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 .
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 – 2, 4 – 7, 9, 27 – 30, 33 – 45, and 48 – 53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079) as evidenced by National Center for Biotechnology Information (2026). PubChem Compound Summary for CID 71621331, Futibatinib. Retrieved April 3, 2026 from https://pubchem.ncbi.nlm.nih.gov/compound/Futibatinib.
Regarding claims 1 – 2, 4 – 7, 9, 27 – 30, 33 – 45, and 48 – 53, Goyal et. al. teach that intrahepatic cholangiocarcinoma (ICC) (claims 1, 31, 39, 45, and 52) is an aggressive malignancy of the liver bile ducts with poor outcomes and rising incidences (page 2 paragraph 1). Goyal et. al. teach that the standard of care, which is palliative chemotherapy with gemcitabine and cisplatin, only offers patients with ICC a median survival of less than one year (page 3 paragraph 1). Thus Goyal et.al. suggest the need for improved treatment options for patients suffering from ICC that can extend the median survival. Moreover, Goyal et. al. teach that ICCs exhibit an array of genomic alterations of known oncogenic drivers and tumor suppressors, suggesting the potential for targeted therapies for subsets of patients (page 3 paragraph 1) that carry these genomic alterations. Furthermore, Goyal et. al. teach that the 3rd generation irreversible FGFR inhibitor TAS-120, is (S)-1-[(3)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one (claims 1, 39, and 52) as evidenced by PubChem, covalently binds to a highly conserved P-loop cysteine residue in the ATP pocket of FGFR (C492 in the FGFR2-IIIb isoform)(page 3 paragraph 3).
Additionally, Goyal et. al. teach that TAS-120 exhibits an in vitro potency at low nanomolar concentrations and has high specificity against wild-type FGFR1–4 as well as against some FGFR2 kinase domain mutations (page 3 paragraph 3). And Goyal et. al. teach that preliminary results, from a phase I basket study of TAS-120 in patients with refractory advanced solid tumors, showed an objective response rate (ORR) of 25.0% and a disease control rate (DCR) of 78.6% in 28 patients with ICC harboring FGFR2 fusions (instant claims 1, 39, and 52), including some patients who had received prior therapy with other ATP-competitive FGFR inhibitors (page 3 paragraph 3).
Specifically, Goyal et. al. teach that among the six patients with advanced FGFR2 fusion-positive ICC (claims 1 – 2, 4, 39, 41, 45, and 52) who received care after treatment with BGJ398 or Debio1347, other ATP-competitive FGFR inhibitors, four patients subsequently enrolled in the phase I trial of TAS-120 to received secondary treatment (page 4 paragraph 2). Moreover, Goyal et. al. teach that each of the four patients showed benefit after TAS-120 treatment with two of the patients achieving a partial response and the other two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of 5.1 to 17.2 months (page 4 paragraph 2). Goyal et. al. teach that no additional cancer-relevant genomic alterations were detected in the pre-treatment biopsies (claim 29), with the exception of copy number increases of the FGFR1 and MYC loci (claim 1, 9, and 27 – 28) in the biopsy from patient #3 (page 4 paragraph 2). Thus, Goyal et. al. teach that patient 3 had ICC that was not only FGFR2 fusion positive but also had the cancer driver gene MYC (instant claim 1). Moreover, Goyal et. al. Goyal et. al. teach that genetic alterations were screened before the administration of TAS-120 as recited in claim 29.
Specifically, Goyal et. al. teach that patient 3 is a 28-year-old male with Crohn’s disease and FGFR2-INA (claims 5, 41 – 42, and 52) fusion-positive ICC who presented with a 5.4 cm liver mass concurrently with liver, lung, peritoneal, and lymph node metastases (page 4 paragraph 2). Moreover, Goyal et. al. teach that patient 3 has undergone treatment with gemcitabine/docetaxel, T11 palliative radiation (claims 33 – 34, 48 – 49, and 53) prior to the administration of TAS-120 (page 29 Table 1A). Additionally, Goyal et. al. teach that patient 3 achieved a maximum response of −22% with the TAS-120 treatment, that was administered orally (claims 35, 39, and 50 – 52) at 20 mg of TAS-120 once a day (claims 36 – 37, 39, and 52) for days 1 – 21 in a 21 day cycle (claims 38, 39, and 52) (page 12 paragraph 2). Furthermore, Goyal et. al. teach that patient 3 exhibited disease progression at 5.1 months with a mixed response in the liver and growth of lung and bone lesions (page 4 paragraph 2).
Furthermore, Goyal et. al. teach that in an in vivo patient-derived xenograft (PDX) model of ICC for FGFR alterations, the model harbored a FGFR2-KIAA1217 fusion (claims 6 – 7, and 43 – 44) (designated MG69) (Supplemental Figure S1G) and was treated with TAS-120 (starting when the volume reached ~500 mm3) leading to tumor regression and complete proliferative arrest, with prominent effects evident within three days and persisting over a 14-day course (Figure 2E, F) (page 7 paragraph 2).
Claims 39 – 41, 45, 48, and 50 – 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1) as evidenced by National Center for Biotechnology Information (2026). PubChem Compound Summary for CID 71621331, Futibatinib. Retrieved April 3, 2026 from https://pubchem.ncbi.nlm.nih.gov/compound/Futibatinib.
