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
Claims 11, 15-17, 19-20, 39-48 are pending in the instant application.
Claims 12, 13, 21-23, 25-27, 29-31, 33-35, 37, and 38 have been cancelled
Claims 11 and 20 have been amended.
New claims 39-48 have been added.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/25/2025 has been entered.
Claim Rejections Withdrawn
The rejection to claims 12, 13, 21-23, 25-27, 29-31, 33-35, 37, and 38 are moot in view of claim cancelation.
The rejection to claims 11, 15-17, 19-20, 39-48 under 35 § 103 are withdrawn in view of claim amendment.
The rejection to claims 11, 15-17, 19-20, 39-48 under nonstatutory double patenting are withdrawn in view of claim amendment.
Claim Rejections Necessitated by Amendment
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 11, 15-17, 19-20, 39-41, 43-45 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017150725 (Miura A et al. reference of record) evidenced by English translation of WO 2017150725 (Miura A et al. reference of record) and further in view of Sweis RF et al. (Cancer Immunol Res. 2016 4(7): 563–568 reference of record), US 20170145102 (Pierce K et al. reference of record), and Bellmunt J et al. (N Engl J Med 2017;376:1015-1026 reference of record).
The English translation of WO 2017150725 (Miura A et al.) by Google is cited for the page reference in the teachings of Miura below.
Miura taught compound 1 as (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib (page 15, paragraph 45). Miura taught the compound of general formula (I), which includes compound 1: 1) is an antitumor agent with excellent FGFR inhibitory action; and 2) used in combination with other compounds having antitumor effects, has the effect of enhancing the antitumor effect (page 17, paragraph 90); and 3) in combination with the antibody targeted immune checkpoint inhibitor pembrolizumab (page 18, paragraph 95). Miura taught the method of combination treatment of bladder cancer with the compound of general formula (I), which includes compound 1 and immune checkpoint inhibitors (page 19, paragraph 109). Miura taught compound 1 effectively inhibits human bladder cancer tumor growth and is dose responsive with 5 and 15 mg (Fig 1A). Miura taught combination therapy with compound 1 showed synergistic cell death regardless of the mechanism of action of the chemotherapeutic agent in human urothelial cancer cells (page 30, paragraph 206 and 7A-B). Miura taught combination treatment is highly effective not only for tumors having wild-type FGFR but also for tumors in which FGFR is amplified or mutated (page 25, paragraph 162). Miura taught the daily dosage of the compound represented by the general formula (I), which includes compound 1, or the pharmaceutically acceptable salt thereof is administered in a more preferably dose of 4 - 50 mg per day (page 20, paragraph 115).
Miura did not teach: 1) a single embodiment of combination treatment with the FGFR inhibitor futibatinib and the immune checkpoint inhibitor pembrolizumab; 2) the tumor being treated having resistance to immune checkpoint inhibitors; 3) the patient not previously receiving immune checkpoint inhibitors; and 4) the dose of the immune checkpoint inhibitor pembrolizumab, but this is obvious in view of Sweis, Pierce, and Bellmunt.
Sweis taught the presence of an existing antitumor T cell response in all cancers is important for the activity of immunotherapies, including checkpoint blockade (page 563, left to right column bridging sentence). Sweis taught FGFR3 was activated in non-T cell-inflamed bladder urothelial cancer tumors (abstract). Sweis taught non-T cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies (abstract). Sweis taught FGFR3 was the most common mutation exclusive to non-inflamed bladder cancer tumors (P < 0.0001) and that the mutations were activating mutations (page 567, left column, first paragraph). Sweis taught FGFR3 represents a targetable potential pathway of tumor-intrinsic immunotherapy resistance and modulation of FGFR3 could prove useful to overcome primary resistance to immune checkpoint blockade such as PD-1/PD-L1-targeted therapies (abstract). Sweis taught the availability of FGFR3 inhibitors for clinical testing provides a rationale and feasibility for combination with monoclonal antibodies to PD-1 or PD-L1 (page 567, right column, second paragraph).
Pierce taught a method of treating cancer in a subject comprising administering to the subject a fibroblast growth factor receptor 2 (FGFR2) inhibitor and the programmed cell death 1 (PD-1) inhibitor pembrolizumab (page 30, paragraph 270-275). Pierce taught combination with a FGFR2 antibody and anti-PD1 antibody significantly decreased cancer growth in vivo (Figures 4a and 4b). Pierce taught anti-PD1 antibody administration was ineffective to inhibit tumor growth in vivo when administered alone and not significantly different than control (Figures 4a and 4b).
