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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/2/26 has been entered.
Claim 98 has been added by Applicant.
Claims 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 74, 76, and 98 are pending.
Claims 40 and 76 have been amended by Applicant.
Claims 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 74, 76, and 98 are currently under consideration.
Objections Withdrawn
The objection to claim 40 is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, and 76 remain rejected and claim 98 is rejected under 35 U.S.C. 103(a) as being unpatentable over Liu et al (Journal of Hematology & Oncology, 2018, 11(100): 1-12; 3/2/23 IDS) in view of Hamid et al (Journal of Clinical Oncology, 2017, 35(15): Abstract 6010), Ayers et al (JCI, 2017, 127(8): 2930-2940; 3/2/23 IDS) and Van Den Eynde et al (US 2011/0159017 A1; 6/30/11).
Liu et al teaches IDO1 is an enzyme that functions downstream of PD-1 in cancer cells that catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), resulting in an increase in Kyn that promotes: immunosuppression, neovascularization, and tumor development (Fig. 3, in particular). Liu et al further teaches expression levels of IDO1 are significantly higher in head and neck squamous cell carcinoma (HNSCC/SCCHN) as compared to corresponding normal tissue (Fig. 2, in particular). Liu et al further teaches the IDO1 inhibitor epacadostat increased rates of overall response and disease control without any noticeable increase in side effects when administered to patients with head-and-neck cancers when administered in combination with an anti-PD-1 antibody (left column on page 8, in particular) in a study that appears to be that of Hamid et al. Liu et al further teaches administering a combination of IDO1 inhibitor indoximod and the anti-PD-1 antagonist antibody pembrolizumab to patients with advanced cancer led to a 20% complete response rate, a 41% partial response rate, and a survival rate “suggesting a synergistic antitumor therapeutic effect” (left column on page 8, in particular). Liu et al further teaches the IDO1 inhibitor PF-06840003 enhanced the antitumor efficacy of anti-PD-1 antibodies in mice (left column on page 9, in particular). Liu et al further teaches doses of up to 2000 mg orally twice a day are safe doses of IDO1 inhibitor indoximod (right column on page 5, in particular). Liu et al further teaches the IDO1 inhibitor epacadostat has been shown to increase rates of overall response and disease control with head and neck cancer patients treated with anti-PD-1 antibodies (left column on page 8, in particular).
Figure 3 of Liu et al:
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Liu et al further teaches anti-PD-1 inhibitors include pembrolizumab and nivolumab (right column on page 8, in particular). Table 1 of Liu et al further teaches IDO1 inhibitors include epacostat, indoxymod, and BMS-986205 (same as “lindrostat”).
Liu et al does not specifically teach administering a combination of an IDO1 inhibitor and an anti-PD-1 antagonist to a subject identified as having (a) a high IFNg inflammatory signature score and (b) low TDO2 gene expression score. However, these deficiencies are made up in the teachings of Hamid et al, Ayers et al, and Van Den Eynde et al.
Hamid et al teaches the IDO1 inhibitor epacadostat in combination with anti-PD-1 pembrolizumab is associated with encouraging response rates in HNSCC/SCCHN patients (Abstract, in particular).
Ayers et al teaches “responder” cancer patients, including HNSCC/SCCHN cancer patients, with a high IFNg inflammatory signature score (comprising increased expression of IFNg, CXCL10, CXCL9, HLA-DRA, IDO1, STAT1, CCR5, CXCL11, GZMA, and PRF1 mRNA levels in formalin-fixed paraffin-embedded tumor tissue samples) respond better to administered anti-PD-1 antagonist pembrolizumab treatment than “nonresponder” cancer patients with a low IFNg inflammatory signature score that is an average expression of the genes in the IFNg inflammatory signature panel in cancer tumor tissue samples obtained from a population of subjects afflicted with cancer (Figures 1-3 and Table 2, in particular). Further, a high IFNg inflammatory signature score of a tumor tissue sample of Ayers et al is predictably higher than a corresponding tissue of subjects without a tumor because tissue of subjects without tumors lack T cell-inflamed tumor microenvironment comprising inflamed T cells that induce IFNg signaling (right column on page 2930 and Figure 8, in particular). The cancer patients of Ayers et al have locally advanced or metastatic cancer (left column on page 2938, in particular).