Regarding claims 39 – 41, 45, 48, and 50 – 52, Meric-Bernstam et. al. teach that TAS-120, is (S)-1-[(3)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one as evidenced by PubChem, is an oral administered (claims 39 and 52) and highly selective, irreversible FGFR1-4 tyrosine kinase inhibitor, that has demonstrated inhibition of cancer cell growth in human xenografts of tumors bearing FGFR aberrations (page 1 paragraph 1). Specifically, Meric-Bernstam et. al. teach that TAS-120 was administered to adult patients with cholangiocarcinoma (CCA) (claim 39) at 16 mg, 20 mg (claims 39 and 51), and 24 mg (claim 50) once a day over the course of the therapy (page 1 paragraph 2). Meric-Bernstam et. al. teach that patients were treated with TAS-120 until disease progression or unacceptable toxicity was reached (page 1 paragraph 2) with a median time of treatment of 7.4 months to ongoing (page 1 paragraph 3). Now while Meric-Bernstam et. al. does not specifically state 21 days, Meric-Bernstam et. al. does teach that the median time of treatment was 7.4 months; thus, one of ordinary skill in the art can envisage that TAS-120 was administered for at least 21 days and as such anticipates claims 39 and 52 for a method of treatment over a 21 day cycle. Moreover, Meric-Bernstam et. al. teach that of the 45 patients with CCA 41 patients had intrahepatic CCA (claims 45 and 52) (page 1 paragraph 3).
Furthermore, Meric-Bernstam et. al. teach that patients with CCA which was 28 patients (62%) had FGFR2 gene fusions (claims 41 and 52) and 17 (38%) had other FGF/FGFR aberrations, such as mutations, amplifications, and re-arrangements (claims 40) (page 1 paragraph 3). Additionally, Meric-Bernstam et. al. teach that all patients had received prior systemic therapies (claims 48 and 52) and 13 patients had received at least one prior reversible FGFR inhibitor (claim 48) (page 1 paragraph 3). Moreover, Meric-Bernstam et. al. teach that of the 28 patients with FGFR2 gene fusions, 20 (71%) experienced tumor shrinkage and seven achieved confirmed partial response (cPR) with six of the seven patients remaining on treatment, including one patient with an ongoing cPR of > 1 year (page 1 paragraph 3). Meric-Bernstam et. al. teach that the overall disease control rate was 79% (page 1 paragraph 3). Additionally, Meric-Bernstam et. al. teach that out of 17 patients with other FGF/FGFR aberrations, three had cPR (two with FGFR2 re-arrangement and one with co-expression of FGFR2 re-arrangement and amplification) (page 1 paragraph 3). Furthermore, Meric-Bernstam et. al. teach that out of 13 patients who had received prior FGFR inhibitors (claim 52), four (three with FGFR2 gene fusions and one with FGFR2 amplification) had cPR on TAS-120 (page 1 paragraph 3).
Claim Rejections - 35 USC § 103
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.
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 42 – 44, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1) as applied to claims 39 – 41, 45, 48, and 50 – 52 above, and further in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079).
The teachings of Meric-Bernstam et. al. as they relate to claims 39, from which claims 42 – 44, and 49 depend, are given previously in this office action and are fully incorporated here.
While the prior art of Meric-Bernstam et. al. taught that all patients had received prior systemic therapies with 13 patients having received at least one prior reversible FGFR inhibitor (page 1 paragraph 3); the prior art is silent about a method wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin (claim 49). Moreover, Meric-Bernstam et. al. fails to teach a method wherein the FGFR2 fusion is selected from the group consisting of FGFR2-KIAA1217 (claims 42 – 44).
Nevertheless, Goyal et. al. teach that intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the liver bile ducts with poor outcomes and rising incidences (page 2 paragraph 1). Goyal et. al. teach that the standard of care, which is palliative chemotherapy with gemcitabine and cisplatin, only offers patients with ICC a median survival of less than one year (page 3 paragraph 1). Thus Goyal et.al. suggest the need for improved treatment options for patients suffering from ICC that can extend the median survival. Moreover, Goyal et. al. teach that ICCs exhibit an array of genomic alterations of known oncogenic drivers and tumor suppressors, suggesting the potential for targeted therapies for subsets of patients (page 3 paragraph 1) that carry these genomic alterations. Furthermore, Goyal et. al. teach that the 3rd generation irreversible FGFR inhibitor TAS-120, is (S)-1-[(3)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one as evidenced by PubChem, covalently binds to a highly conserved P-loop cysteine residue in the ATP pocket of FGFR (C492 in the FGFR2-IIIb isoform)(page 3 paragraph 3).
Additionally, Goyal et. al. teach that TAS-120 exhibits an in vitro potency at low nanomolar concentrations and has high specificity against wild-type FGFR1–4 as well as against some FGFR2 kinase domain mutations (page 3 paragraph 3). And Goyal et. al. teach that preliminary results, from a phase I basket study of TAS-120 in patients with refractory advanced solid tumors, showed an objective response rate (ORR) of 25.0% and a disease control rate (DCR) of 78.6% in 28 patients with ICC harboring FGFR2 fusions, including some patients who had received prior therapy with other ATP-competitive FGFR inhibitors (page 3 paragraph 3).