Pierce taught in vivo administration with an anti-FGFR2 antibody results in an increase in NK cells, T cells and an increase in PD-L1 expressing cells within tumor tissue (page 36, paragraph 408). Pierce taught while subjects treated with vehicle had T cell infiltration only at the periphery of the tumors, subjects treated with anti-FGFR2 resulted in an infiltration of CD3, CD8 and CD4 positive T cells within the tumor center (page 36, paragraph 417). Pierce taught the anti-FGFR2 antibody works in concert with the innate and adaptive immune system to drive changes in the tumor microenvironment that result in sustained tumor growth inhibition in immune competent mice (page 39, paragraph 445).
Bellmunt taught pembrolizumab at a dose of 200 mg every 3 weeks was associated with significantly longer overall survival and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma.
Regarding instant claims 11, 15-17, and 19-20, 39-41, it would have been obvious for a person having ordinary skill in the art to take the method of Miura for treatment of a human bladder cancer patient with (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib, in combination with the antibody targeted immune checkpoint inhibitor pembrolizumab in an effective amount to inhibit tumor growth – and further include: 1) specifically the combination with pembrolizumab; 2) subjects with tumors that have resistance to immunotherapies; 3) wherein the tumor is a urothelial cancer bladder tumor with a genetic FGFR aberration; and 4) administer the futibatinib with 4 - 50 mg daily, which overlaps with 20 mg daily; and dose the pembrolizumab with 200 mg every three weeks.
This is obvious because 1)-3) Sweis taught FGFR3 represents a targetable potential pathway of tumor-intrinsic immunotherapy resistance in urothelial cancer and that modulation of FGFR3 could prove useful to overcome primary resistance to immune checkpoint blockade such as PD-1/PD-L1-targeted therapies; and 4a) futibatinib is described by Miura to be administered as a preferred dose of 4 - 50 mg per day and 20 mg is within that range; and 4b) Bellmunt taught pembrolizumab at a dose of 200 mg every 3 weeks was associated with significantly longer overall survival and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. Thus, the combination would be expected to be effective at these doses.
This would produce a method of treatment for a human bladder urothelial cancer patient (instant claim 20) with genetic aberration of FGFR3 by administering (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib, in combination with the immune checkpoint inhibitor pembrolizumab in an effective amount to inhibit tumor growth, wherein the patient is administered 4 - 50 mg futibatinib daily, which overlaps with 20 mg daily, and 200 mg pembrolizumab every three weeks (instant claims 19 and 40-41 ). This method would naturally result in a sustained response in an individual after cessation of treatment (instant claim 39). This method would meet the claim limitations of instant claims 15 and 16 because the combination would be required to be administered either before, simultaneously with, or after pembrolizumab; and futibatinib would be required to be administered continuously or intermittently. This method would further meet the claim limitation of administering the combination with one therapeutic regimen in instant claim 17 because the instant specification defines one therapeutic regimen to include combination therapy together or separately (instant specification, page 35, paragraph 123).
There is a reasonable expectation of success because:
1) choosing the specific combination of futibatinib and the immune checkpoint inhibitor pembrolizumab would: i) inhibit cancer cell growth and promote infiltration of T cells with the FGFR inhibitor; and ii) allow the infiltrating immune cells to kill the cancer cells without being blocked by suppressive PD-1 signaling with pembrolizumab;
2) and 3) Sweis taught FGFR3 represents a targetable potential pathway of tumor-intrinsic immunotherapy resistance and modulation of FGFR3 in bladder urothelial cancer to overcome primary resistance to immune checkpoint blockade such as PD-1/PD-L1-targeted therapies. Sweis taught the availability of FGFR3 inhibitors for clinical testing provides a rationale and feasibility for combination with monoclonal antibodies to PD-1;
3) Further, futibatinib is able to inhibit more than one FGFR family member and would affect the immune cell infiltration. Pierce taught subjects treated with an FGFR2 inhibitor resulted in an infiltration of CD3, CD8 (cytotoxic T cells) and CD4 (helper T cells) positive T cells within the tumor center. Thus, the FGFR inhibitor in combination with pembrolizumab would increase immune cell infiltration into the cancer and result in a sustained response in an individual after cessation of treatment; and
4a) futibatinib is described by Miura to be administered in a preferable dose of 4 - 50 mg per day and 20 mg is within that range. Further, 5 and 15 mg were effective and dose responsive to cancer; and 4b) Bellmunt taught pembrolizumab at a dose of 200 mg every 3 weeks was associated with significantly longer overall survival and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. Thus, the combination would be expected to be effective at these doses.
