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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/2/2025 has been entered.
Claims 1, 3-8, 12-14, 16-18, 20-26, 29-31, 33, and 67-72 are now pending. Claims 1, 3-8, 17, 18, 20, 21-26, and 31 are amended. Claim 68-72 are new. Claims 1, 3-8, 12-14, 16-18, 20-26, 29-31, 33, and 67-72 are pending and under prosecution.
New Rejections
(Necessitated by Amendments)
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 recites the limitation "first immune checkpoint inhibitor". Claim 17 depends on claim 1 and claim 1 does not recite a first immune checkpoint inhibitor. There is insufficient antecedent basis for this limitation in the claim.
Maintained Rejection
(Arguments Addressed)
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.
Claim(s) 1, 3-8, 12-14, 16-18, 20-26, 29-31, 33, and 67-72 remain rejected under 35 U.S.C. 103 as being unpatentable over Karkera et al (US20160287699 A1 – Published 10/6/2016), in view of Pierce et al (WO2017091580 A1; Published 6/1/2017; IDS), Holash et al (WO2016134234 A1; Published 8/25/2016; IDS), Yonekura et al (US20220125793 A1; Priority to: 2/28/2019), Freeman et al (US20150210769 A1; Published 7/30/2015), Saxty et al (US20130072457 A1; Published 3/21/2013; IDS), and Seront et al (Immune Checkpoint Inhibitors as a Real Hope in Advanced Urothelial Carcinoma. Future Science OA, 4(10), Published 10/4/2018).
Karkera teaches a method of treating bladder cancer in a patient, the method comprising administering a therapeutically effective amount of an immune checkpoint inhibitor to the patient. [Abstract, 0005, 0036, 0044-0045, 0057-0058] Karkera teaches that the patient has an FGFR variant, such as FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIA P2L1; FGFR3:TACC3-Intron; FGFR3:TACC3V1; FGFR3:TACC3V3; or any combination thereof. [0005-0006, 0037-0039, 0049, 0051; claims 1, 8-9] Karkera teaches that the patient has been treated with an FGFR inhibitor, such as erdafitinib (Formula I) [00034-0035; claim 20] Karkera specifically states that “the antibody and FGFR inhibitor can be administered sequentially in either order”, and further states “that in some aspects, the FGFR inhibitor can be administered first, followed by an antibody that blocks the interaction between PD-1 and PD-L1.” [0035] Karkera teaches that the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1, such as pembrolizumab, atezolizumab, or nivolumab. [0033, 0048]
Karkera also teaches the efficacy of the antibody can be monitored by, for example, evaluating the patient's symptoms for progression of the cancer, evaluating the severity of the cancer symptoms, evaluating the frequency of the cancer symptoms, measuring tumor size, or any combination thereof. See [0047]
However, Karkera does not explicitly teach:
the immune checkpoint inhibitor is cetrelimab (claim 1) and the cancer treated is locally advanced or metastatic urothelial cancer, including patients who progressed during or following platinum-containing chemotherapy (limitations of claim 30)
that prior to step of administering the immune checkpoint inhibitor, the patient exhibited disease progression in response to the FGFR inhibitor (claim 3)
patient was previously treated with immune checkpoint inhibitor and exhibited disease progression (claim 4)
the treatment regimen as recited in claim 18
that erlotinib is administered at a dose between 8 mg and 9 mg daily (claims 71-72)
Pierce teaches a method of treating cancer in a patient, the method comprising administering an immune checkpoint inhibitor. Pierce teaches that combination of FGFR inhibitors with inhibitors of PD-1 or PD-L1 allow for additive effects. Pierce teaches that treatment with an FGFR inhibitor leads to an increase in PD-L1 expressing cells in tumor tissue, and that FGFR inhibitor benefit a human bladder cancer subject. Pierce teaches and demonstrates that FGFR2 inhibitors may alter the tumor microenvironment and may therefore enhance tumor-killing immune responses, either alone or in combination with a PD- 1/PD-L1 inhibitor. [0010] Pierce teaches that the immune checkpoint inhibitors, are PD-1//PD-L1 inhibitors, such as nivolumab or