Specifically, Goyal et. al. teach that among the six patients with advanced FGFR2 fusion-positive ICC who received care after treatment with BGJ398 or Debio1347, other ATP-competitive FGFR inhibitors, four patients subsequently enrolled in the phase I trial of TAS-120 to received secondary treatment (page 4 paragraph 2). Moreover, Goyal et. al. teach that each of the four patients showed benefit after TAS-120 treatment with two of the patients achieving a partial response and the other two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of 5.1 to 17.2 months (page 4 paragraph 2). Goyal et. al. teach that no additional cancer-relevant genomic alterations were detected in the pre-treatment biopsies, with the exception of copy number increases of the FGFR1 and MYC loci in the biopsy from patient #3 (page 4 paragraph 2).
Specifically, Goyal et. al. teach that patient 3 is a 28-year-old male with Crohn’s disease and FGFR2-INA fusion-positive ICC who presented with a 5.4 cm liver mass concurrently with liver, lung, peritoneal, and lymph node metastases (page 4 paragraph 2). Moreover, Goyal et. al. teach that patient 3 has undergone treatment with gemcitabine/docetaxel, T11 palliative radiation (claim 49) prior to the administration of TAS-120 (page 29 Table 1A). Additionally, Goyal et. al. teach that patient 3 achieved a maximum response of −22% with the TAS-120 treatment, that was administered orally at 20 mg of TAS-120 once a day for days 1 – 21 in a 21 day cycle (page 12 paragraph 2). Furthermore, Goyal et. al. teach that patient 3 exhibited disease progression at 5.1 months with a mixed response in the liver and growth of lung and bone lesions (page 4 paragraph 2).
Furthermore, Goyal et. al. teach that in an in vivo patient-derived xenograft (PDX) model of ICC for FGFR alterations, the model harbored a FGFR2-KIAA1217 fusion (claims 42 – 44) (designated MG69) (Supplemental Figure S1G) and was treated with TAS-120 (starting when the volume reached ~500 mm3) leading to tumor regression and complete proliferative arrest, with prominent effects evident within three days and persisting over a 14-day course (Figure 2E, F) (page 7 paragraph 2).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Meric-Bernstam et. al., that is for treating patients with ICC with a FGFR2 fusion mutation using TAS-120 in view of Goyal et. al., that is to administer TAS-120 in a method of treating a patient with ICC that has previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only have a median survival of less than one year. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 months.
Claims 17 – 18, 21 – 22, 31, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079) as applied to claims 1 – 2, 4 – 7, 9, 27 – 30, 33 – 39, 40 – 45, and 48 – 53 above, and further in view of Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327) and evidenced by Wikipedia (2026). KMT2D. Retrieved April 3, 2026 from https://en.wikipedia.org/wiki/KMT2D.
The teachings of Goyal et. al. as they relate to claims 1 and 39, from which claims 17 – 18, 21 – 22, 31, and 46 depend, are given previously in this office action and are fully incorporated here.
However the prior art of Goyal et. al. fail to teach a method for treating a subject with cholangiocarcinoma wherein the cholangiocarcinoma is extrahepatic cholangiocarcinoma (claims 31 and 46). Moreover, Goyal et. al. fail to teach a method for treating CCA with a FGFR2 gene fusion or arrangement with a cancer driver gene wherein the cancer driver gene is MLL2 (claim 17) further wherein the genetic alteration in MLL2 is a short-variant mutation (claim 18) or the cancer driver gene is IKBKE (claim 21) further wherein the genetic alteration in IKBKE is a short-variant mutation or a copy-number alteration (claim 22).
Nevertheless, Montal et. al. teach that cholangiocarcinoma (CCA) has been classified as either intrahepatic (iCCA) or extrahepatic (eCCA) (claims 31 and 46), with the second-order bile ducts acting as the separation point between iCCa and eCCA. And Montal et. al. teach that eCCA can be further divided into perihilar (pCCA) and distal (dCCA) depending on whether they originate above or below the cystic duct (page 316 column 1 paragraph 1). Furthermore, Montal teach that currently there are no molecular targeted therapies that have demonstrated survival benefits in eCCA, which may be due in part to the limited understanding of the biological mechanisms driving recurrence (page 317 paragraph 2). Consequently, Montal teach the need for a comprehensive molecular characterization of a large cohort of clinically annotated patients with eCCA (n = 189) at both genomic and transcriptomic levels, to expose major structural genomic alterations in eCCA driving recurrence, and to reveal novel molecular targets with potential therapeutic implications (page 317 column 1 paragraph 4).
Montal et. al. teach that KMT2D, which is MLL2 (claim 17) as evidenced by Wikipedia, has an alteration frequency in eCCA of about 1% that is frameshift indel (claim 18) (page 320 Figure 1. A). Additionally, Montal et. al. teach that IKBKE (claim 19) has an alteration frequency in eCCA of about 1 % that is missense (claim 20) (page 320 Figure 1. A). Thus Montal et. al. teach that even though both KMT2D and IKBKE occur at lower frequency levels both are still cancer driver genes that were detected in the eCCA samples collected and are potential molecular targets for therapeutics.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Goyal et. al., that is for a method of treating eCCA patients with FGFR2 fusion by administering TAS-120 in view of Montal et. al. that is for the treatment of an CCA with FGFR2 fusion combined with the cancer driver gene KMT2D or IKBKE. One of ordinary skill in the art would have been motivated to make this modification because both KMT2D and IKBKE are structural genomic alterations in eCCA. One of ordinary skill in the art would have a reasonable expectation of success because both are two of the major structural genomic alterations identified in eCCA samples driving recurrence.