Regarding instant claims 43-45 and 47, it would have been obvious for a person having ordinary skill in the art to take the method of Miura, Sweis, Pierce, and Bellmunt above – and treat a human patient that was not previously administered immune checkpoint inhibitors, but had noninflamed urothelial cancer with intrinsic tumor resistance to immune checkpoint inhibitors due to a lack of infiltration of T cells.
This is obvious because: Sweis taught non-inflamed urothelial cancers that lack immune cell infiltration have intrinsic resistance to checkpoint inhibitors. Thus, previous administration of immune checkpoint inhibitors is not required for resistance.
This would produce a method of treatment for human patients with bladder urothelial cancer (instant claims 45 and 47) with genetic aberration of FGFR3 that had not previously been administered immune checkpoint inhibitors (instant claim 43), but had intrinsic tumor resistance to immune checkpoint inhibitor administration (instant claim 44), by administering (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib, in combination with the immune checkpoint inhibitor pembrolizumab in an effective amount to inhibit tumor growth, wherein the patient is administered 4 - 50 mg futibatinib daily, which overlaps with 20 mg daily, and 200 mg pembrolizumab every three weeks. This method would naturally result in a sustained response in an individual after cessation of treatment. This method would be required to be administered either before, simultaneously with, or after pembrolizumab; and futibatinib would be required to be administered continuously or intermittently. This method would further comprise administering the combination with one therapeutic regimen because the instant specification defines one therapeutic regimen to include combination therapy together or separately (instant specification, page 35, paragraph 123).
There is a reasonable expectation of success because non-inflamed urothelial cancers would have intrinsic resistance to immune checkpoint inhibitors in the absence of prior therapy because the immune cells are excluded from the tumor. The combination therapy would cause FGFR-mediated immune cell infiltration and the PD-1 inhibitor pembrolizumab would block immune checkpoint suppression of immune cell mediated cancer cell death.
Response to Arguments
Applicant has amended the independent claim 11 and claim 20 and added new claims 39-48.
The rejection has been updated to include the amended and new subject matter above.
Applicant argues one skilled in the relevant art would clearly recognize that the
anti-tumor effects of immune checkpoint inhibitors are improved by reducing MDSCs through administration of compound I in the present invention. Further, Example 2 of the present specification confirms an increase in CD4-positive T cells and an increase in CD8-positive T cells, indicating that the antitumor effects of these T cells were obtained.
Therefore, it is clear that according to the present invention, not only does
compound I or a salt thereof itself exhibit an anti-tumor effect, but also the administration of compound I or the salt thereof leads to relief from immunosuppression mechanisms, as shown by the reduction in MDSCs, the increase in CD4-positive T cells, and the increase in CD8- positive T cells, thereby enhancing the effects of immune checkpoint inhibitors, and the combined use of compound I or the salt thereof and the immune checkpoint inhibitor achieves higher antitumor effects.
In response, the Applicant's arguments filed 8/25/2025 have been fully considered but they are not persuasive. The claims do not require a decrease of MDSC, but if they did, the effect of FGFR inhibitors on MDSCs was previously known to a person having ordinary skill in the art as taught by Liu L et al. (Cellular Physiology and Biochemistry (2014) 33 (3): 633–645 reference of record), and Katoh M et al. (Int J Mol Med. 2016 38(1):3-15.). Liu taught immunological function of MDSCs is to suppress T-cells proliferation (page 643, paragraph 2). Liu taught treatment with the FGFR inhibitor AZD4547 decreased the number of MDSCs in the spleen and peripheral blood mononuclear cells in tumor bearing subjects (page 643, paragraph 2). Liu taught AZD4547 strikingly reduced the expansion of MDSCs, resulting in increased CD4+ and CD8+ T-cells responses in tumor bearing subjects (page 643, paragraph 2). Katoh taught cancer immunity and immune tolerance in the tumor microenvironment are regulated by the interaction between cancer cells and immune cells, wherein A) CD8+ T cells, NK cells and NKT cells are immune effector cells involved in tumor elimination; and B) myeloid-derived suppressor cells (MDSCs), tumor-associating macrophages of M2 type (M2-TAMs) and regulatory T (Treg) cells are immune modifier cells involved in immune evasion and tumor growth (page 10, left column, second paragraph). Katoh taught treatment of subjects with cancer with an inhibitor of the FGFR family, BGJ398, results in tumor regression and disappearance of MDSCs (page 10, left column, third paragraph). Katoh taught treatment of subjects with cancer with an inhibitor of the FGFR family, AZD4547 treatment inhibits the proliferation and metastasis of cancer cells, and reduces MDSCs in the tumor microenvironment and systemic circulation (page 10, left column, third paragraph). Katoh taught FGFR inhibitors induce the reduction or disappearance of MDSCs from the tumor microenvironment, partly by targeting cytokine-producing CAFs (page 10, left column, third paragraph). Thus, FGFR inhibitor suppression of MDSCs was known.
