DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/10/2025 has been entered.
Claims Status
Claims 1, 4, 6-11, 15, 17, & 21 filed on 12/10/2025 are pending. Claims 13, 25, & 26 are withdrawn from consideration as being drawn to a non-elected invention. Claims 9, 10, 17, & 21 are currently under examination directed to the elected species of CALM2, KRT5, an antibody, and Erdafitinib, respectively (see response dated 10/25/2024). The cancellation of claims 12-14, & 16 in the reply filed on 12/10/2025 and the previous cancellation of claims 2, 3, 5, 18-20, 22-24, & 27-31 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1, 4, 6-11, 15, 17, & 21 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.
Regarding the newly amended claim 1, the claim recites “the ratio between expression levels” in line 8 of the claim. There is insufficient antecedent basis for this limitation in the claim. In addition, the recitation of “the gene encoding for FGFR2 and FGFR3” in lines 5-7 followed by the recitation of “the expression levels of the genes encoding for FGFR2 and FGFR3” in lines 8-9 of the claim is unclear if the recitation in lines 5-7 is referring to a singular gene, or is a typographical error and is supposed to read “the genes encoding for FGFR2 and FGFR3” since the recitation in lines 8-9 of the claim refers to determining a ratio in expression levels between genes of FGFR2 and FGFR3.
Regarding newly amended claim 17, the recitation of “set forth in Table 5” is indefinite. As stated in MPEP 2173.05(s), the claims should be complete to themselves and the reference to a table in the specification renders the claim incomplete. Claims which recited tables are only permitted in exceptional circumstances where there is not practical way to define the invention in words or where it is more concise to incorporate by reference than duplicating a drawing or table into the claim.
Claims 4, 6-11, 15, & 21 are rejected due to their independence on claim 1.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4, 6, 7, 11, & 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi (WO 2016/105503), as cited in the IDS dated 10/01/2024, in view of Baldia (Baldia et al.; Oncotarget, Vol. 7, pages 71429-71439, September 2016) and Nassar (Nassar et al.; JCO Precision Oncology, vol. 2, pages 1-6, July 24th, 2018).
Regarding amended claim 1, Choi teaches measuring FGFR3 expression levels (determining the expression level of an alter FGFR variant) in bladder cancer samples compared to wild-type samples (normalized expression level of FGFR3) that were classified into three groups, the red group (consisting of non-muscle invasive bladder cancer (NMIBC) samples), the yellow group (consisting of muscle invasive bladder cancer (MIBC) and metastatic samples), and the green group (consisting of rapidly-recurring NMIBC) in which the green group was classified as significantly higher expression levels of FGFR3 compared to the red and yellow groups that were classified as having lower FGFR3 expression compared to the green group (pg. 58 lines 26-40; pg. 59 lines 1-6; pg. 71 claim 12 lines 1-8). In addition, Choi teaches a classification of a sample with high FGFR3 expression represents good candidates (good prognosis) for treatment with FGFR3 antagonists (anti-cancer agent) (classifying the sample of said patient into good or poor prognosis for treatment with an anti-cancer agent) (pg. 59 lines 33-35; pg. 71 claim 12 lines 1-8). Choi also teaches that mutations (alterations) in FGFR3 drive higher expression levels of FGFR3 and teaches the detection of frequent FGFR3 mutations (presence or absence of an alteration in the FGFR3 gene) in the green group that was classified as significantly higher FGFR3 expression levels (pg. 58 lines 26-40). Finally, Choi also teaches detecting the expression of one or more biomarkers, including FGFR3, for treating, diagnosing, or providing a prognosis for bladder cancer (abstract lines 1-2).
Choi fails to teach determining the normalized expression levels of FGFR2, classifying a sample as having poor prognosis for treatment with an anti-cancer agent wherein the anti-cancer agent is an immune checkpoint inhibitor, and administering an FGFR inhibitor to a patient classified as a bad prognosis for treatment with the anti-cancer agent in step b).
