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 .
This action is in response to the papers filed on January 8, 2026.
Claim Status and Action Summary
Currently, claims 21 and 24-25 are pending.
Claims 1-20 and 22-23 were canceled.
Claims 21 and 24-25 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
Priority/Effective Filing Date
This application claims the benefit of priority to 63/274,338, filed November 1, 2021 and 63/142,764, filed January 28, 2021.
63/142,764 does not provide support for the claim terms “FKBP14, PSAT1, and C1QBP”. Furthermore, 63/274,338 and 63/142,764 do not provide support for the claim term “muscle-invasive bladder cancer”. Therefore, claims 21 and 24-25 receive the benefit of the January 28, 2022 filing date.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 102
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 21 and 24 are/remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Woonyoung Choi, et al., “Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy”, Cancer Cell, Volume 25, Issue 2, 2014, Pages 152-165 as evidenced by NCBI GEO Accession Platform GPL6947, NCBI GEO Accession Platform GPL10558 and NCBI GEO Accession GSE48277 and NCBI GEO Accession GSE47993.
Regarding claim 1, Choi teaches a method comprising: (i) analyzing gene expression in bladder tumor cells (i.e. a tumor sample) collected from responsive (cisplatin sensitive) and nonresponsive (cisplatin resistant) patients (Choi, page 156, column 1, line 9-20) using the Illumina HT12v3 and HT12v4 chips (Choi, page 164, column 1, line 8-12). Furthermore, Choi teaches that human subjects with muscle-invasive bladder cancer (MIBC) were analyzed (Choi page 156, col. 1. As evidenced by GPL6947 and GPL10558, corresponding to the HT12v3 and HT12v4 chips, respectively, the chips comprise probes that measure expression of at least the four elected genes, namely C15orf41, FKBP14, PSAT1 and C1QBP. Choi teaches gene expression signatures associated with responses to MVAC (a chemotherapy combination comprising cisplatin) (Choi, page 159, column 2). Furthermore, Choi teaches “Presurgical (neoadjuvant) cisplatin-based chemotherapy (NAC) is the current standard-of-care for high-risk MIBC (i.e. treating a subject with cisplatin) (Choi, page 159, column 2).
Choi teaches administering cisplatin to each of the subjects. Choi also teaches that each of the elected genes are higher expressed in a subset of MVAC-responsive tumors compared to non-cancer controls (i.e. those that are suitable to be treated with cisplatin) (Choi data visualized for individual probes with GEO “Profile graph” function, see non-final office action dated January 10, 2025). Choi teaches conducting mRNA expression level analyses wherein at least the four genes are higher expressed in tumor samples compared to non-cancerous controls (Choi page 163, col. 2- page 164, col. 1, paragraph 1 and NCBI GEO Accession GSE48277 and NCBI GEO Accession GSE47993). It is noted that the cited GEO Accessions are the raw data produced by Choi (Choi page 164, col. 1, paragraph 8) and are therefore part of the disclosure made by Choi. GSE48277 was made public on February 10, 2014 and was last updated on June 22, 2020. GSE47993 was made public on February 17, 2014 and was last updated on August 15, 2018. Therefore, ALL of the gene expression data was necessarily disclosed prior to the effective filing date of the claimed invention and all of this data taught by Choi is prior art under U.S.C. 102(a)(1). Thus, Choi teaches each method step of the claimed invention (i.e. reporting that a subject should be treated with cisplatin “the current standard-of-care for high-risk MIBC” and treating with cisplatin). The open claim language “based on expressing mRNA or protein levels… for at least four genes… compris[ing] C15orf41, C1QBP, FKBP14, and PSAT1” does not differentiate the claimed subject matter from the disclosure of Choi that teaches measuring signatures of MVAC-responsiveness in MIBC tumor samples using microarrays comprising probes that measure the expression of all of the claimed genes.