pembrolizumab. [0012] Pierce teaches that the cancer treated may be bladder cancer or urothelial cancer. Pierce teaches that the cancer comprises an FGFR-genetically altered tumor [0025, 00103-00110, 0200, 00201] Pierce teaches that the inhibitors may be administered separately, that the checkpoint inhibitor may be administered prior and received a complete course prior to administering the FGFR inhibitor. Pierce teaches the FGFR2 inhibitor is administered during a second course of immune stimulating agent therapy. Pierce teaches that one or more doses of the FGFR2 inhibitor are administered prior to administering an immune stimulating agent. [0027, 00199] Pierce teaches that the subject has previously received PD-1/PD-L1 inhibitor therapy, and is an inadequate responder. [00205-00208] Pierce teaches that the method is effective in achieving a complete or partial response in the patient. [00466-00467]
Holash teaches a method of treating cancer in a patient, the method comprising administering an immune checkpoint inhibitor, wherein the patient has been treated with previous therapeutic interventions for cancer. [0018-0021] Holash teaches that the immune checkpoint inhibitor may be block the interaction between PD-1 and PD-L1 or CTLA-4, and may be pembrolizumab, nivolumab, or tremelimumab. [0014-0015] Holash teaches that FGFR inhibition has previously been shown to decrease immune response, and one of ordinary skill in the art would not have expected the administration of an inhibitor to increase the anti-cancer effects of PD1, therefore, Holash demonstrated surprising results that the combination slowed tumor growth and that the combination of the agents is clinically important. [00066] Holash also teaches that FGFR mutation and expression has been shown to be associated with a non-inflamed tumor phenotype in bladder cancer, and that it may be indicative of a tumor that is unlikely to respond to an immune checkpoint inhibitor. [0067] Holash demonstrates that an agent that blocks FGFR improves the immune status of the tumor and making the tumor more likely to respond to checkpoint inhibitors, and that treatment with the FGFR agent may be administered prior or at the same time with treatment of the immune checkpoint inhibitor. [0067; Examples 2-3]
Yonekura teaches a method for treating cancer with resistance to an immune checkpoint inhibitor, with a FGFR inhibitor and an immune checkpoint inhibitor. Yonekura teaches that the immune checkpoint inhibitor is cetrelimab. [Claims]
Freeman teaches a method of treating cancer comprising administering immune checkpoint inhibitor, such as an anti-PD-1 antibody. [Abstract] Freeman teaches that the cancer treated is urothelial cancer. [0146] Freeman teaches that the anti-PD-1 antibody is combined with an FGFR inhibitor. [0191, 0560, 0611, 0612-0616, 0654] Freeman teaches that the FGFR inhibitor is administered at a dose 3 mg to 10 mg. [0616]. Freeman teaches treating with cisplatin and the anti-PD1 antibody. [0519-0520]
Saxty teaches a method of treating cancer, comprising administering an FGFR inhibitor.[1023] Saxty teaches that overexpression of FGFR3 is common in urothelial carcinoma, and the use of FGFR inhibitors will be useful in these cancers. [1019] Saxty teaches that these inhibitors can be administered in combination with other anti-cancer agent, such as immune checkpoint inhibitors, Pertuzumab. [1135-1186]
Seront teaches that urothelial carcinoma (UC) accounts for more than 90% of bladder cancer, and more than 50% of patients develop metastases. Seront teach and demonstrate the efficacy of immune checkpoint inhibitors for patients with advanced urothelial carcinoma. [Whole document]