Applicant argues Miura fails teach a single embodiment of the combination of compound I or a salt thereof and pembrolizumab. Pierce and Bellmunt describe pembrolizumab, but are silent about compound 1. Neither Sweis nor Liu contains specific descriptions of compound I and pembrolizumab. All of the FGFR inhibitors disclosed in Pierce are compounds having structures different from that of the present invention. Further, the only compound where its effect on MDSCs has been experimentally confirmed in Liu is AD4547, which is a specific compound having a structure completely different from compound 1.
Applicant argues accordingly, one skilled in the relevant art would not have arrived at the claimed subject matter with a reasonable expectation of success that the administration of compound I or a salt thereof would reduce MDSCs, that the reduction of MDSCs would enhance the effect of pembrolizumab, the immune checkpoint inhibitor, and that the combined use of compound I or a salt thereof and pembrolizumab achieves excellent anti-tumor effects.
In response, the Applicant's arguments filed 8/25/2025 have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, 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). Regarding instant claims 11, 15-17, and 19-20, 39-41, the obvious rational is above for why it would have been obvious with a reasonable expectation of success for a person having ordinary skill in the art to take the method of Miura for treatment of a human bladder cancer patient with (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib, in combination with the antibody targeted immune checkpoint inhibitor pembrolizumab in an effective amount to inhibit tumor growth – and further include: 1) specifically the combination with pembrolizumab; 2) subjects with tumors that have resistance to immunotherapies; 3) wherein the tumor is a urothelial cancer bladder tumor with a genetic FGFR aberration; and 4) administer the futibatinib with 4 - 50 mg daily, which overlaps with 20 mg daily; and dose the pembrolizumab with 200 mg every three weeks.
Regarding MDSC, the claims do not require a decrease of MDSC, but if they did, the effect of FGFR inhibitors on MDSCs was previously known to a person having ordinary skill in the art as taught by Liu L et al. (Cellular Physiology and Biochemistry (2014) 33 (3): 633–645 reference of record), and Katoh M et al. (Int J Mol Med. 2016 38(1):3-15.). As described above Liu taught AZD4547 strikingly reduced the expansion of MDSCs, resulting in increased CD4+ and CD8+ T-cells responses in tumor bearing subjects (page 643, paragraph 2). Katoh taught treatment of subjects with cancer with an inhibitor of the FGFR family, BGJ398, results in tumor regression and disappearance of MDSCs (page 10, left column, third paragraph). Thus, FGFR inhibitor suppression of MDSCs was known.
Applicant argues the present specification discloses that the combined use of
compound I or a salt thereof and pembrolizumab in patients can provide therapeutic effects that cannot be expected from monotherapies, separately using each of them. Applicant argues specifically, FIG. 2 and the Results section of Ooki Appendix 2 (which corresponds to Ooki A et al. Phase 1b study of futibatinib plus pembrolizumab with or without chemotherapy in patients with esophageal carcinoma: Updated results of antitumor activity.(J Clin Onc 2024 42(16 Supplement) Abstract 4047)
Cohort D ( a cohort of patients who are receiving first-line treatment and have not been treated with chemotherapy or immune checkpoint inhibitors), the overall response rate (ORR) was 70%;
Cohort A (a cohort of patients who are receiving second-line or subsequent treatment and have not been treated with immune checkpoint inhibitors), the ORR was 42.9%, the median progression-free survival (mPFS) was 5.8 months, and the median overall survival (mOS) was 11.9 months;
Cohort B (a cohort of patients who are receiving second-line or subsequent treatment and are resistant to immune checkpoint inhibitors), the ORR was 6.1 %, the mPFS was 3.0 months, and mOS was 8.8 months.