Claims 3, 8, 10 – 16, 19 – 20, 23 – 26, 32, 40, and 47, are rejected under 35 U.S.C. 103 as being unpatentable over Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079) as applied to claims 1 – 2, 4 – 7, 9, 27 – 30, 33 – 45, and 48 – 53 above, and further in view of Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025).
The teachings of Goyal et. al. as they relate to claims 1 and 39, from which claims 3, 8, 10 – 16, 19 – 20, 23 – 26, 32, 40, and 47 depend, are given previously in this office action and are fully incorporated here.
However the prior art of Goyal et. al. fail to teach a method for treating a subject with cholangiocarcinoma wherein the cholangiocarcinoma is unresectable (claims 32 and 47). Also Goyal et. al. fail to teach a method wherein the genetic alteration in FGFR2 is a FGFR2 rearrangement (claims 3 and 40). Additionally, Goyal et. al. fail to teach a method wherein the cancer driver gene is TP53 (claims 8 and 11) with a short-variant mutation (claim 12); BAP1 (claims 8, 10, and 13) with either a short-variant mutation or a copy-number alteration (claim 14); ARID1A (claims 8, 10, 15) with a short-variant mutation (claim 16); PIK3C2B (claim 19) with either a short-variant mutation or a copy-number alteration (claim 20); MCL1 (claim 23) with a copy-number alteration (claim 24); or MDM4 (claim 25) with either a short-variant mutation or a copy-number alteration (claim 26).
Nevertheless, Silverman et. al. teach that Cholangiocarcinoma (CCA) is the most common primary malignancy of the bile duct and accounts for 3% of all gastrointestinal tumors (page 327 column 1 paragraph 1). Thus Silverman et. al. suggest in a broader sense that cholangiocarcinoma is a species of cancers involving the bile duct. Additionally, Silverman et. al. teach that the prognosis of patients with cholangiocarcinoma is poor; with surgery as the only potentially curative therapeutic option page 327 column 1 paragraph 1). However, Silverman et. al. teach that most newly diagnosed patients present with advanced stages of the disease and as such only approximately one third of newly diagnosed patients qualify for surgery (page 327 column 1 paragraph 1). Furthermore, Silverman et.al. teach that among patients who are qualified to undergo potentially curative resection, most (∼76%) will experience a relapse within 2 years (page 327 column 1 paragraph 1).Thus, Silverman et. al. suggest that there is a number of patients suffering from CCA that either has unresectable (claims 32 and 47) CCA because it was diagnosed too late or recurring CCA.
Furthermore, Silverman et. al. teach that genomic profiling, based on next-generation sequencing (NGS) of a panel of genes known to be altered in cancer; allows for the simultaneous detection of numerous genomic alteration (GA) types, including mutations, copy-number alterations, and fusions or rearrangements (page 327 column 2 paragraph 2). Additionally, Silverman et. al. teach that the technique of NGS provides a powerful basis for guiding the choice of targeted therapy, improving diagnosis, and identifying prognostic and predictive biomarkers (page 327 column 2 paragraph 2). Silverman et. al. also teach that genomic analysis of patients with cholangiocarcinoma has revealed alterations of targetable oncogenes in almost 50% of patients; with recurrent alterations in IDH1 and FGFR2 occurring almost exclusively in patients with intrahepatic cholangiocarcinoma (ICCA) compared with extrahepatic cholangiocarcinoma (ECCA) (page 327 column 2 paragraph 2).
Moreover, Silverman et. al. teach that FGFR2 fusions or rearrangements (claims 3 and 40) are observed in 10 to 16% of patients with ICCA (page 327 column 2 paragraph 2). Additionally, Silverman et. al. teach that in the Fibroblast Growth factor receptor inhibitor in oncology and Hematology Trial (FIGHT-202; NCT02924376), a phase II multicenter open-label study of Pemigatinib, an oral FGFR1-3 inhibitor, was administered as a monotherapy to previously treated patients, with locally advanced, metastatic, or surgically unresectable cholangiocarcinoma (claims 32 and 47), included patients with FGFR2 fusions or rearrangements (claims 3 and 40) (page 327 column 2 paragraph 3 and page 328 column 1 paragraph 1).
Furthermore, Silverman et. al. teach that the primary analysis of 107 patients from the study, included patients the only harbored FGFR2 fusions or rearrangements (page 328 column 1 paragraph 1). Moreover, Silverman et. al. teach that the administration of Pemigatinib as a monotherapy to these primary 107 patients, resulted in an independent centrally confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months, and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6) months (page 328 column 1 paragraph 1). Thus Silverman et. al. teach the administration of a FDA approved oral FGFR2 inhibitor, that is Pemigatinib, that was administered to CCA patients with FGFR2 fusions or rearrangements.
