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 .
Claims Status
Claims 1, 4, 6-11, 15, 17, & 21 filed on 04/21/2026 are pending. Claims 25 & 26 are withdrawn from consideration as being drawn to a non-elected invention.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). 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 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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 amended claim 1, 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, or their normalized expression levels, respectively.
Claims 4, 6-11, 15, 17, & 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 (a ratio between the normalized expression level of FGFR3, respectively) 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 (a ratio between the normalized expression level of FGFR2, respectively) 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, Baldia, and Nassar fail to teach or suggest the method of currently pending independent claim 1, from which claim 8 and 9 ultimately depend, as Choi, Baldia, and Nassar fail to teach or suggest all of the features of the method of currently pending independent claim 1. Specifically, the response asserts that Choi, Baldia, and Nassar, alone or in combination, fail to teach or suggest a method of classifying a sample of a patient comprising determining a ratio between the expression levels of the genes encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively, for identifying patients who are unlikely to respond to immune checkpoint inhibitor therapy. 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, 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/ a ratio between the normalized expression level of FGFR3, respectively) and Baldia teaches measuring reduced overall expression of FGFR2 in bladder cancer samples compared to normal tissues (normalized expression of FGFR2/ a ratio between the normalized expression level of FGFR2, respectively) as discussed in further detail above in paragraph 6. 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 (a ratio between the normalized expression level of FGFR3, respectively) 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 (a ratio between the normalized expression level of FGFR2, respectively) 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 fails to teach or suggest determining FGFR2 expression together with FGFR3, forming a ratio between FGFR2 and FGFR3, and that a low FGFR2:FGFR3 ratio predicts poor response to and immune checkpoint inhibitor. These arguments have been thoroughly reviewed but were not found persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, claim 1, as currently amended, does not require forming a ratio between FGFR2 and FGFR3 as claim 1, as currently amended, recites “determining a ratio between the expression levels of the gene encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively”. Therefore, claim 1, as currently amended, requires determining a ratio between expression levels for FGFR2 and FGFR3 or requires determining a ratio of normalized expression levels for FGFR2 and FGFR3, respectively (i.e., a ratio of normalized expression levels for FGFR2 and a ratio of normalized expression levels for FGFR3). Further, the combination of Choi, Baldia, and Nassar teach all of the features of the currently pending amended claim 1 as discussed above.
The response also asserts that Baldia cannot fill the deficiencies left by Choi and that while Baldia mentions FGFR2 and FGFR3 in bladder cancer, Baldia fails to teach or suggest a connection between FGFR2 and FGFR3 as required by the method in claim 1 and, in particular, Baldia fails to teach or suggest using an FGFR2:FGFR3 expression ratio as the biomarker. These arguments have been thoroughly reviewed but were not found persuasive as, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) and for the reasons set forth above.
The response also asserts that like Baldia, Nassar cannot fill the deficiencies left by Choi or Baldia and Choi combined as Nassar does not teach or suggest 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 based on the features required in independent claim 1. Specifically, the response asserts that even if Nassar was relevant to the use of an FGFR inhibitor in a subset of bladder cancer, Nassar does not teach or suggest performing at least the steps of “determining a ratio between the expression levels of the genes encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively” or “classifying a sample… when the ratio between the expression levels of FGFR2 and FGFR3 is low compared to a control sample” as required in independent claim 1. These arguments have been thoroughly reviewed but were not found persuasive as, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) and for the reasons set forth above.
The response also asserts that one of ordinary skill in the art at the time of the invention would understand that Choi and Baldia fail to teach or suggest that the clinically relevant step determining a ratio between the expression levels of the genes encoding for FGFR2 and FGFR3 or classifying a sample when the ratio between the expression levels of FGFR2 and FGFR3 is low compared to a control sample and that the claimed low ratio relative to a control is the relevant threshold. These arguments have been thoroughly reviewed but were not found persuasive as claim 1, as currently amended, does not require forming a ratio between FGFR2 and FGFR3 as claim 1, as currently amended, recites “determining a ratio between the expression levels of the gene encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively”. Therefore, claim 1, as currently amended, requires determining a ratio between expression levels for FGFR2 and FGFR3 or requires determining a ratio of normalized expression levels for FGFR2 and FGFR3, respectively (i.e., a ratio of normalized expression levels for FGFR2 and a ratio of normalized expression levels for FGFR3). Further, the combination of Choi, Baldia, and Nassar teach all of the features of the currently pending amended claim 1 as discussed above.
The response also asserts that one of ordinary skill, at the time of the invention, would not have been motivated to combine the cited references in a way that would render the claimed methods obvious and that the office appears to combine three separate references in a way that appears to be guided by the claim language, rather than by a clear teaching in the prior art itself. Further, the response asserts that, most importantly, the cited references does not appear to disclose or suggest using the specific FGFR2:FGFR3 expression ratio as the key biomarker for identifying patients who are likely to response well to ICI therapy. Further, the response asserts that one of ordinary skill in the art would not have been motivated to look to Baldia to modify the method of Choi at least because Choi fails to provide one of ordinary skill in the art for any guidance on what other biomarker can be combined to determine a ratio for identifying patients who are likely to respond well to ICI therapy. These arguments have been thoroughly reviewed but were not found persuasive. First, as discussed above, as claim 1, as currently amended, does not require forming a ratio between FGFR2 and FGFR3, as claim 1, as currently amended, recites “determining a ratio between the expression levels of the gene encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively”. Therefore, claim 1, as currently amended, requires determining a ratio between expression levels for FGFR2 and FGFR3 or requires determining a ratio of normalized expression levels for FGFR2 and FGFR3, respectively (i.e., a ratio of normalized expression levels for FGFR2 and a ratio of normalized expression levels for FGFR3). Second, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Choi 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). Further, 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 (taught motivation to combine cited references) (abstract lines 19-21). Further, 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 (a ratio between the normalized expression level of FGFR3, respectively) 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 (a ratio between the normalized expression level of FGFR2, respectively) 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.
The response also asserts that the combined teachings of Choi, Baldia, and Nassar cannot suggest the method as claimed at least because Choi fails to provide motivation to include “determining a ratio between the expression levels of the gene encoding for FGFR2 and FGFR3, or their normalized expression levels, respectively”. Further, the response asserts that the only way to arrive at the claimed system is to use the currently pending claimed subject matter as a blueprint for such a combination in which the motivation to combine references cannot come from the disclosure itself and, further, that the only arguable combination alleged by the office action is one that uses the limitation in claim 1 and in the specification regarding determining a ratio between expression levels of the genes encoding for FGFR2 and FGFR3. These arguments have been thoroughly reviewed but were not found persuasive for the reasons set forth above and, as discussed above, claim 1, as currently amended, does not require determining a ratio between the genes encoding for FGR2 and FGFR3 as the claim recites the alternative of determining normalized expression levels for FGFR2 and FGFR3.
The response also asserts that Choi, Baldia, and Nassar 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, Baldia, 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, Baldia, 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, Baldia, 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, Baldia, and Nassar, Choi, Baldia, Nassar, and Sjodhal, Choi, Baldia, Nassar, and Sun, and Choi, Baldia, 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, Baldia, 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.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
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