FKBP14 probe: ILMN_2150294
C15orf41 probe: ILMN_1747217
C1QBP probe: ILMN_1668996
PSAT1 probe: ILMN_1692938
Response to arguments
The response extensively reviews the findings of Choi et al. and the NCBI GEO accession “deposited as part of the Choi et al. publication”.
The response argues, in summary, that the Choi et al. reference does not anticipate the present claims because “FKBP14 is not mentioned… in Choi et al., … the material cited is post hoc… and the FKBP14 expression overlaps between groups, varies within subtypes, and lacks disclosed thresholds or classifiers”.
These arguments have been considered and are not persuasive.
Choi et al. explicitly references the GEO data produced as part of their study, which are maintained, time-stamped, and made publicly available by NCBI. The mere fact that these data are not (cannot) be reproduced in full within the Choi et al. paper does not exclude these data from the disclosure of the Choi et al. reference.
The broad claim language positively recites “receiving a… report that a human subject is suitable for… treat[ment] with Cisplatin… based on expressing mRNA or protein levels in a muscle-invasive bladder cancer… for at least four genes that are higher than non-cancerous control levels, wherein… [the] genes comprise C15orf41, C1Qbp, FKBP14, and PSAT1” and “treating… with a platinum-based cancer drug…”.
As presently claimed, the method requires only: i) observing elevated expression of any set of genes comprising the recited markers in muscle invasive bladder cancer (i.e. the claim encompasses measuring gene expression in said cancer with any microarray comprising the four markers) and ii) treating the subject with a platinum-based cancer drug.
As has previously been described, Choi et al. demonstrate examples wherein the expression of the recited genes are higher than a control, measured on a microarray platform that comprises probes for all of the recited genes, and the subjects are treated with a platinum-based cancer drug.
Therefore, Choi et al. teach methods comprising all of the positively recited method steps. Accordingly, the rejection is maintained.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Woonyoung Choi, et al., “Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy”, Cancer Cell, Volume 25, Issue 2, 2014, Pages 152-165 as evidenced by NCBI GEO Accession Platform GPL6947, NCBI GEO Accession Platform GPL10558 and NCBI GEO Accession GSE48277 and NCBI GEO Accession GSE47993 in view of Silva et al., “Quantifying gene expression: the importance of being subtle”, Mol Syst Biol. 2016 Oct 26; 12(10):855.
Regarding claim 25, Choi teaches a method comprising: (i) analyzing gene expression in bladder tumor cells (i.e. a tumor sample) collected from responsive (cisplatin sensitive) and nonresponsive (cisplatin resistant) patients (Choi, page 156, column 1, line 9-20) using the Illumina HT12v3 and HT12v4 chips (Choi, page 164, column 1, line 8-12). As evidenced by GPL6947 and GPL10558, corresponding to the HT12v3 and HT12v4 chips, respectively, the chips comprise probes that measure expression of at least the four elected genes, namely C15orf41, FKBP14, PSAT1 and C1QBP. Choi teaches gene expression signatures associated with responses to MVAC (a chemotherapy combination comprising cisplatin) (Choi, page 159, column 2). Furthermore, Choi teaches “Presurgical (neoadjuvant) cisplatin-based chemotherapy (NAC) is the current standard-of-care for high-risk MIBC (i.e. treating a subject with cisplatin) (Choi, page 159, column 2).
Choi teaches administering cisplatin to each of the subjects. Choi also teaches that each of the elected genes are higher expressed in a subset of MVAC-responsive tumors compared to non-cancer controls (i.e. those that are suitable to be treated with cisplatin) (Choi data visualized for individual probes with GEO “Profile graph” function, see non-final office action dated January 10, 2025). Furthermore, Choi teaches that said data can be used to prospectively identify the patients who most likely will not benefit from chemotherapy comprising Cisplatin (Choi, page 152, Significance box) (i.e. transmitting/receiving a report…).
Choi does not explicitly teach measuring expression levels of proteins encoded by the claimed genes.
