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 .
Detailed Action
The Amendments and Remarks filed 6/17/26 in response to the Office Action of 2/17/26 are acknowledged and have been entered.
Claims 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 74, 76, and 98 are pending and currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 76, and 98 remain 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 an enzyme expressed in some tumor cells and, like the IDO1 enzyme of Liu et al (see Figure 3 of Liu et al), TDO2 is another enzyme that catalyzes the conversion of Trp into Kyn ([0003], in particular) and that degradation of Trp by TDO2 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 enzyme that could otherwise compensate for IDO1 inhibition blocking conversion of Trp into Kyn (by otherwise converting Trp into Kyn). Patients with an absence of TDO2 expression predictably benefit from IDO1 inhibition to enhance tumor surveillance by the immune system because TDO2 could otherwise “compensate” for IDO1 inhibition and maintain immunosuppression. 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 6/17/26, Applicant argue neither Van den Eynde nor Hamid teach or suggest that low or absent TDO2 in a subject is favorable for combination treatment with an anti-PD-1 antagonist and IDO inhibitor. Applicant further argues Hamid provides no reason to stratify patients based on TDO2 expression, or expression of any other biomarker, to achieve better response rates. Applicant further argues Ayers does not provide any indication as to whether a low TDO2 gene expression score combined with a high IFNg inflammatory signature would correlate with an improved response to therapy comprising an anti-PD-1 antagonist and an IDO1 inhibitor. Applicant further argues Van Den Eynde is directed to methods of treating cancer by inhibiting TDO2 itself, not to patient selection for IDO1 inhibitor therapy. Applicant further argues Flynn (Expert Opinion on Pharmacotherapy, 2017, 18(14): 1477-1490; cited as evidence in the 2/17/26 Non-Final Office Action) does not provide any indication as to whether a low TDO2 gene expression score combined with a high IFNg inflammatory signature would correlate with an improved response to therapy comprising an anti-PD-1 antagonist and an IDO1 inhibitor. Applicant further cites [0053] of Van den Eynde as teaching “Expression of TDO2 or both TDO2 and IDO by the cancer cells indicates that the patient is a candidate to be treated with an inhibitor of TDO2 or both TDO2 and IDO to increase susceptibility of the cancer cells to T cell attack” is a teaching that is “opposite” to low or absent TDO2 in a subject as being a favorable for combination treatment with an anti-PD-1 antagonist and IDO inhibitor. Applicant further argues a lack of reason to modify the disclosure of any of Liu, Van den Eynde, and Hamid to arrive at the claimed invention because Van den Eynde teaches positive TDO2 expression as a precondition for administering an IDO inhibitor and Hamid fails to distinguish between high and low TDO2 expression. Applicant further argues the Examiner’s assertion that absence of TDO2 expression would indicate patients who would benefit from IDO1 inhibition because TDO2 could otherwise “compensate” for IDO1 inhibition is not supported by cited references and represents impermissible hindsight. Applicant further argues the claimed methods are non-obvious because the instant specification discloses: Example 4 shows patients with low TDO2 expression have a two-fold greater response rate, compared to patients with high TDO2; Example 6 and Figure 6B show in a non-melanoma subset, a composite biomarker of IFNg and TDO2 gene expression was more significantly associated with response than the IFNy signature alone; Figures 7A and 7B shows in the non-melanoma subset, IFNγ and TDO2 expression, performed numerically better as a predictor of response than IFNγ alone and signature and IFNγ signature with TDO2 gene expression can function as a composite biomarker to identify patients with certain tumor types more likely to respond to linrodostat mesylate and nivolumab treatment; and Example 5 (specifically, FIG. 5A) and Example 7 (specifically, FIG. 7B) provide data illustrating that the claimed biomarkers are associated with increased responsiveness to a therapy comprising an anti-PD- 1 antagonist and an IDO1 inhibitor in subjects afflicted with bladder cancer or SCCHN.