Moreover, Silverman et. al. teach that from the total 1,206 patients in the FIGHT-202 study 5,547 genomic alterations (Gas) were identified in 335 genes, accounting for a mean of 4.6 GAs per patient (page 328 column 2 paragraph 2). Specifically, Silverman et. al. teach that of the total 1,206 patients samples taken TP53 (claims 8 and 11) had a total frequency of about 40 % with about 35 % being a short-variant mutation (claim 12); BAP1 (claims 8, 10, and 13) had a total frequency of about 10 % with about 9 % being a short-variant mutation and 1% > a copy-number alteration (claim 14); and ARID1A (claims 8, 10, and 15) had a total frequency of about 15 % with about 15 % being a short-variant mutation (claim 16) (page 329 Figure 1 A).
Additionally, Silverman et. al. teach that in a sub sample of with initial tumor shrinkage followed by progressive disease using available tumor tissue (n = 6) or plasma (n = 2; Table 2) (page 333 column 1 paragraph 3) 8 patients with FGFR2 rearrangements (claim 3) treated with Pemigatinib had genomic profiling completed (page 333 column 1 paragraph 3). Silverman et. al. teach that patient 3 had baseline mutations of PIK3C2B (claim 19) which was an amplified alteration, that is classified as a copy-number alteration (claim 20) (page 334 Table 2). Moreover, Silverman et. al. teach that patient 3 also had a MDM4 (claim 25) genetic alteration that which was an amplified alteration, that is classified as a copy-number alteration (claim 26) (page 334 Table 2). Furthermore, Silverman et. al. teach that patient 7 had a MCL1 (claim 23) genetic alteration that was an amplified alteration, that is classified as a copy-number alteration (claim 24) (page 334 Table 2). Additionally, Silverman et. al. teach that there were considerable advances made into understanding FGFR2 rearrangements, and mechanisms of primary and acquired resistance to Pemigatinib in patients with cholangiocarcinoma; which should serve as a foundation for the advancement of treatment options for these patients (page 337 column 1 paragraph 2).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Goyal et. al. for a method of treating CCA or unresectable CCA in patients with FGFR2 fusion by administering TAS-120 in view of Silverman et. al. that is for the treatment of an CCA with FGFR2 fusion or rearrangement with co-cancer driver genes selected from TP53, BAP1, ARID1A, PIK3C2B, MCL1, or MDM4. One of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success because co-cancer driver genes selected from TP53, BAP1, ARIDIA, PIK3C2B, MCL1, or MDM4 were identified in patients with FGFR2 fusion or rearrangement. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 10 of U.S. Patent No. US 9108973 B2 to Sagara et.al. (herein after Sagara’973) in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079), Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1), Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025), and Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327).
Sagara’973 recite a compound represented by Formula (I)
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or a salt thereof (reference claims 1 – 7). More specifically, Sagara’973 recite the compound according to claim 1 wherein the compound is selected from the following group of compounds that includes (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 (reference claim 8; instant claims 1, 39, and 52). Additionally, Sagara’973 recite a pharmaceutical composition comprising the compound or a salt thereof according to (reference) claim 1, and a pharmacologically acceptable carrier (reference claim 9) and a method for treating a tumor by the inhibition of FGFR comprising administering an effective amount of the compound or a salt thereof according to (reference) claim 1 to a patient in need of such a treatment (reference claim 10).
While, Sagara’973 recites the use of the compounds in method for treating a tumor by inhibiting FGFR; Sagara’973 fails to explicitly recite the use for (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 in a method of treating a subject with cholangiocarcinoma (instant claims 30 – 32) having a co-occurring genetic alteration in FGFR2 (instant claims 2 – 7) and a cancer driver gene selected from the group consisting of TP53, BAP1, ARIDJA, MLL2, PIK3C2B, IKBKE, MCLJ, MDM4, and MYC (instant claims 1, 8 – 28) comprising administering the compound orally (instant claims 35), once a day (instant claims 36 – 37) for at least 21 days (instant claims 38) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 33 – 34); a method of treating a subject with cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 39) at 20 mg (instant claims 50 – 51) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 48 – 49); and a method of treating a subject with previously treated, unresectable, intrahepatic cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 52) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claim 53).
The teachings of Goyal et. al., Meric-Bernstam et. al., Silverman et. al., and Montal et. al. as they relate to the prior art rejections of instant claims 1 – 53, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of Sagara’ 973, that is (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, in view of both Goyal et. al. and Meric-Bernstam et. al., that is in a method for the treating patients with iCCA or eCCA with a FGFR2 fusion mutation or patients with iCCA or eCCA with a FGFR2 fusion mutation and a cancer driver gene that may have previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin and in further view of Silverman et. al., and Montal et. al., that is wherein the cancer driver gene is selected from TP53, BAP1, ARID1A, MLL2, PIK3C2B, IKBKE, MCL1, MDM4, and MYC. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only has a median survival of less than one year.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 month. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
Claims 1 – 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 8 of U.S. Patent No. US 10124003 B2 to Sootome (herein after Sootome’003) in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079), Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1), Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025), and Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327).
Sootome’003 recites a method for treating a tumor patient comprising administering a 3,5-disubstituted benzene alkynyl compound represented by Formula (I) to a patient in need of such treatment:
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or a salt thereof (reference claims 1) wherein the tumor is resistant to at least one FGFR inhibitor selected from the group consisting of ponatinib, regorafenib, intedanib, dovitinib lactate, lenvatinib mesylate, cediranib, oratinib, brivanib alaninate, AZD4547, NVP-BGJ398, sulfatinib, ARQ-087, S-49076, IMCA1, PRO001, and R3Mab (reference claim 2; instant claims 33 and 48); wherein the tumor patient has a mutation at N550, V565, E566, K660 of FGFR2 (reference claims 3 – 6; instant claim 1, 39, and 52). More specifically, Sootome’003 recites the method according to (reference) claim 1 wherein the 3,5-disubstituted benzene alkynyl compound is (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 (reference claim 8; instant claims 1, 39, and 52).