The results show that anti-tumor effects were observed in a certain proportion of patients in each cohort. Appendix 2 discloses in the Conclusion section that "[f]utibatinib plus pembrolizumab/chemotherapy demonstrated antitumor activity exceeding historical efficacy data for 1st line pembrolizumab/chemotherapy in 1st line advanced or metastatic EC (70% ORR vs 45% ORR in KEYNOTE 590)" and that "[f]utibatinib plus pembrolizumab showed encouraging anti-tumor activity in patients with ICI-naive, advanced or metastatic EC ( 43% ORR)," indicating that the combined use of futibatinib and pembrolizumab is useful.
In response, the Applicant's arguments filed 8/25/2025 have been fully considered but they are not persuasive. The results of Ooki are not commensurate in scope with currently claimed invention to show unexpected results. MPEP 716.02(d) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). The surprising results of Ooki encompasses a method of treating an esophageal cancer tumor in a patient comprising administering 20 mg of (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one once a day and 200 mg pembrolizumab in 3 week intervals. The current claims do not claim the surprising subject matter in a single embodiment.
Claims 11, 15-17, 19-20, and 39-48 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017150725 (Miura A et al. reference of record), Sweis RF et al. (Cancer Immunol Res. 2016 4(7): 563–568 reference of record), US 20170145102 (Pierce K et al. reference of record), and Bellmunt J et al. (N Engl J Med 2017;376:1015-1026 reference of record) as applied to claims 11, 15-17, 19-20, 39-41, 43-45 and 47 above, and further in view of Chen B et al. (Cancer Biol Ther. 2017 Dec 19;19(1):76–86.), Shah MA et al. (JAMA Oncol 2019;5;(4):546-550 Published Online December 20, 2018), Liu L et al. (Cellular Physiology and Biochemistry (2014) 33 (3): 633–645 reference of record), and Katoh M et al. (Int J Mol Med. 2016 38(1):3-15.).
Miura is described above.
Miura further taught a compound of formula (I), which includes compound 1, and a molecularly targeted drug (page 7, paragraph 26) for treatment of esophageal cancer (page 7, paragraph 28), wherein malignant esophageal cancer was a preferable cancer for combination treatment of the invention (page 19, paragraphs 104-106), and wherein the other compound having antitumor effects as a molecularly targeted drug of an immune checkpoint inhibitor (page 18, paragraph 92), wherein pembrolizumab was taught as an example immune checkpoint inhibitor (page 18, paragraph 95). Miura taught combination therapy with compound 1 showed synergistic cell death regardless of the mechanism of action of the chemotherapeutic agent in human urothelial cancer cells, breast cancer cells, lung cancer cells, ovarian cancer cells, and gastric cancer cells (page 30, paragraph 206 and 7A-B).
Miura did not teach: 1) a single embodiment of combination treatment with the FGFR inhibitor futibatinib and the immune checkpoint inhibitor pembrolizumab in esophageal cancer; 2) the tumor being treated having resistance to immune checkpoint inhibitors; and 3) the patient not previously receiving immune checkpoint inhibitors, but this is obvious in view of Chen, Shah, Liu and Katoh.
Chen taught FGFR1 gene expression predicted worse overall survival in esophageal cancer in humans and administration of an agent that blocked FGFR-1 signaling, PD173074, caused a potent esophageal cancer growth arresting effect (abstract).
Shah taught 200 mg pembrolizumab was administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer that were previously treated with other therapeutics (abstract). Shah taught pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer (abstract). Shah taught patients were excluded from pembrolizumab treatment if they received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 immune checkpoint inhibitors (page Supplement 1, page 31, exclusion criteria #6).
Liu taught immunological function of MDSCs is to suppress T-cells proliferation (page 643, paragraph 2). Liu taught treatment with the FGFR inhibitor AZD4547 decreased the number of MDSCs in the spleen and peripheral blood mononuclear cells in tumor bearing subjects (page 643, paragraph 2). Liu taught AZD4547 strikingly reduced the expansion of MDSCs, resulting in increased CD4+ and CD8+ T-cells responses in tumor bearing subjects (page 643, paragraph 2).