Van Den Eynde et al teaches TDO2 is expressed in some tumor cells and, like IDO1 of Liu et al (see Figure 3 of Liu et al), catalyzes the conversion of Trp into Kyn ([0003], in particular). Van Den Eynde et al further teaches that, like IDO1 of Liu et al, TDO2 expression in tumors results in degradation of Trp that prevents tumor surveillance by the immune system (“immunosuppression”) and thus prevents tumor rejection ([0003], in particular). Van Den Eynde et al further teaches using RT-PCR to detect TDO2 mRNA presence, absence, and levels in cancer cells and tumor tissue samples and that TDO2 mRNA is present in 90% of HNSCC/SCCHN tumor tissues tested and absent in 10% of HNSCC/SCCHN tumor tissues tested (Figure 1, Table 1, and Table 2, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of therapeutically treating human patients with HNSCC/SCCHN by administering a combination of any IDO1 inhibitor (to prevent immunosuppression, neovascularization, and tumor development due to elevated Kyn levels by inhibiting IDO1 from converting Trp into Kyn) of Liu et al and an anti-PD-1 antagonist, such as pembrolizumab or nivolumab, of Liu et al to patients with HNSCC/SCCHN identified as having a tumor biopsy tissue sample with (a) increased expression of IFNg, CXCL10, CXCL9, HLA-DRA, IDO1, STAT1, CCR5, CXCL11, GZMA, and PRF1 mRNA levels as measured by Ayers et al in the tumor biopsy tissue sample (“a high IFNg inflammatory signature score”) and (b) absent TDO2 mRNA expression as measured by Van Den Eynde et al in the tumor biopsy tissue sample (same as “low TDO2 gene expression score”) because Liu et al teaches the target of IDO1 inhibitors is significantly higher in HNSCC/SCCHN tumors as compared to corresponding normal tissue, Liu et al teaches the IDO1 inhibitor epacadostat increased rates of overall response and disease control without any noticeable increase in side effects when administered to patients with head-and-neck cancers when administered in combination with an anti-PD-1 antibody, Liu et al teaches administering a combination of IDO1 inhibitor indoximod and the anti-PD-1 antagonist antibody pembrolizumab to patients with advanced cancer appears to result in a “synergistic antitumor therapeutic effect”, Liu et al further teaches the IDO1 inhibitor epacadostat has been shown to increase rates of overall response and disease control with head and neck cancer patients treated with anti-PD-1 antibodies, Hamid et al teaches the IDO1 inhibitor epacadostat in combination with anti-PD-1 pembrolizumab is associated with encouraging response rates in HNSCC/SCCHN patients, Ayers et al teaches increased expression of IFNg, CXCL10, CXCL9, HLA-DRA, IDO1, STAT1, CCR5, CXCL11, GZMA, and PRF1 mRNA levels in tumor samples from HNSCC/SCCHN cancer patients indicates the patients will therapeutically respond to the anti-PD-1 antagonist of Liu et al, and absence of TDO2 mRNA expression in tumor samples from the patients indicates the patients lack TDO2 that could otherwise compensate for IDO1 inhibition blocking conversion of Trp into Kyn (by otherwise converting Trp into Kyn). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 2/2/26, Applicant argues cited references do not teach or suggest treating a cancer derived from a squamous cell head and neck (HNSCC/SCCHN) by administering an anti-PD-1 antagonist and an IDO1 inhibitor to a subject that has (a) a high IFNg inflammatory signature score and (b) a low TDO2 gene expression score. Applicant further argues cited references do not teach or suggest patients having (a) a high IFNg inflammatory signature score and (b) a low TDO2 gene expression score would be more responsive to a therapy comprising an anti-PD-1 antagonist and an IDO1 inhibitor. Applicant further argues the characterization of the results of Hamid showing “encouraging response rates” was made by Hamid and one of ordinary skill in the art would not have had sufficient information to draw that conclusion based on data presented by Hamid. Applicant points-out Hamid reports an ORR for patient with 1-2 prior therapies of 24% and an ORR for patients with 3 or more prior therapies of 14%, but does not provide control data for comparison. Without such data, Applicant argues a person of ordinary skill in the art would not have been able to conclude that a combination of epacadostat and pembrolizumab would be effective in treating HNSCC/SCCHN patients. Applicant further indicates the claimed method is non-obvious because the specification unexpectedly demonstrates (a) HNSCC/SCCHN patients with low TDO2 gene expression respond better to a combined therapy encompassed by the claims than HNSCC/SCCHN patients with higher TDO2 gene expression and (b) a combination of a high IFNg inflammatory signature score and a low TDO2 gene expression score predicts response of a group of ”non-melanoma” cancer patients.