While, Sootome’003 recites the use of the compound in method for treating a tumor; Sootome’003 fails to explicitly recite the use for (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 in a method of treating a subject with cholangiocarcinoma (instant claims 30 – 32) having a co-occurring genetic alteration in FGFR2 (instant claims 2 – 7) and a cancer driver gene selected from the group consisting of TP53, BAP1, ARIDJA, MLL2, PIK3C2B, IKBKE, MCLJ, MDM4, and MYC (instant claims 1, 8 – 28) comprising administering the compound orally (instant claims 35), once a day (instant claims 36 – 37) for at least 21 days (instant claims 38) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 33 – 34); a method of treating a subject with cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 39) at 20 mg (instant claims 50 – 51) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 48 – 49); and a method of treating a subject with previously treated, unresectable, intrahepatic cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 52) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claim 53).
The teachings of Goyal et. al., Meric-Bernstam et. al., Silverman et. al., and Montal et. al. as they relate to the prior art rejections of instant claims 1 – 53, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of Sootome’003, that is for a method of treating a tumor using (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, in view of both Goyal et. al. and Meric-Bernstam et. al., that is in a method for the treating patients with iCCA or eCCA tumors with a FGFR2 fusion mutation or patients with iCCA or eCCA tumors with both a FGFR2 fusion mutation and a cancer driver gene that may have previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin and in further view of Silverman et. al., and Montal et. al., that is wherein the cancer driver gene is selected from TP53, BAP1, ARID1A, MLL2, PIK3C2B, IKBKE, MCL1, MDM4, and MYC. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only has a median survival of less than one year.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 month. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
Claims 1 – 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 9 – 23, and 25 – 31 of U.S. Patent No. US 10835536 B2 to Sootome (herein after Sootome’536) in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079), Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1), Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025), and Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327).
Sootome’536 recites a method of treating a patient having tumor cells resistant to an FGFR inhibitor (reference claims 11 – 15, 22 – 24, and 29 – 30), comprising administering an effective amount of a 3,5-disubstituted benzene alkynyl compound or a salt thereof to the patient, the 3,5-disubstituted benzene alkynyl compound being represented by Formula (I):
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or a salt thereof wherein the effective amount is 0.05 to 1,000 mg for an oral preparation (reference claims 5, 9, and 20; instant claims 35, 39, and 50 – 52), 0.01 to 500 mg for an injection, and 1 to 1,000 mg for a suppository (reference claims 1, 9, 16, and 25); wherein the 3,5-disubstituted benzene alkynyl compound is (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 (reference claims 2, 10, 17, and 26; instant claims 1, 39, and 52); wherein the tumor is resistant to at least one FGFR inhibitor selected from the group consisting of ponatinib, regorafenib, intedanib, dovitinib lactate, lenvatinib mesylate, cediranib, oratinib, brivanib alaninate, AZD4547, NVP-BGJ398, sulfatinib, ARQ-087, S-49076, IMCA1, PRO001, and R3Mab (reference claims 3, 11, 18, and 27; instant claims 33 and 48); wherein the tumor patient has a mutation at N550, V565, E566, K660 of FGFR2 (reference claims 4, 12 – 15, 19, and 28; instant claim 1, 39, and 52).
More specifically, Sootome’536 recites the method according to (reference) claim 1 wherein the patient is diagnosed with cancer selected from the group consisting of gastric cancer, liver cancer, cholangiocarcinoma (reference claim 7, 21, and 31; instant claims 1, 30 – 32, 39, 44 – 46, and 52), breast cancer, head and neck cancer, esophagus cancer, colon cancer, rectum cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma, soft-tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, and mesothelioma (reference claims 6, 16, and 25).
While, Sootome’536 recites the use of the compound in method for treating cholangiocarcinoma; Sootome’536 fails to explicitly recite the use for (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 in a method of treating a subject with cholangiocarcinoma (instant claims 30 – 32) having a co-occurring genetic alteration in FGFR2 (instant claims 2 – 7) and a cancer driver gene selected from the group consisting of TP53, BAP1, ARIDJA, MLL2, PIK3C2B, IKBKE, MCLJ, MDM4, and MYC (instant claims 1, 8 – 28) comprising administering the compound orally (instant claims 35), once a day (instant claims 36 – 37) for at least 21 days (instant claims 38) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 33 – 34); a method of treating a subject with cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 39) at 20 mg (instant claims 50 – 51) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 48 – 49); and a method of treating a subject with previously treated, unresectable, intrahepatic cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 52) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claim 53).