However, it is well known in the art that gene expression can be measured by measuring the abundance of proteins encoded by particular genes of interest and that this is particularly important for genes that are regulated post-translationally. Furthermore, Silva et al. teaches that “in mammalian cells the correlation [between mRNA abundance and abundance of corresponding protein] has been shown to be much lower and variable depending on the cell type and state. The situation becomes even more complicated for cells that have been subjected to a stimulus.” (Silva et al., page 1, column 1, paragraph 1)
Well known reagents/methods of measuring gene expression at the level of protein comprise affinity reagents (i.e. antibodies, aptamers, etc.) and whole-proteome methods such as mass spectrometry.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have measured or reported/received a report comprising expression levels of at least the four proteins encoded by the recited genes, because it is evident from the data made public by Choi that each of said genes are expressed higher at the mRNA level in a subset of MIBC. The ordinary artisan would have been motivated to measure expression of the recited genes at the protein level because of the teaching of Silva et al. that changes in protein abundance are not always indicated by the abundance of mRNA in the cell, and that protein-level regulation (which is not observable at the level of mRNA abundance) contributes to defining tissue- and cell-type-specific functions (Silva et al., page 2, column 2). The ordinary artisan would have been reasonably confident that measuring protein levels would have provided a more direct measure of the active gene product(s) recited by the claims.
Response to Arguments
The response asserts that Silva et al. does not address the alleged deficiencies of the Choi et al. reference as discussed above [in response to the 102 rejection]. This assertion is not persuasive for at least the reasons described above.
Response to arguments in previous response
Applicants argued that the rejection of claims 1, 11-13, and 15 under U.S.C. 102 as being anticipated by Choi et al. on the grounds: (a) the Choi et al. reference does not mention the recited genes in the body of the text and did not recognize the recited genes as comprising a “chemosensitivity signature” (b) the response asserts that searching for the recited genes in the raw data using the GEO “profile graph” function constitutes “creating a new reference” and (c) said search constitutes “hindsight reconstruction”.
These arguments have been thoroughly reviewed and are not found to be persuasive as elaborated above in the revised 102 rejection necessitated by the claim amendments filed on April 8, 2025. In particular, the assertion that searching the raw data published by Choi et al, which is explicitly cited in the Choi et al. reference constitutes “creating a new reference” and is “improper hindsight reconstruction” is not persuasive because the cited GEO Accessions are the raw data produced by Choi (Choi page 164, col. 1, paragraph 8) and are therefore part of the disclosure made by Choi using the Illumina HT12v3 and HT12v4 chips. GSE48277 was made public on February 10, 2014 and was last updated on June 22, 2020. GSE47993 was made public on February 17, 2014 and was last updated on August 15, 2018. Therefore, ALL of the gene expression data was necessarily disclosed prior to the effective filing date of the claimed invention and all of this data taught by Choi is prior art under U.S.C. 102(a)(1). Furthermore, Choi teaches measuring at least the expression of these genes and administering Cisplatin commensurate in scope with the claims. The “profile graph function” built into the NCBI GEO database in which the raw data is stored explicitly states “This tab allows you to view a specific gene expression profile graph by entering the corresponding identifier from the ID column of the Platform record. This feature does not perform any calculations; it merely displays the expression values of the gene across Samples.” The raw data is stored as a table of probe/gene identifiers and numerical values. The “profile graph function” merely displays the numerical data as a chart and “does not perform any calculations.”
The assertion that Choi et al. did not recognize that the recited genes are constituents of a Cisplatin chemosensitivity signature is not persuasive because the features upon which applicant relies (i.e., a cisplatin sensitivity signature or a method of deriving said signature) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, the limitation “at least four genes comprise C15orf41, C1QBP, FKBP14, and PSAT1” recited in amended claim 21 is clearly anticipated by genes analyzed using Illumina HT12v3 and HT12v4 chips, which has been elaborated above in the maintained/revised rejection of claims 21 and 24 under 35 U.S.C. 102(a)(1) as being anticipated by Choi, et al. (2014).
Conclusion
No claim is allowed.
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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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