The amendments to the claims and the arguments found in the Reply of 2/2/26 have been carefully considered, but are not deemed persuasive. In regard to arguments that (1) cited references do not teach or suggest treating a cancer derived from a squamous cell head and neck (HNSCC/SCCHN) by administering an anti-PD-1 antagonist and an IDO1 inhibitor to a subject that has (a) a high IFNg inflammatory signature score and (b) a low TDO2 gene expression score and (2) that cited references do not teach or suggest patients having (a) a high IFNg inflammatory signature score and (b) a low TDO2 gene expression score would be more responsive to a therapy comprising an anti-PD-1 antagonist and an IDO1 inhibitor: The examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of therapeutically treating human patients with HNSCC/SCCHN by administering a combination of an IDO1 inhibitor (to prevent immunosuppression, neovascularization, and tumor development due to elevated Kyn levels by inhibiting IDO1 from converting Trp into Kyn) of Liu et al and an anti-PD-1 antagonist, such as pembrolizumab or nivolumab, of Liu et al to patients with HNSCC/SCCHN identified as having a tumor biopsy tissue sample with (a) increased expression of IFNg, CXCL10, CXCL9, HLA-DRA, IDO1, STAT1, CCR5, CXCL11, GZMA, and PRF1 mRNA levels as measured by Ayers et al in the tumor biopsy tissue sample (“a high IFNg inflammatory signature score”) and (b) absent TDO2 mRNA expression as measured by Van Den Eynde et al in the tumor biopsy tissue sample (same as “low TDO2 gene expression score”) because Liu et al teaches the target of IDO1 inhibitors is significantly higher in HNSCC/SCCHN tumors as compared to corresponding normal tissue, Liu et al teaches the IDO1 inhibitor epacadostat increased rates of overall response and disease control without any noticeable increase in side effects when administered to patients with head-and-neck cancers when administered in combination with an anti-PD-1 antibody, Liu et al teaches administering a combination of IDO1 inhibitor indoximod and the anti-PD-1 antagonist antibody pembrolizumab to patients with advanced cancer appears to result in a “synergistic antitumor therapeutic effect”, Liu et al further teaches the IDO1 inhibitor epacadostat has been shown to increase rates of overall response and disease control with head and neck cancer patients treated with anti-PD-1 antibodies, Hamid et al teaches the IDO1 inhibitor epacadostat in combination with anti-PD-1 pembrolizumab is associated with encouraging response rates in HNSCC/SCCHN patients, Ayers et al teaches increased expression of IFNg, CXCL10, CXCL9, HLA-DRA, IDO1, STAT1, CCR5, CXCL11, GZMA, and PRF1 mRNA levels in tumor samples from HNSCC/SCCHN cancer patients indicates the patients will therapeutically respond to the anti-PD-1 antagonist of Liu et al, and absence of TDO2 mRNA expression in tumor samples from the patients indicates the patients lack TDO2 that could otherwise compensate for IDO1 inhibition blocking conversion of Trp into Kyn (by otherwise converting Trp into Kyn). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
In regards to the arguments that the characterization of the results of Hamid showing “encouraging response rates” was made by Hamid and one of ordinary skill in the art would not have had sufficient information to draw that conclusion based on data presented by Hamid and that a person of ordinary skill in the art would not have been able to conclude that a combination of epacadostat and pembrolizumab would be effective in treating HNSCC/SCCHN patients based on controls not taught by Hamid, the examiner disagrees. Before the effective filing date of the claimed invention, those of skill of the art were of the opinion that subjects with HNSCC/SCCHN would benefit from a combination of epacadostat and anti-PD-1 treatments. For example, page 11 of Prendergast et al (Cancer Research, 2017, 77(24): 6795-6811) teaches:
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Further, at pages 132 and 134 of Davar et al (Targeted Oncology, 2018, 13: 125-140) describes the study of Hamid as showing “remarkable” response rates:
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Further, page 1484 of the prior art of Flynn et al (Expert Opinion on Pharmacotherapy, 2017, 18(14): 1477-1490) describes the study of Hamid as evidence supporting synergy of IDO1 inhibitors and checkpoint inhibitors in the clinic, describes ORR of 23% or 34% for HNSCC/SSCCHN patients treated with a combination of epacadostat and anti-PD-1 inhibitors nivolumab or pembrolizumab, and describes such a combination as providing “deep and durable responses”:
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Further, Liu et al teaches the IDO1 inhibitor epacadostat increased rates of overall response and disease control without any noticeable increase in side effects when administered to patients with head-and-neck cancers when administered in combination with an anti-PD-1 antibody (left column on page 8, in particular) in a study that appears to be that of Hamid et al.