Katoh taught cancer immunity and immune tolerance in the tumor microenvironment are regulated by the interaction between cancer cells and immune cells, wherein A) CD8+ T cells, NK cells and NKT cells are immune effector cells involved in tumor elimination; and B) myeloid-derived suppressor cells (MDSCs), tumor-associating macrophages of M2 type (M2-TAMs) and regulatory T (Treg) cells are immune modifier cells involved in immune evasion and tumor growth (page 10, left column, second paragraph). Katoh taught treatment of subjects with cancer with an inhibitor of the FGFR family, BGJ398, results in tumor regression and disappearance of MDSCs (page 10, left column, third paragraph). Katoh taught treatment of subjects with cancer with an inhibitor of the FGFR family, AZD4547 treatment inhibits the proliferation and metastasis of cancer cells, and reduces MDSCs in the tumor microenvironment and systemic circulation (page 10, left column, third paragraph). Katoh taught FGFR inhibitors induce the reduction or disappearance of MDSCs from the tumor microenvironment, partly by targeting cytokine-producing CAFs (page 10, left column, third paragraph).
Regarding instant claims 42, 46, and 48, it would have been obvious for a person having ordinary skill in the art to take the method of Miura, Sweis, Pierce, and Bellmunt above of a method of treatment for a human bladder urothelial cancer patient with genetic aberration of FGFR by administering (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib, in combination with the immune checkpoint inhibitor pembrolizumab in an effective amount to inhibit tumor growth, wherein the patient is administered 4 - 50 mg futibatinib daily, which overlaps with 20 mg daily, and 200 mg pembrolizumab every three weeks
– and 1) treat esophageal cancer as taught by Miura; 2) treat an esophageal tumor having resistance to immune checkpoint inhibitors because FGFR inhibitors were taught to decrease the number of MDSC that were circulating and in the tumor microenvironment by Liu and Katoh; and 3) treat an esophageal tumor wherein the patient had not previously received immune checkpoint inhibitors as pembrolizumab was taught by Shah to be effective in cancers not previously administered checkpoint inhibitors and decrease of MDSC by FGFR inhibitors as described by Liu and Katoh would further be helpful for patients not previously administered immune checkpoint inhibitors.
This is obvious because:
1a) Miura taught treatment of esophageal cancer and that futibatinib is effective in several types of cancer; 1b) Chen taught FGFR1 gene expression predicted worse overall survival in esophageal cancer in humans and administration of an agent that blocked FGFR-1 signaling, PD173074, caused a potent esophageal cancer growth arresting effect. Thus, FGFR inhibitors are known to be effective against esophageal cancer; 1c) Shah taught 200 mg pembrolizumab administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer, wherein the patients were not previously administered anti-PD-1, anti-PD-L1, or anti-PD-L2 immune checkpoint inhibitors. Thus, pembrolizumab is known to be effective against esophageal cancer;
2a) FGFR inhibitors are known to decrease the number of MDSCs in the tumor microenvironment, spleen and peripheral blood mononuclear cells in tumor bearing subjects and MDSCs are no longer able to suppress CD4+ and CD8+ T-cells responses as taught by Katoh and Liu.
2b) Pierce taught in vivo administration with an anti-FGFR2 antibody results in an increase in NK cells, T cells and an increase in PD-L1 expressing cells within tumor tissue, with infiltration of CD3, CD8 and CD4 positive T cells within the tumor center. Thus, FGFR inhibitors are known to decrease tumor promoting MDSC and increase tumor killing NK and T cells, which would decrease checkpoint inhibitor resistance of cancers by increasing the number of tumor killing cells within the tumor and decreasing tumor promoting MDSC;
3) Shah taught 200 mg pembrolizumab administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer, wherein the patients were not previously administered anti-PD-1, anti-PD-L1, or anti-PD-L2 immune checkpoint inhibitors. Further, decrease of MDSC by FGFR inhibitors as described by Liu and Katoh would further be helpful for patients not previously administered immune checkpoint inhibitors
This would produce a method of treatment for human patients with esophageal cancer (instant claim 42) with genetic aberration of FGF3 that either i) had not previously been administered immune checkpoint inhibitors (instant claim 46); or ii) had intrinsic tumor resistance to immune checkpoint inhibitor administration (instant claim 48), by administering (S) -1- (3- (4-amino-3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one, which is also known as futibatinib, in combination with the immune checkpoint inhibitor pembrolizumab in an effective amount to inhibit tumor growth, wherein the patient is administered 4 - 50 mg futibatinib daily, which overlaps with 20 mg daily, and 200 mg pembrolizumab every three weeks. This method would naturally result in a sustained response in an individual after cessation of treatment. This method would be required to be administered either before, simultaneously with, or after pembrolizumab; and futibatinib would be required to be administered continuously or intermittently. This method would further comprise administering the combination with one therapeutic regimen because the instant specification defines one therapeutic regimen to include combination therapy together or separately (instant specification, page 35, paragraph 123).