Baldia teaches measuring reduced overall expression of FGFR2 in bladder cancer samples compared to normal tissues (normalized expression of FGFR2) (abstract lines 14-17; pg. 71430 column 1 2nd full paragraph lines 1-6; pg. 71431 column 1 1st full paragraph lines 1-4; pg. 71431-71432 paragraph bridging pg. 71431 & pg. 71432 lines 1-4). Baldia also teaches that this method of measuring expression levels in FGFR1-3 in bladder cancer samples hold cues for novel therapeutic regimens and what bladder cancer tumors may benefit from FGFR3-targeted therapies (abstract lines 19-21).
Nassar teaches that higher FGFR3 expression and FGFR3 pathway mutations (including FGFR3-TACC3 fusion alterations) are strongly associated with immune exclusion in bladder cancer and also teaches determining the presence or absence of a FGFR3-TACC3 fusion (alteration in an FGFR gene) in bladder cancer and classifying the sample into at least two classifications of good and poor candidates for immune checkpoint inhibitors (ICI) therapy (pg. 1 column 1 paragraph 1 lines 1-11; pg. 1 column 1 paragraph 2 lines 1-9; pg. 1 paragraph bridging column 1 & 2 lines 9-17). In addition, Nassar teaches classifying a sample into a classification of poor candidates for ICI therapy (poor prognosis for treatment with an anti-cancer agent of an immune checkpoint inhibitor (pg. 1 paragraph bridging column 1 & 2 lines 9-17). Nassar also teaches administration of a FGFR3 inhibitor with an anti-PD-LI blockade in the case of the patient being a poor candidate for ICI therapy (poor prognosis for treatment with an anti-cancer agent of an immune checkpoint inhibitor) (pg. 1 paragraph bridging column 1 & 2 lines 9-17; pg. 1 column 2 1st full paragraph lines 1-8; pg. 3 paragraph bridging column 1 & 2 lines 6-10). Finally, Nassar teaches that administration of an FGFR3 inhibitor following classifying a sample as a poor candidate for ICI therapy can lead to tumor microenvironment changes that enhance ICI response (pg. 1 column 2 1st full paragraph lines 1-8).
Choi, Baldia, and Nassar are considered to be analogous to the claimed invention because they are all in the same field of determining alterations and expression levels in FGFR genes for analysis of bladder cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring one or more biomarkers, including measuring normalized FGFR3 expression levels and classifying the samples into good or poor prognosis with an anti-cancer agent in bladder cancer samples in Choi to incorporate measuring the normalized expression levels of FGFR2 in bladder cancer samples as taught in Baldia because Baldia teaches that doing so would provide a method developing novel therapeutic regimens and determining which bladder cancer tumors may benefit from FGFR3-targeted therapies and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring FGFR3 expression levels and classifying the samples into good or poor prognosis with an anti-cancer agent in Choi to incorporate administrating a FGFR3 inhibitor to a patient classified as a bad prognosis for treatment with ICI therapy as taught in Nassar because Nassar teaches that doing so would provide a method for administering an FRFR3 inhibitor therapy that can lead to tumor microenvironment changes that enhance ICI response.
Regarding claim 4, Choi teaches that the expression level of FGFR3 is determined by a quantitative PCR assay (pg. 37 lines 33-38) and that the expression level of FGFR3 may be determined by an immunohistochemical method (pg. 38 lines 1-5).
Baldia teaches that the expression level of FGFR2 is determined by fluorescence in situ hybridization (FISH) (a hybridization based method in which labeled, single stranded probes are used) and through analysis of FGFR2 protein expression by immunohistochemical staining (a immunological method, wherein said method comprised uses of one or more target-specific protein binders) (pg. 71430 column 1 2nd full paragraph lines 1-6; pg. 71431 column 1 1st full paragraph lines 1-4).
Regarding claim 6, Choi teaches that measuring the expression level of FGFR3 (mRNA of altered FGFR variant) refers to the amount of a mRNA that is measured in the biological sample (pg. 10 lines 3-5; pg. 71 claim 12 lines 1-8) and that this expression level is compared to the reference level of at least one gene from a healthy individual (expression level of at least one FGFR wildtype mRNA) (pg. 10 lines 39-40; pg. 71 claim 12 lines 1-8) and these expression levels are determined by a quantitative PCR assay (pg. 37 lines 33-38).