The teachings of Goyal et. al., Meric-Bernstam et. al., Silverman et. al., and Montal et. al. as they relate to the prior art rejections of instant claims 1 – 53, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of Sootome’536, that is for a method for treating cholangiocarcinoma comprising 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, in view of both Goyal et. al. and Meric-Bernstam et. al., that is in a method for the treating patients with iCCA or eCCA with a FGFR2 fusion mutation or patients with iCCA or eCCA with a FGFR2 fusion mutation and a cancer driver gene that may have previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin and in further view of Silverman et. al., and Montal et. al., that is wherein the cancer driver gene is selected from TP53, BAP1, ARID1A, MLL2, PIK3C2B, IKBKE, MCL1, MDM4, and MYC. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only has a median survival of less than one year.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 month. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
Claims 1 – 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4, 6, and 9 – 11 of U.S. Patent No. US 11975002 B2 to Miura et. al. (herein after Miura’002) in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079), Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1), Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025), and Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327).
Miura’002 recite a method for treating a tumor comprising administering a) (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 (instant claim 1, 39, and 52) or a pharmaceutically acceptable salt thereof, and b) one or more additional compound(s) having an antitumor effect or pharmaceutically acceptable salt(s) thereof, selected from the group consisting of tegafur/ gimeracil/oteracil potassium, 5-fluorouracil, gemcitabine, paclitaxel, cisplatin (instant claims 33 – 34, and 48 – 49), everolimus, 8-[4-(1 -aminocyclobutyl)phenyl]-9-phenyl-1 ,2,4-triazolo[3,4-f] [1 ,6]naphthyridin-3(2H)-one, and gefitinib, to a patient in need thereof (reference claim 1); wherein the tumor is selected from the group consisting of lung cancer, esophagus cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer (reference claims 4 and 6; instant claims 1, 39, and 52), pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, and skin cancer (reference claim 3); wherein the tumor to be treated has a mutation in FGFR (reference claim 9; instant claims 1, 39, and 52); wherein the (S)-1-(3-( 4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1 -one or a pharmaceutically acceptable salt thereof, and the additional compound having an antitumor effect or a pharmaceutically acceptable salt thereof are administered simultaneously, separately, or sequentially (reference claim 11).
While Miura’002 recite a method for treating a tumor wherein the tumor is selected from a group that contains biliary tract cancer comprising administering a) (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; Miura’002 fail to explicitly recite the use for (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 in a method of treating a subject with cholangiocarcinoma (instant claims 30 – 32) having a co-occurring genetic alteration in FGFR2 (instant claims 2 – 7) and a cancer driver gene selected from the group consisting of TP53, BAP1, ARIDJA, MLL2, PIK3C2B, IKBKE, MCLJ, MDM4, and MYC (instant claims 1, 8 – 28) comprising administering the compound orally (instant claims 35), once a day (instant claims 36 – 37) for at least 21 days (instant claims 38) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 33 – 34); a method of treating a subject with cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 39) at 20 mg (instant claims 50 – 51) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 48 – 49); and a method of treating a subject with previously treated, unresectable, intrahepatic cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 52) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claim 53).
The teachings of Goyal et. al., Meric-Bernstam et. al., Silverman et. al., and Montal et. al. as they relate to the prior art rejections of instant claims 1 – 53, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of Miura’002, that is for a method for treating a tumor comprising administering a) (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, in view of both Goyal et. al. and Meric-Bernstam et. al., that is in a method for the treating patients with iCCA or eCCA with a FGFR2 fusion mutation or patients with iCCA or eCCA with a FGFR2 fusion mutation and a cancer driver gene that may have previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin and in further view of Silverman et. al., and Montal et. al., that is wherein the cancer driver gene is selected from TP53, BAP1, ARID1A, MLL2, PIK3C2B, IKBKE, MCL1, MDM4, and MYC. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only has a median survival of less than one year.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 month. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
Claims 1 – 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4 and 11 of U.S. Patent No. US 11883404 B2 to Miura et. al. (herein after Miura’404) in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079), Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1), Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025), and Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327).
Miura’404 recite an antitumor agent comprising a) (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 (instant claims 1, 32, and 52) or a pharmaceutically acceptable salt thereof, and b) trans-3-amino-l -methyl-3-( 4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof (reference claim 1). Additionally, Miura’404 recite a method for treating a tumor comprising administering a) (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 (instant claims 1, 32, and 52) or a pharmaceutically acceptable salt thereof, and b) trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof (reference claim 2); wherein the tumor is selected from the group consisting of lung cancer, esophagus cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer (instant claims 1, 39, and 52) pancreatic cancer, colorectal cancer, ovarian cancer, uterine cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, and skin cancer (reference claim 4); wherein the (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or the pharmaceutically acceptable salt thereof, and the trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof are administered simultaneously, separately, or sequentially (reference claim 11).
While Miura’404 recite a method for treating a tumor wherein the tumor is selected from a group that contains biliary tract cancer, comprising administering a) (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; Miura’404 fails to explicitly recite the use 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 in a method of treating a subject with cholangiocarcinoma (instant claims 30 – 32) having a co-occurring genetic alteration in FGFR2 (instant claims 2 – 7) and a cancer driver gene selected from the group consisting of TP53, BAP1, ARIDJA, MLL2, PIK3C2B, IKBKE, MCLJ, MDM4, and MYC (instant claims 1, 8 – 28) comprising administering the compound orally (instant claims 35), once a day (instant claims 36 – 37) for at least 21 days (instant claims 38) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 33 – 34); a method of treating a subject with cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 39) at 20 mg (instant claims 50 – 51) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 48 – 49); and a method of treating a subject with previously treated, unresectable, intrahepatic cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 52) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claim 53).