There is a reasonable expectation of success because:
1a) Miura taught that futibatinib is effective against several types of cancer; 1b) Chen taught FGFR1 gene expression predicted worse overall survival in esophageal cancer in humans and administration of an agent that blocked FGFR-1 signaling, PD173074, caused a potent esophageal cancer growth arresting effect. Thus, FGFR inhibitors are known to be effective against esophageal cancer; 1c) Shah taught 200 mg pembrolizumab administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer, wherein the patients were not previously administered anti-PD-1, anti-PD-L1, or anti-PD-L2 immune checkpoint inhibitors. Thus, pembrolizumab is known to be effective against esophageal cancer. Thus, the combination would be expected to be effective against esophageal cancer;
2a) FGFR inhibitors are known to decrease the number of MDSCs in the tumor microenvironment, spleen and peripheral blood mononuclear cells in tumor bearing subjects and MDSCs are no longer able to suppress CD4+ and CD8+ T-cells responses as taught by Katoh and Liu.
2b) In vivo administration with an anti-FGFR2 antibody results in an increase in NK cells, T cells and an increase in PD-L1 expressing cells within tumor tissue, with infiltration of CD3, CD8 and CD4 positive T cells within the tumor center. Thus, FGFR inhibitors are known to decrease tumor promoting MDSC and increase tumor killing NK and T cells, which would decrease checkpoint inhibitor resistance of cancers by increasing the number of tumor killing cells within the tumor and decreasing tumor promoting MDSC. The effects of the FGFR inhibitors would be expected to affect NK cells, T cells, and MDSC in esophageal cancers as well;
3) Shah taught 200 mg pembrolizumab administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer, wherein the patients were not previously administered anti-PD-1, anti-PD-L1, or anti-PD-L2 immune checkpoint inhibitors. Thus, pembrolizumab is known to be effective against esophageal cancer not previously treated with immune checkpoint inhibitors. Further, decrease of MDSC by FGFR inhibitors as described by Liu and Katoh would also be helpful for patients not previously administered immune checkpoint inhibitors to promote immune cell killing of cancer cells. Thus, the MDSCs cells would still be inhibited by the combination therapy and the combination would be expected to be effective against esophageal cancer that were either previously treated with immune checkpoint inhibitors or not.
Response to Arguments
Applicant has amended the independent claim 11 and claim 20 and added new claims 39-48.
The rejection has been updated to include the amended and new subject matter above. The discussion of surprising results is also discussed in the Response to Arguments above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 11, 15-17, 19-20, and 39-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22-27, 33-35, 41-46, 51-53, 59-64, 69-71, and 77-82 of copending Application No. 17/434,573 in view of Shah MA et al. (JAMA Oncol 2019;5;(4):546-550 Published Online December 20, 2018).
‘573 taught a method of treating a tumor with resistance to an immune checkpoint inhibitor comprising administering a therapeutically effective amount of 20 mg of (S)-1-(3-(4-amino-3- ((3,5-dimethoxyphenyl)ethynyl)-iH-pyrazolo[3,4-d]pyrimidin-i-yl)pyrrolidin-1-yl)prop-2-en-i-one and a therapeutically effective amount of an immune checkpoint inhibitor, that is not pembrolizumab, to a cancer patient with resistance to immune checkpoint inhibitors, (pending claim 22), wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist (pending claims 23-24), wherein the PD-1 pathway antagonist is an anti-PD-1 antibody (pending claim 25-26), wherein the antibody is nivolumab (pending claims 27), wherein treatment with the antitumor agent results in a sustained response in an individual after cessation of the treatment (pending claim 33), wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one is used before, simultaneously with, or after the immune checkpoint inhibitor (pending claim 34) or is used continuously or intermittently (pending claim 35), wherein the cancer is esophageal cancer (pending claim 78).
