-PD-L1 and IFNγ when IRF2 is downregulated in the cancer cells because (1) IRF2 downregulation is correlated with PD-L1 upregulation which is a positive biomarker of checkpoint inhibitor response (Wu and Higgs) and (2) administering IFNγ rescues the action of downregulated IFNγ and increases PD-L1 expression which in turn increases the effectiveness of anti-PD-1/PD-L1 therapy.
Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Higgs J Clin Oncol 34, 2016, Wu et al. EMBO J. 2018, Liao et al. Cancer Cell March 2019 (of record), and Mimura et al. Cancer Sci. 2017 (of record) as applied to Claims 1, 5, 7-13, and 21-24 above, and further in view of Lai et al, Oncogene. 2018 (of record) and Hicks et al, Oncoimmunology. 2018 (of record).
The teachings of Higgs, Wu, Liao, and Mimura as they apply to Claims 1, 5, 7-13, and 21-24 are outlined in the rejection above. Higgs, Wu, Liao, and Mimura fail to teach treating a subject with a checkpoint inhibitor and an epigenetic modifier if IRF2 is below a reference level and PD-L1 is above a reference level (Claim 1(d)(ii)). The epigenetic modifier is a DNA methyltransferase (DNMT) inhibitor or a histone deacetylase (HDAC) inhibitor (Claim 15); the epigenetic modifier is a DNMT inhibitor and an HDAC inhibitor (Claim 16); the HDAC inhibitor is Vorinostat (Claim 17); and the DNMT inhibitor is Decitabine (Claim 18).
Lai teaches that IFNγ induces PD-L1 expression and predicts high response rates to anti-PD-1 and anti-PD-L1 therapy where loss of IFN signals causes resistance and low response rates to checkpoint blockade therapies (abstract). Lai found that supplementing anti-PD-1 therapy with Decitabine improved anti-tumor efficiency in vivo (abstract). Specifically, the addition of Decitabine rescues the response to IFN in lung cancer patients with anti-PD-1 or anti-PD-L1 resistance (abstract).
Hicks also teaches that patients with resistance to anti-PD-1 or anti-PD-L1 therapies often have poor PD-L1 expression as well as defects in IFNgamma signaling (page 13, col. 1, par. 3). Hicks teaches that treatment with the pan-HDAC inhibitor Vorinostat enhanced PD-L1 expression both in vitro and in carcinoma xenografts (abstract). Hicks concludes that combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockage increases patient responses to the anti-PD-1/PD-L1 therapies (abstract).
It would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cancer with biomarker-driven checkpoint inhibitor therapy as taught in Higgs, Wu, Liao, and Mimura to include combination therapy comprising a checkpoint inhibitor and an epigenetic modifier as taught in Lai and Hicks. Because Liao teaches that IRF2 is a transcription factor of IFN and IFNγ is upregulated when IRF2 is overexpressed, it is obvious that IFNγ would be downregulated when IRF2 is under expressed. Both Lai and Hicks teach that IFNγ benefits anti-PD1/PD-L1 therapy by upregulating PD-L1 expression. Lai teaches that combination treatment with Decitabine rescues IFN response and improves checkpoint inhibitor therapy. Similarly, Hicks teaches that combination treatment with Vorinostat increases PD-L1 expression and improves checkpoint inhibitor therapy. Therefore, it would be obvious to treat patients with both anti-PD-L1 and an epigenetic modifier when IRF2 is below a reference level (ie when IFNγ is down regulated). While these references do not explicitly teach the combination of both a DNMT inhibitor (ie Decitabine) and a HDAC inhibitor (ie Vorinostat), it would have been obvious to combine two agents that are both known to enhance response to anti-PD-1/PD-L1 as combination therapy is well established in the art of cancer treatment. The motivation to combine an epigenetic modifier with a checkpoint inhibitor is to rescue the action of IFNγ and increase PD-L1 expression which in turn increases the effectiveness of anti-PD-1/PD-L1 therapy.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675