Regarding claim 7, Choi teaches determining the expression level of a at least one reference gene and comparing this to the expression level in FGFR3 (pg. 71 claim 12 lines 1-8) and an increase in expression refers to a level compared to the reference level (normalizing the expression level so that the expression level measured from FGFR3 is relative to the reference level) (pg. 10 line 13).
Baldia teaches measuring reduced overall expression of FGFR2 in bladder cancer samples compared to normal tissues (normalized expression of FGFR2) (abstract lines 14-17; pg. 71430 column 1 2nd full paragraph lines 1-6; pg. 71431 column 1 1st full paragraph lines 1-4; pg. 71431-71432 paragraph bridging pg. 71431 & pg. 71432 lines 1-4).
Regarding claim 11, Choi teaches a method of determining whether a patient having bladder cancer is likely to respond to an anti-cancer therapy (pg. 71 claim 12 lines 1-2) and that the cancer can be characterized as stage T2, T3, or T4 cancer (pg. 24 lines 11-13 & 31-35).
Regarding claim 17, Choi teaches an increase in expression level of FGFR3 compared to a reference level indicates the patient is likely to respond to an anti-cancer therapy (pg. 71 claim 12 lines 1-8) in which the anti-cancer therapy is a FGFR3 antagonist (pg. 59 lines 33-35; pg. 71 claim 16 lines 1-2) and this FGFR3 antagonist is an antibody (pg. 72 claim 17 lines 1-2).
Nassar teaches administration of a FGFR3 inhibitor with an anti-PD-LI blockade (an anti-cancer agent comprising an immune checkpoint inhibitor antibody) in the case of the patient being a poor candidate for ICI therapy (poor prognosis for treatment with an anti-cancer agent) (pg. 1 paragraph bridging column 1 & 2 lines 9-17; pg. 1 column 2 1st full paragraph lines 1-8; pg. 3 paragraph bridging column 1 & 2 lines 6-10).
Claim(s) 8 & 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi (WO 2016/105503), as cited in the IDS dated 10/01/2021, Baldia (Baldia et al.; Oncotarget, Vol. 7, pages 71429-71439, September 2016), and Nassar (Nassar et al.; JCO Precision Oncology, vol. 2, pages 1-6, July 24th, 2018), as applied to claims 1, 4, 6, 7, 11, & 17 above, and further in view of Worst (Worst et al.; Scientific Reports, vol. 8, pages 1-10, September 26th, 2018), as cited in the IDS dated 10/01/2021.
The teachings of Choi, Baldia, and Nassar with respect to claims 1 & 7 are discussed above.
Regarding claims 8 & 9, Choi, Baldia, and Nassar fail to teach that the reference gene is a housekeeping gene of CALM2.
Worst teaches measuring the RNA expression of CDKN2A and FGFR3 in relation to the housekeeping gene calmodulin 2 (CALM2) (pg. 7-8 paragraph bridging pg. 7 & pg. 8 lines 1-2 & 16). In addition, Worst teaches measuring with RNA expression with qRT-PCR provides a higher sensitivity when comparing expression profiles (pg. 5-6 paragraph bridging pg. 5 & pg. 6 lines 9-10).
Choi, Baldia, Nassar, and Worst are considered to be analogous to the claimed invention because they are all in the same field of FGFR3 analysis of bladder cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring a reference gene in Choi to incorporate the use of the housekeeping gene, CALM2, as taught in Worst because Worst teaches that doing so would provide a highly sensitive method for comparing the expression profiles of CDKN2A and FGFR3 with a reference housekeeping gene.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi (WO 2016/105503), as cited in the IDS dated 10/01/2024, Baldia (Baldia et al.; Oncotarget, Vol. 7, pages 71429-71439, September 2016), and Nassar (Nassar et al.; JCO Precision Oncology, vol. 2, pages 1-6, July 24th, 2018), as applied to claims 1, 4, 6, 7, 11, & 17 above, and further in view of Sjödahl (Sjödahl et al.; Journal of Pathology, vol. 242, pages 113-125, March 28th, 2017).