The amendments to the claims and the argument found in the Reply of 3/24/22 have been carefully considered, but are not deemed persuasive. In regards to the arguments that neither Van den Eynde nor Hamid teach or suggest that low or absent TDO2 in a subject is favorable for combination treatment with an anti-PD-1 antagonist and IDO inhibitor, Hamid provides no reason to stratify patients based on TDO2 expression (or expression of any other biomarker) to achieve better response rates, Ayers does not provide any indication as to whether a low TDO2 gene expression score combined with a high IFNg inflammatory signature would correlate with an improved response to therapy comprising an anti-PD-1 antagonist and an IDO1 inhibitor, Van Den Eynde is not directed to patient selection for IDO1 inhibitor therapy, and Flynn does not provide any indication as to whether a low TDO2 gene expression score combined with a high IFNg inflammatory signature would correlate with an improved response to therapy comprising an anti-PD-1 antagonist and an IDO1 inhibitor, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In regards to the citation of [0053] of Van den Eynde as teaching “Expression of TDO2 or both TDO2 and IDO by the cancer cells indicates that the patient is a candidate to be treated with an inhibitor of TDO2 or both TDO2 and IDO to increase susceptibility of the cancer cells to T cell attack” is a teaching that is “opposite” to low or absent TDO2 in a subject as being a favorable for combination treatment with an anti-PD-1 antagonist and IDO inhibitor, Van den Eynde recognizes TDO2 and IDO are both enzymes that catalyze degradation of tryptophan (trp) into kynureine (kyn) in tumor cells, which results in a local drop in extracellular tryptophan, which is deleterious to T lymphocyte survival and proliferation in the microenvironment and renders the tumor cells resistant to immune rejection (see [0002]-[0003], in particular). In line with cited teachings of Van den Eynde, because TDO2-mediated degradation of tryptophan can “compensate” for IDO1-mediated degradation of tryptophan (and vice-versa), expression of TDO2 or both TDO2 and IDO by the cancer cells of a patient predictably indicates that the patient is responsive to treatment with an inhibitor of TDO2 (when TDO2 is expressed) or both TDO2 and IDO (when both TDO2 and IDO are expressed) to increase susceptibility of the cancer cells to T cell attack. Likewise, patients with an absence of TDO2 expression predictably benefit from IDO1 inhibition to enhance tumor surveillance by the immune system because TDO2 could otherwise “compensate” for IDO1 inhibition by catalyzing degradation of trp into kyn to maintain immunosuppression.
In regards to the argument that there is a lack of reason to modify the disclosure of any of Liu, Van den Eynde, and Hamid to arrive at the claimed invention because Van den Eynde teaches positive TDO2 expression as a precondition for administering an IDO inhibitor and Hamid fails to distinguish between high and low TDO2 expression, the examiner disagrees. As stated above, 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 enzyme that could otherwise compensate for IDO1 inhibition blocking conversion of Trp into Kyn (by otherwise converting Trp into Kyn). Patients with an absence of TDO2 expression predictably benefit from IDO1 inhibition to enhance tumor surveillance by the immune system because TDO2 could otherwise “compensate” for IDO1 inhibition and maintain immunosuppression. 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 argument that the Examiner’s assertion that absence of TDO2 expression would indicate patients who would benefit from IDO1 inhibition because TDO2 could otherwise “compensate” for IDO1 inhibition is not supported by cited references and represents impermissible hindsight, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). It is apparent from Van Den Eynde et al that TDO2 could otherwise “compensate” for IDO1 inhibition. Van Den Eynde et al teaches TDO2 is an enzyme expressed in some tumor cells and, like the IDO1 enzyme of Liu et al (see Figure 3 of Liu et al), TDO2 is another enzyme that catalyzes the conversion of Trp into Kyn ([0003], in particular) and that degradation of Trp by TDO2 prevents tumor surveillance by the immune system (“immunosuppression”) and thus prevents tumor rejection ([0003], in particular). Patients with an absence of TDO2 expression predictably benefit from IDO1 inhibition to enhance tumor surveillance by the immune system because TDO2 could otherwise “compensate” for IDO1 inhibition and maintain immunosuppression.
In regards to the argument the claimed methods are non-obvious because Example 4 shows patients with low TDO2 expression have a two-fold greater response rate, compared to patients with high TDO2, the examiner disagrees. Results of Example 4 are not unexpected and results of Example 4 are not commensurate in scope with the claims. "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). It is not unexpected that patients with low TDO2 expression have a two-fold greater response rate, compared to patients with high TDO2 because IDO1 inhibition therapeutically functions by inhibiting IDO1 from catalyzing the conversion of Trp into Kyn. Patients with low TDO2 expression would be expected to have a much higher response rate to IDO1 inhibition than patients with high TDO2 expression because TDO2 is an enzyme that also catalyzes the conversion of Trp into Kyn, predictably compensating for IDO1 inhibition. The results of Example 4 are not commensurate in scope with the claims because the claims are limited to treatment of SCCHN and bladder cancer, while Example 4 is not limited to treatment of SCCHN and bladder cancer.