In regards to the indication the claimed method is non-obvious because the specification unexpectedly demonstrates (a) HNSCC/SCCHN patients with low TDO2 gene expression respond better to a combined therapy encompassed by the claims than HNSCC/SCCHN patients with higher TDO2 gene expression and (b) a combination of a high IFNg inflammatory signature score and a low TDO2 gene expression score predicts response of a group of ”non-melanoma” cancer patients, the examiner disagrees. HNSCC/SCCHN patients with high IFNg inflammatory signature scores predictably benefit from the combined method, which comprises administering anti-PD-1 antagonist, because Ayers et al teaches increased expression of IFNg, CXCL10, CXCL9, HLA-DRA, IDO1, STAT1, CCR5, CXCL11, GZMA, and PRF1 mRNA levels in tumor samples from HNSCC/SCCHN cancer patients indicates the patients will therapeutically respond to the anti-PD-1 antagonist of Liu et al. As compared to HNSCC/SCCHN patients that highly express TDO2, patients with absence of TDO2 expression in tumor samples predictably benefit from the combined method that comprise administering an IDO1 inhibitor to block conversion of Trp into Kyn that would otherwise be converted by TDO2 (see Van Den Eynde et al).
Claim Rejections - 35 USC § 103
Claim(s) 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 74, and 76 remain and claim 98 is rejected rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (Journal of Hematology & Oncology, 2018, 11(100): 1-12; 3/2/23 IDS) in view of Hamid et al (Journal of Clinical Oncology, 2017, 35(15): Abstract 6010), Ayers et al (JCI, 2017, 127(8): 2930-2940; 3/2/23 IDS) and Van Den Eynde et al (US 2011/0159017 A1; 6/30/11) as applied to claims 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 76, and 98 above, and further in view of Force et al (ImmunoTargets and Therapy, 2017, 1-10).
Teachings of Liu et al, Hamid et al, Ayers et al, and Van Den Eynde et al are discussed above.
Liu et al, Hamid et al, Ayers et al, and Van Den Eynde et al do not specifically teach methods wherein an anti-PD-1 antibody is administered intravenously at a 240 mg every two weeks or 480 mg dose every four weeks, and IDO1 inhibitor is administered orally at a 100 mg or 200 mg dose every day. However, these deficiencies are made up in the teachings of Force et al.
Force et al teaches the anti-PD-1 antagonist antibodies pembrolizumab and nivolumab are approved by the FDA for treating cancers (left column on page 2, in particular). Force et al further teaches anti-PD-1 antagonist antibodies are administered intravenously and teaches administered doses of anti-PD-1 antagonist antibodies include 240 mg every two weeks (right column on page3, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Liu et al, Hamid et al, Ayers et al, and Van Den Eynde et al wherein anti-PD-1 antagonist antibodies (either pembrolizumab or nivolumab) are administered at various doses (including intravenous administration of Force et al and doses of 240 mg every two weeks of Force et al) and the IDO1 inhibitor is administered at various doses (including just any doses of up to 2000 mg orally up to twice a day of IDO1 inhibitor indoximod of Liu et al) in an effort to optimize dosing of the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing In re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, given the known function of both anti-PD-1 antagonist antibodies and IDO1 inhibitors in cancer treatment, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the dosages and timing of administration instantly claimed, where the combination is expected to provide therapeutic cancer treatment. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 2/2/26, Applicant repeats arguments that have been addressed above.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642