The teachings of Choi, Baldia, and Nassar with respect to claim 1 are discussed above.
Regarding claim 10, Choi, Baldia, and Nassar fail to teach that the expression of at least one more gene, KRT5, is determined.
Sjödahl teaches a global mRNA expression analysis method in which the expression levels for FGFR3 and KRT5 are determined (pg. 114 column 2 paragraph 1 lines 1-14; pg. 114 column 2 paragraph 2 lines 1-7). Sjödahl also teaches that measuring the expression levels of various genes, including FGFR3 and KRT5, can lead to grouping the bladder cancer samples into different classifications which can help bridge the gap to molecular pathology (pg. 122 paragraph bridging column 1 & 2 lines 1-3; pg. 122 column 2 1st full paragraph lines 1-5; pg. 123 paragraph bridging column 1 & 2 lines 1-3 & 34-36).
Choi, Baldia, Nassar, and Sjödahl are considered to be analogous to the claimed invention because they are all in the same field of FGFR3 analysis of bladder cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Choi of measuring expression levels to incorporate the determination of the expression level of an additional gene, KRT5, as taught in Sjödahl because Sjödahl teaches that doing so would provide a method to classify bladder cancer samples into different subtypes in order to bridge the gap between expression profiles and molecular pathology.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi (WO 2016/105503), as cited in the IDS dated 10/01/2024, Baldia (Baldia et al.; Oncotarget, Vol. 7, pages 71429-71439, September 2016), and Nassar (Nassar et al.; JCO Precision Oncology, vol. 2, pages 1-6, July 24th, 2018), as applied to claims 1, 4, 6, 7, 11, & 17 above, and further in view of Sun (Sun; Molecular Diagnostics Techniques and Applications for the Clinical Laboratory, Chapter 4, pages 35-47, 2010).
The teachings of Choi, Baldia, and Nassar with respect to claim 1 are discussed above.
Regarding claim 15, Choi, Baldia, and Nassar fail to teach that the sample is treated with silica-coated magnetic particles and a chaotropic salt, for the purification of nucleic acid samples in the sample.
Sun teaches a method purifying a sample with silica-coated or glass magnetic particles in high concentrations of chaotropic salts (pg. 40 column 1 1st full paragraph lines 1-10). In addition, Sun teaches the importance of needing purified and readily available DNA or RNA material to detect changes in expression levels of human genes (pg. 35 column 1 paragraph 1 lines 1-11) and that this method of purification with silica-coated magnetic beads and chaotropic salts is simple and can be automated and it handles cellular debris better than other purification methods (pg. 40 column 1 3rd full paragraph lines 7-11).
Choi, Baldia, Nassar, and Sun are considered to be analogous to the claimed invention because they are all in the same field of obtaining purified nucleic acids from samples for further analysis of genes in the sample. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Choi and the method of Nassar to incorporate the purification of nucleic acids in the sample with silica-coated magnetic beads and chaotropic salts prior to determining expression level and or mutation (alteration) in FGFR3 or prior to determining the presence or absence of a FGFR3-TACC3 fusion (alteration), respectively, as taught in Sun because Sun teaches that doing so would provide a method to purify the nucleic acids in a sample in a simpler method that also purifies the nucleic acids from other cellular debris better.
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi (WO 2016/105503), as cited in the IDS dated 10/01/2024, Baldia (Baldia et al.; Oncotarget, Vol. 7, pages 71429-71439, September 2016), and Nassar (Nassar et al.; JCO Precision Oncology, vol. 2, pages 1-6, July 24th, 2018), as applied to claims 1, 4, 6, 7, 11, & 17 above, and further in view of Karkera (Karkera et al.; Molecular Cancer Therapy, vol. 16, pages 1717-1726, August 2017).
The teachings of Choi, Baldia, and Nassar with respect to claim 1 are discussed above.
Regarding claim 21, Choi, Baldia, and Nassar fail to teach that the FGFR inhibitor is a FGFR tyrosine kinase inhibitor of erdafitinib.