In regards to the argument the claimed methods are non-obvious because Example 6 and Figure 6B show in a non-melanoma subset, a composite biomarker of IFNg and TDO2 gene expression was more significantly associated with response than the IFNy signature alone, the examiner disagrees. Results of Example 6 and Figure 6B are not unexpected and results of Example 6 and Figure 6B are not commensurate in scope with the claims. "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). It is not unexpected that a composite biomarker of IFNg and TDO2 gene expression was more significantly associated with response than the IFNy signature alone because IDO1 inhibition therapeutically functions by inhibiting IDO1 from catalyzing the conversion of Trp into Kyn. Patients with IFNg biomarker indicative of response and low TDO2 expression would be expected to have a much higher response rate to IDO1 inhibition than patients IFNg biomarker indicative of response alone because TDO2 is an enzyme that also catalyzes the conversion of Trp into Kyn, predictably compensating for IDO1 inhibition. The results of Example 6 and Figure 6B are not commensurate in scope with the claims because the claims are limited to treatment of SCCHN and bladder cancer, while Example 6 and Figure 6B are not limited to treatment of SCCHN and bladder cancer.
In regards to the argument the claimed methods are non-obvious because Figures 7A and 7B shows in the non-melanoma subset, IFNγ and TDO2 expression, performed numerically better as a predictor of response than IFNγ alone and IFNγ signature with TDO2 gene expression can function as a composite biomarker to identify patients with certain tumor types more likely to respond to linrodostat mesylate and nivolumab treatment, the examiner disagrees. Results of Figures 7A and 7B are not unexpected and results of Figures 7A and 7B are not commensurate in scope with the claims. "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). It is not unexpected that a composite biomarker of IFNg and TDO2 gene expression performed numerically better as a predictor of response than IFNy signature alone because IDO1 inhibition therapeutically functions by inhibiting IDO1 from catalyzing the conversion of Trp into Kyn. Patients with IFNg biomarker indicative of response and low TDO2 expression would be expected to have a much higher response rate to IDO1 inhibition than patients IFNg biomarker indicative of response alone because TDO2 is an enzyme that also catalyzes the conversion of Trp into Kyn, predictably compensating for IDO1 inhibition. Further, it is not unexpected that a composite biomarker of IFNg signature and TDO2 gene expression predict response to combined treatment with IDO1 inhibitor linrodostat mesylate and the PD-1 inhibitor nivolumab because: Liu et al teaches the IDO1 inhibition 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 enzyme that could otherwise compensate for IDO1 inhibition blocking conversion of Trp into Kyn (by otherwise converting Trp into Kyn). Patients with an absence of TDO2 expression predictably benefit from IDO1 inhibition to enhance tumor surveillance by the immune system because TDO2 could otherwise “compensate” for IDO1 inhibition and maintain immunosuppression. The results of Figures 7A and 7B are not commensurate in scope with the claims because the claims are limited to treatment of SCCHN and bladder cancer, while Figures 7A and 7B are not limited to treatment of SCCHN and bladder cancer.
In regards to the argument the claimed methods are non-obvious because Example 5 (specifically, FIG. 5A) and Example 7 (specifically, FIG. 7B) provide data illustrating that the claimed biomarkers are associated with increased responsiveness to a therapy comprising an anti-PD- 1 antagonist and an IDO1 inhibitor in subjects afflicted with bladder cancer or SCCHN, the examiner disagrees. Results of Example 5 (specifically, FIG. 5A) and Example 7 (specifically, FIG. 7B) are not unexpected and results of Example 5 (specifically, FIG. 5A) and Example 7 (specifically, FIG. 7B) are not commensurate in scope with the claims. "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). It is not unexpected that claimed biomarkers are associated with increased responsiveness to a therapy comprising an anti-PD- 1 antagonist and an IDO1 inhibitor in subjects afflicted with bladder cancer or SCCHN. As stated above, 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 enzyme that could otherwise compensate for IDO1 inhibition blocking conversion of Trp into Kyn (by otherwise converting Trp into Kyn). Patients with an absence of TDO2 expression predictably benefit from IDO1 inhibition to enhance tumor surveillance by the immune system because TDO2 could otherwise “compensate” for IDO1 inhibition and maintain immunosuppression. 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. The results of Figures 5A are not commensurate in scope with the claims because the claims are limited to treatment based on a combination of scores (IFNg inflammatory signature score & TDO2 expression), while Figure 5A is limited to a single score (TDO2 expression). The results of Figures 7B are not commensurate in scope with the claims because the claims are limited to treatment of SCCHN and bladder cancer, while Figure 7B is not limited to treatment of SCCHN and bladder cancer.
Claim Rejections - 35 USC § 103
Claim(s) 1, 3, 12, 14, 15, 17, 19, 21, 22, 24, 33, 39, 40, 43, 74, 76, and 98 remain 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 6/17/26, Applicant repeats arguments addressed above.
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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