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to treat bladder cancer or locally advanced or metastatic urothelial cancer, that is FGFR-genetically altered, comprising administering cetrelimab, wherein the patient has previously been treated with erdaftinib 8 mg or 9 mg daily. (1) Karkera teaches a method of treating cancer, comprising administering immune checkpoint inhibitor, after a patient has been administered erdaftinib (an FGFR inhibitor), (2) Pierce teaches a method of treating urothelial cancer, comprising administering an immune checkpoint inhibitor, and teaches that the patient may have been treated with an FGFR inhibitor, and Pierce teaches that combination of FGFR inhibitors with inhibitors of PD-1 or PD-L1 allow for additive effect (3) Freeman teaches a method of treating cancer, comprising administering an immune checkpoint inhibitor and an FGFR inhibitor, (4) Saxty teaches a method of treating cancer, and teaches that FGFR3 is common in urothelial carcinoma, and that the use of FGFR inhibitors is useful in this cancer, in combination with other agents, (5) Saxty teaches a method of treating urothelial cancer comprising administering an FGFR inhibitor at a dose between 3 mg to 10 mg, (6) Seront teaches that immune checkpoint inhibitors are efficacious in the treatment of urothelial carcinoma, (7) Holash teaches a method of treating cancer, comprising administering an immune checkpoint inhibitor, wherein the patient has been treated with previous anti-cancer agents, (8) Holash also teaches that FGFR mutation and expression has been shown to be associated with a non-inflamed tumor phenotype in bladder cancer, and that it may be indicative of a tumor that is unlikely to respond to an immune checkpoint inhibitor, (9) Holash demonstrates that an agent that blocks FGFR improves the immune status of the tumor and making the tumor more likely to respond to checkpoint inhibitors, and that treatment with the FGFR agent may be administered prior or at the same time with treatment of the immune checkpoint inhibitor, (10) Yonekura teaches and demonstrates a method of treating cancer after a patient fails treatment an immune checkpoint inhibitor, comprising administering an FGFR inhibitor and an immune checkpoint inhibitor, and (11) Yonekura teaches that the immune checkpoint inhibitor may be cetrelimab. Thus, one of skill in the art could have substituted one known immune checkpoint inhibitor for another, and the results of cancer treatment, would have been predictable.
It is noted that claims 3 and 4 require that prior to step of administering the immune checkpoint inhibitor the patient exhibited disease progression in response to the FGFR inhibitor or immune checkpoint inhibitor, respectively. This limitation would have been obvious to those of ordinary skill in the art, because: (1) Karkera, Pierce, and Holash all teach a method of treating cancer, such as bladder cancer, comprising administering an immune checkpoint inhibitor and an FGFR inhibitor and monitoring cancer progression in response to treatment, (2) Karkera teaches that the patient has been treated with an FGFR inhibitor, such as erdafitinib (Formula I), (3) Pierce teaches that the subject have been previously treated with PD-1/PD-L1 inhibitor therapy and are inadequate responders, (4) Holash teaches that that the patient has been previously treated with therapeutic interventions for cancer, (5) Pierce teaches that combination of FGFR inhibitors with inhibitors of PD-1 or PD-L1 allow for additive effect, (6) Holash teaches that after patients fail FGFR inhibitor treatment, the combination of agents slowed growth significantly, (7) that an agent that blocks FGFR will improve immune status even in cancers where they are unlikely to respond to immune checkpoint inhibitors, and (8) Yonekura teaches and demonstrates a method of treating cancer after a patient fails treatment an immune checkpoint inhibitor, comprising administering an FGFR inhibitor and an immune checkpoint inhibitor. Given the recognized need to treat cancer in patients who exhibited disease progression after cancer treatment failure, given the known methods of treating cancer with an immune checkpoint inhibitor and/or an FGFR inhibitor, and given the known successes of utilizing these agents after treatment failure as demonstrated by the cited art, one of skill in the art could have pursued treating cancer in a patient with an immune checkpoint inhibitor, wherein the patient exhibits disease progression after being treated with an immune checkpoint inhibitor and/or an FGFR inhibitor, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat a patient diagnosed with cancer in the method as recited