Karkera teaches the administration of the FGFR inhibitor erdafitinib to a bladder cancer patient with the FGFR3-TACC3 translocation (alteration in the FGFR gene) (pg. 1717 abstract lines 10-13 & 18-29). In addition, Karkera teaches that erdafitinib showed the highest potency compared to other FRGR inhibitors and a partial response in the patient with the FGFR3-TACC3 translocation (alteration in the FGFR gene) (pg. 1723 column 2 1st full paragraph lines 5-13).
Choi, Baldia, Nassar, and Karkera are considered to be analogous to the claimed invention because they are all in the same field of FGFR3 analysis of bladder cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Nassar for treatment of samples with an FGFR inhibitor, in the samples that have a poor prognosis of treatment with an immune checkpoint inhibitor, to incorporate the use of the FGFR inhibitor erdafitinib as taught in Karkera because Karkera teaches that doing so would provide a method to treat samples with an FGFR inhibitor that showed a higher potency compared to other FGFR inhibitors.
Response to Arguments
The response traverses the rejection. The response asserts that Choi and Nassar fail to teach or suggest all of the features of the method of currently pending independent claim 1, and that specifically, Choi and Nassar, alone or in combination, fail to teach or suggest a method of classifying a sample of a patient that suffers from or being at risk for developing urothelial or bladder cancer and treating the patient, comprising steps of determining the ratio between the expression levels of the genes encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively. These arguments have been thoroughly reviewed but were not found persuasive, as the combination of Choi, Baldia, and Nassar, as applied to amended independent claim 1 as necessitated by amendment, teach all of the features of the currently pending amended claim 1 as discussed above. Specifically, Choi teaches measuring FGFR3 expression levels (determining the expression level of an alter FGFR variant) in bladder cancer samples compared to wild-type samples (normalized expression level of FGFR3) and Baldia teaches measuring reduced overall expression of FGFR2 in bladder cancer samples compared to normal tissues (normalized expression of FGFR2) as discussed in further detail above in paragraph 7. Further, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring one or more biomarkers, including measuring normalized FGFR3 expression levels and classifying the samples into good or poor prognosis with an anti-cancer agent in bladder cancer samples in Choi to incorporate measuring the normalized expression levels of FGFR2 in bladder cancer samples as taught in Baldia because Baldia teaches that doing so would provide a method developing novel therapeutic regimens and determining which bladder cancer tumors may benefit from FGFR3-targeted therapies and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring FGFR3 expression levels and classifying the samples into good or poor prognosis with an anti-cancer agent in Choi to incorporate administrating a FGFR3 inhibitor to a patient classified as a bad prognosis for treatment with ICI therapy as taught in Nassar because Nassar teaches that doing so would provide a method for administering an FRFR3 inhibitor therapy that can lead to tumor microenvironment changes that enhance ICI response.
The response also asserts that Choi, Nassar, and Worst fail to teach or suggest all the features of the method of the currently pending independent claim 1, from which claims 8 and 9 ultimately depend. The response also asserts that Choi, Nassar, and Sjodahl fail to teach or suggest all the features of the method of the currently pending independent claim 1, from which claim 10 depends. The response also asserts that Choi, Nassar, and Sun fail to teach or suggest all the features of the method of the currently pending independent claim 1, from which claim 15 depends. The response also asserts that Choi, Nassar, and Karkera fail to teach or suggest all the features of the method of the currently pending independent claim 1, from which claim 21 depends. Specifically, the response asserts that Choi, Nassar, and Worst, Choi, Nassar, and Sjodhal, Choi, Nassar, and Sun, and Choi, Nassar, and Karkera alone or in combination, fail to teach a method of classifying a sample of a patient that suffers from or being at risk of developing urothelial or bladder cancer and treating the patient, comprising steps of determining the ratio between the expression levels of the genes encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively. These arguments have been thoroughly reviewed but were not found persuasive, as the combination of Choi and Nassar teach all of the features of the currently pending, amended claim 1 for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1, 4, 6-11, 15, 17, & 21 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682