‘573 taught a method of treating a tumor in a cancer patient comprising administering a therapeutically effective amount of 20 mg of (S)-1-(3-(4-amino-3- ((3,5-dimethoxyphenyl)ethynyl)-iH-pyrazolo[3,4-d]pyrimidin-i-yl)pyrrolidin-1-yl)prop-2-en-i-one and a therapeutically effective amount of an immune checkpoint inhibitor, that is not pembrolizumab, to a cancer patient that has not previously been administered immune checkpoint inhibitors, (pending claim 41), wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist (pending claims 42-43), wherein the PD-1 pathway antagonist is an anti-PD-1 antibody (pending claim 44-45), wherein the antibody is nivolumab (pending claims 46), wherein treatment with the antitumor agent results in a sustained response in an individual after cessation of the treatment (pending claim 51), wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one is used before, simultaneously with, or after the immune checkpoint inhibitor (pending claim 52) or is used continuously or intermittently (pending claim 53), wherein the cancer is esophageal cancer (pending claim 80).
‘573 taught a method of treatment with a combination of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one and a PD-1 pathway antagonist is an anti-PD-1 antibody, but ‘573 did not teach pembrolizumab as the anti-PD-1 antibody, but this is obvious in view of Shah.
Shah taught 200 mg pembrolizumab was administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer that were previously treated with other therapeutics (abstract). Shah taught pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer (abstract). Shah taught patients were excluded from pembrolizumab treatment if they received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 immune checkpoint inhibitors (page Supplement 1, page 31, exclusion criteria #6).
Regarding instant claims 11, 15-17, 19-20, 39-48, it would have been obvious for a person having ordinary skill in the art to take the method of ‘573 in pending claims 22-27, 33-35, 41, and 78 for:
a method of treating: i) a tumor with resistance to an immune checkpoint inhibitor; or ii) a cancer patient that has not previously been administered immune checkpoint inhibitors, (pending claim 41) comprising administering a therapeutically effective amount of 20 mg of (S)-1-(3-(4-amino-3- ((3,5-dimethoxyphenyl)ethynyl)-iH-pyrazolo[3,4-d]pyrimidin-i-yl)pyrrolidin-1-yl)prop-2-en-i-one and a therapeutically effective amount of an immune checkpoint inhibitor, that is not pembrolizumab, to a cancer patient with resistance to immune checkpoint inhibitors, (pending claim 22), wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist (pending claims 23-24), wherein the PD-1 pathway antagonist is an anti-PD-1 antibody (pending claim 25-26), wherein the antibody is nivolumab (pending claims 27), wherein treatment with the antitumor agent results in a sustained response in an individual after cessation of the treatment (pending claim 33), wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one is used before, simultaneously with, or after the immune checkpoint inhibitor (pending claim 34) or is used continuously or intermittently (pending claim 35), wherein the cancer is esophageal cancer (pending claim 78).
– and 1) exchange nivolumab in the treatment method for pembrolizumab and dose the pembrolizumab with 200 mg every three weeks.
This is obvious with a reasonable expectation of success because copending claim 22 taught administration of a PD-1 inhibitor in combination with 20 mg futibatinib and: 1) Shah taught 200 mg pembrolizumab was administered intravenously every 3 weeks to patients with advanced, metastatic esophageal cancer that were previously treated with other therapeutics and provided durable antitumor activity with manageable safety in patients with esophageal cancer.
This would produce a method of treating an esophageal tumor (instant claims 20, 42, 44, and 47-48 ) with either i) immune checkpoint resistance or ii) that has not previously been administered immune checkpoint inhibitors (instant claims 43, and 45-46), in a patient comprising:
administering 20 mg of (S)-1-(3-(4-amino-3- ((3,5-dimethoxyphenyl)ethynyl)-iH-pyrazolo[3,4-d]pyrimidin-i-yl)pyrrolidin-1-yl)prop-2-en-i-one, also known as futibatinib, in combination with 200 mg of the immune checkpoint inhibitor, pembrolizumab, every three weeks, wherein treatment with the antitumor agent results in a sustained response in an individual after cessation of the treatment (instant claim 39), wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one is used before, simultaneously with, or after the immune checkpoint inhibitor (instant claim 15) or is used continuously or intermittently (instant claim 16), wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one and the immune checkpoint inhibitor are administered in treatment with one therapeutic regimen (instant claim 17), (instant claims 11, 19, and 40-41)
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant has amended the independent claim 11 and claim 20 and added new claims 39-48.
The rejection has been updated to include the amended and new subject matter above. The discussion of surprising results is also discussed in the Response to Arguments in the 103 rejection of claims 11, 15-17, 19-20, 39-41, 43-45 and 47 above.
Conclusion
No claims are allowable.
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