by claim 18. One would have been motivated to, because: (1) Karkera, Pierce, and Holash all teach a method of treating cancer, such as bladder cancer, comprising administering an immune checkpoint inhibitor and an FGFR inhibitor, (2) Pierce teaches that the subject have been previously treated with PD-1/PD-L1 inhibitor therapy and are inadequate responders, (3) Pierce teaches that the FGFR inhibitor and the immune checkpoint inhibitor are not administered at the same time, and that the immune checkpoint inhibitor is administered prior to administering the FGFR inhibitor, and (4) Holash teaches that that the patient has been previously treated with therapeutic interventions for cancer. One of ordinary skill in the art would have a reasonable expectation of success, because: (1) Pierce teaches that combination of FGFR inhibitors with inhibitors of PD-1 or PD-L1 allow for additive effect, (2) Holash teaches that after patients fail FGFR, the combination of agents slowed growth significantly, and (3) that an agent that blocks FGFR will improve immune status even in cancers where they are unlikely to respond to immune checkpoint inhibitors. Given the recognized need to treat cancer in patients who exhibited disease progression after treatment with an immune checkpoint inhibitor, given the known methods of treating cancer with an immune checkpoint inhibitor and/or an FGFR inhibitor, and given the known regimens as demonstrated by Pierce, one of skill in the art could have pursued treating cancer with the recited dosing regimen, with a reasonable expectation of success.
Response to Relevant Arguments
Applicant argues that the cited references do not teach or suggest the claimed treatment regimen. Applicant amended the claims to recite administration of erdaftinib followed by cetrelimab.
Karkera: Applicant notes that they unexpectedly observed in a clinical setting that treatment of a patient with erdaftinib improved the patient’s subsequent response to an immune checkpoint inhibitor. [paragraph 0033] In paragraph [0131] Applicant notes that the findings of the described experiment indicates that the sequential administration of erdaftinib followed by cetrelimab could boost and prolong the T-cell activation in peripheral blood and there is no evidence of record indicating that these unexpected results could have been predicted based on the disclosures of the cited art. Applicant argue that the Examiner has failed to identify any evidence indicating that the above-described results could have been deduced based on the disclosures of the cited art.
Pierce: Applicants argue that Pierce does not provide a single working example of an FGFR2 inhibitor administered prior to an immune checkpoint inhibitor, and the references made in Peirce are generic as to be non-motivating, or unsupported by examples or data. Applicant argues that there is no support in the examples for administration of a FGFR small molecule inhibitor prior to an immune checkpoint inhibitor. Applicant argues that Pierce focuses on anti-FGFR2 antibodies rather than small molecules.
Holash: Applicant argues that Holash fails to provide a single working example of the administration of an FGFR inhibitor prior to an immune checkpoint inhibitor, and rathe focuses on small molecule inhibitors.
Yonekura: Applicant argues that Yonekura do not remedy the deficiency of Karkera (sequential administration of an FGFR inhibitor followed by an immune checkpoint inhibitor)
Applicant’s arguments have been fully considered but are not persuasive. In this instant case, the treatment of cancer comprising administering an immune checkpoint inhibitor, after a patient has been treated with an FGFR inhibitor, is known in the prior art. As noted before, the cited art does not need to provide a working example to be enabled for obviousness or to provide a reasonable expectation of success. MPEP 2164.02 states that: The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In reBorkowski, 422 F.2d 904, 164 USPQ 642, 645 (CCPA 1970). Additionally, the Examiner has identified the evidence indicating that the above-described results could have been deduced based on the disclosures of the cited art.