The teachings of Goyal et. al., Meric-Bernstam et. al., Silverman et. al., and Montal et. al. as they relate to the prior art rejections of instant claims 1 – 53, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of Miura’404, that is for a method for treating a tumor wherein the tumor is selected from a group that contains biliary tract cancer, comprising administering a) (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, in view of both Goyal et. al. and Meric-Bernstam et. al., that is in a method for the treating patients with iCCA or eCCA with a FGFR2 fusion mutation or patients with iCCA or eCCA with a FGFR2 fusion mutation and a cancer driver gene that may have previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin and in further view of Silverman et. al., and Montal et. al., that is wherein the cancer driver gene is selected from TP53, BAP1, ARID1A, MLL2, PIK3C2B, IKBKE, MCL1, MDM4, and MYC. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only has a median survival of less than one year.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 month. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
Claims 1 – 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 10 of U.S. Patent No. US 11833151 B2 to Kusumoto et. al. (herein after Kusumoto’151) in view of Goyal et. al. ((2019), TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma, Cancer Discov., 9, 1064 – 1079), Meric-Bernstam et. al. ((2018), Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors, Annals of Oncology, 29, O-001, 1), Silverman et. al. ((February 2021), Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib, Cancer Discov., 9, 1064 – 1079; cited on the IDS dated October 23rd, 2025), and Montal et. al. ((2020), Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma, J. Hepatol., 73, 315 – 327).
Kusumoto’151 recite a pharmaceutical composition comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinyl)-2-propen-1-one (instant claims 1, 39, and 52) having the following structure, or a pharmaceutically acceptable salt thereof, and sodium lauryl sulfate:
PNG
media_image2.png
334
234
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Greyscale
(reference claim 1); in the form of syrup, a powder, a granule, a tablet, or a capsule (reference claim 7); wherein said sodium lauryl sulfate is in an amount sufficient to increase the dissolution and/or absorption of said (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinyl)-2-propen-1-one or a pharmaceutically acceptable salt thereof (reference claim 9); wherein said sodium lauryl sulfate is in an amount sufficient to increase the lubricative property and/or flowability of said (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinyl)-2-propen-1-one or a pharmaceutically acceptable salt thereof (reference claim 10).
While, Kusumoto’151 recites a pharmaceutical composition comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinyl)-2-propen-1-one; Kusumoto’151 fails to recite the use of the pharmaceutical composition comprising (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 in a method of treating a subject with cholangiocarcinoma (instant claims 30 – 32) having a co-occurring genetic alteration in FGFR2 (instant claims 2 – 7) and a cancer driver gene selected from the group consisting of TP53, BAP1, ARIDJA, MLL2, PIK3C2B, IKBKE, MCLJ, MDM4, and MYC (instant claims 1, 8 – 28) comprising administering the compound orally (instant claims 35), once a day (instant claims 36 – 37) for at least 21 days (instant claims 38) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 33 – 34); a method of treating a subject with cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 39) at 20 mg (instant claims 50 – 51) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claims 48 – 49); and a method of treating a subject with previously treated, unresectable, intrahepatic cholangiocarcinoma having an FGFR2 rearrangement or fusion, the method comprising: administering to the subject wherein the compound is administered orally once daily for at least 21 days (instant claim 52) wherein the cholangiocarcinoma has previously undergone a chemotherapy regimen prior to the administering (instant claim 53).
The teachings of Goyal et. al., Meric-Bernstam et. al., Silverman et. al., and Montal et. al. as they relate to the prior art rejections of instant claims 1 – 53, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of Kusumoto’151, that is for a pharmaceutical composition comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinyl)-2-propen-1-one, in view of both Goyal et. al. and Meric-Bernstam et. al., that is to use said pharmaceutical composition in a method for the treating patients with iCCA or eCCA with a FGFR2 fusion mutation or patients with iCCA or eCCA with a FGFR2 fusion mutation and a cancer driver gene that may have previously undergone a chemotherapy regimen wherein the chemotherapy regimen comprises at least one anticancer agent selected from the group consisting of gemcitabine, cisplatin, fluorouracil, leucovorin, and oxaliplatin and in further view of Silverman et. al., and Montal et. al., that is wherein the cancer driver gene is selected from TP53, BAP1, ARID1A, MLL2, PIK3C2B, IKBKE, MCL1, MDM4, and MYC. One of ordinary skill in the art would have been motivated to make this modification to improve patient outcomes since patients who only receive the standard palliative chemotherapy with gemcitabine and cisplatin, only has a median survival of less than one year.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to guide targeted therapy, to improve diagnostic capabilities, and to identify prognostic and predictive biomarkers. One of ordinary skill in the art would have had a reasonable expectation of improving patient outcomes because each of the four patients showed benefit after TAS-120 treatment with two patients achieving stable disease by RECIST v1.1 criteria (Figure 1A) with a duration of benefit of up to 17.2 month. One of ordinary skill in the art would have had a reasonable expectation of success because when pemigationib, and alternative FGFR2 inhibitor was administered orally to 107 patients harboring FGFR2 fusions or rearrangements these patients had a confirmed objective response rate (ORR) of 35.5%, a disease control rate of 82% with a median follow-up of 15.4 months, responses, with a median duration of response of 7.5 [95% confidence interval (CI), 5.7−14.5] months; and a median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6).
Conclusion
Claims 1 – 53 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627