. The Examiner relied on the combination of references to render the invention obvious. Applicant's claimed invention fails to patentably distinguish over the state of the art represented by the cited references taken in combination. 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). The primary art, Karkera, teaches the method of treating cancer comprising the sequential administration of FGFR inhibitor followed by an immune checkpoint inhibitor. [see paragraphs 0035 and 0036]. The amended claims now include that the immune checkpoint inhibitor is cetrelimab. The applicant argues that Pierce did not demonstrate support in the examples for administration of a FGFR small molecule inhibitor prior to an immune checkpoint inhibitor. Applicant argues that Pierce focuses on anti-FGFR2 antibodies rather than small molecules. Thus, the primary art teaches FGFR inhibitor, erdafitinib and teaches the sequential administration of FGFR inhibitor followed by an immune checkpoint inhibitor. The Examiner relied on Pierce to further provide support of using an FGFR inhibitor and an immune checkpoint inhibitor. see paragraph [0027] “In some embodiments, the FGFR2 inhibitor and the PD-1 /PD-L1 inhibitor are administered concurrently or sequentially”. “In some embodiments, one or more doses of the FGFR2 inhibitor are administered prior to administering an immune stimulating agent.” “In some embodiments, the subject may receive at least two, at least three, at least three, or at least four doses of the FGFR2 inhibitor prior to administration of immune stimulating agent.” Thus, Piece also provides motivation of using these two agents sequentially. The administration of an FGFR inhibitor followed by an immune checkpoint inhibitor is known as taught by Karkera, Pierce, and Holash. It was taught by Karkera (primary reference) and the secondary references were used to provide motivation and reasonable expectation of success for other limitations within the claim and dependent claims.
Argument #2: The Claimed Therapy Provides Unexpected Results
Applicant argues surprising and unexpected results for the claimed treatment. Applicant points to Example 1, which describes a retrospective analysis of data collected from patients who received the FGFR inhibitor erdafitinib as part of a phase 2, multicenter, open-label study (BLC2001; NCT02365597). (Specification at para. [0096]). Applicant notes that “these findings indicate that sequential administration of erdafitinib followed by cetrelimab could boost and prolong the T cell activation in the peripheral blood.” (/d.). Applicant argues that magnitude of the benefits achieved by sequential as compared to concurrent combination therapy could not have been reasonably expected from the cited references.
Applicant’s arguments have been considered but are not persuasive.
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) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
In this instant case, the surprising and unexpected results argued by Applicants is not unexpected by the prior art. The scope of the claims is the treatment of cancer comprising administering immune checkpoint inhibitor therapy, wherein the patients have previously received an FGFR inhibitor, erdaftinib. The data shown by the Applicant is retrospective data in which patients who received erdaftinib, received subsequent systemic therapy. NCT02365597 was a clinical trial to assess the efficacy and safety of erdaftinib. The retrospective analysis focused on subsequent therapy; however, immune checkpoint inhibitor is known in the art to be given to patients who have locally advanced or metastatic urothelial carcinoma. [see El-Mouallem et al 2018] Therefore, the unexpected results or surprising results noted the Applicant is already known in the prior art, and the subsequent treatment of immune checkpoint inhibitors, is a known course of treatment for this population of patients.
The prior art as noted above clearly teach the sequential treatment of erdaftinib followed by an immune checkpoint inhibitor. The prior art also reasons reasonable expectation of success on why the combination will be successful:
Pierce teaches that the combination (whether this is concurrent or sequential) of an FGFR inhibitor and a PD-1 inhibitor will allow for additive effects. Pierce also states that treatment with an FGFR inhibitor leads to increase in PD-L1 expressing cells in tumor tissues and that these inhibitors may alter the tumor microenvironment and allow for enhanced tumor-killing immune responses. [0010]
Holash teaches that FGFR mutations can be associated with non-inflamed tumor phenotypes, making it unlikely to respond to an immune checkpoint inhibitor, thus, treatment with an FGFR inhibitor prior to treatment with an immune checkpoint inhibitor, will make the tumor more likely to respond to the checkpoint inhibitor. [0067]
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600