92on1DETAILED 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 1-20 are pending. Claims 11 and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Claims 1-2, 10, 12, and 15-17 are amended.
Claims 1-10 and 12-18 are currently under examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/19/25 has been entered.
Priority
The instant application 17/594,119 filed on 10/4/21 is a 371 US national phase of PCT/US2020/026240 filed on 4/1/20, and claims domestic priority to provisional application 62/828,079 filed on 4/2/19. The priority date is determined to be 4/2/19.
Response to Arguments
Applicant’s arguments, see pages 5-7, filed 12/19/25, with respect to the rejections of claims 1-10 and 12-18 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments are made in this Non-Final Office Action.
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.
Claims 1-10 and 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bryant et al. (2012; US 8,278,038 B2; USPat citation A in PTO-892 filed 8/25/25) in view of Genomics of Drug Sensitivity in Cancer (GDSC) – Doxorubicin IC50 data in Glioblastoma multiforme (2016; NPL citation X in PTO-892 filed 3/10/25), Yong et al. (2015; NPL citation 48 in IDS filed 3/7/24; “Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients”; PLOS ONE 10(10): e0141334. https://doi.org/10.1371/journal.pone.0141334), and Valkov et al. (2003; NPL citation V in PTO-892 filed on 8/25/25; "Tumor p53 status and response to topoisomerase II inhibitors"; Drug Resistance Updates 6 (2003) 27-39; doi:10.1016/S1368-7646(02)00143-7).
(i) Bryant et al. teaches limitations relevant to claims 1, 3-10, 12-16, and 18.
Relevant to claim 1, Bryant et al. Abstract teaches "The present invention is directed to the identification of predictive markers that can be used to determine whether patients with cancer are clinically responsive or non-responsive to a therapeutic regimen prior to treatment. In particular, the present invention is directed to the use of certain individual and/or combinations of predictive markers, wherein the expression of the predictive markers correlates with responsiveness or non-responsiveness to a therapeutic regimen. Thus, by examining the expression levels of individual predictive markers and/or predictive markers comprising a marker set, it is possible to determine whether a therapeutic agent, or combination of agents, will be most likely to reduce the growth rate of tumors in a clinical setting."
Further relevant to claim 1, Bryant et al. teaches "In one aspect, one or more of the markers listed in any one of Table 1A, Table 18, Table 2A, Table 2B, and/or Table 3, can be used to identify candidate agents for use in a treatment regimen which will produce a response in a patient" (column 31, lines 28-31). Table 1A includes RPS11, RPS16, and RPS18.
These teachings read on claim 1 A method comprising (a) detecting expression of one or more markers in a biological sample from a subject having cancer, the markers selected from RPS11, RPS16 and RPS18.
Further relevant to claim 1, Bryant et al. teaches "Determining the level of expression of a predictive marker is compared to a reference expression level. For example, a reference expression level can be a predetermined standard reference level of expression in order to evaluate if expression of a marker or marker set is informative and make an assessment for determining whether the patient is responsive or non-responsive" (column 12, lines 45-51).
Further relevant to claim 1, Bryant et al. teaches "The level of expression of a marker or markers may be determined as having increased expression in certain aspects" (column 12, lines 65-66).
Further relevant to claim 1, Bryant et al. teaches “However, if the expression profile of one or more marker sets identified in Table 1A, Table 1B, Table 2A, Table 2B, and/or Table 3 demonstrates increased non-responsiveness in the presence of the agent, then the cancer may have become resistant to proteasome inhibition therapy and/or glucocorticoid therapy, and another treatment protocol should be initiated to treat the patient” (column 44, lines 16-22). Upregulated RPS11, RPS16, and RPS18 demonstrate increased non-responsiveness in Table 1A, and would thus be treated with “another treatment protocol” such as the chemotherapeutic agents included in the Bryant et al. teaching that “Further to the above, the language, proteasome inhibition therapy regimen and/or glucocorticoid therapy regimen can include additional agents in addition to proteasome inhibition agents, including chemotherapeutic agents. A ‘chemotherapeutic agent’ is intended to include chemical reagents which inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable. Chemotherapeutic agents such as… Topoisomerase II inhibitors, e.g., VW-26, topotecan and Bleomycin, strand-breaking agents, e.g., doxorubicin…" (column 32, lines 12-23).
These teachings read on claim 1 (b) administering a topoisomerase 2 (TOP2) poison compound to the subject when the expression of at least one of the one or more markers is increased relative to a control.
Relevant to claims 3-4, Bryant et al. teaches "In certain aspects, determining the level of expression of a predictive marker comprises detection of mRNA" (column 12, lines 34-35).
This teaching reads on claim 3 comprising detecting nucleic acid encoding the marker; and claim 4 wherein detecting nucleic acid encoding the marker comprises detecting mRNA encoding the marker.
Relevant to claim 5, Bryant et al. teaches "As used herein, a 'marker' may also include a cDNA made by reverse transcription of an RNA generated by transcription of genomic DNA (including spliced RNA)" (column 6, lines 11-14).
Further relevant to claim 5, Bryant et al. teaches "An alternative method for determining the level of mRNA corresponding to a marker of the present invention in a sample involves the process of nucleic acid amplification, e.g., by rtPCR… or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art" (column 25, lines 13-26).
These teachings read on claim 5 further comprising performing reverse transcription to prepare a cDNA, amplifying the cDNA to prepare an amplicon, and detecting the amplicon.
Relevant to claims 6, 8-9, and 14, Bryant et al. teaches "An exemplary method for detecting the presence or absence of a nucleic acid or polypeptide corresponding to a marker of the invention in a biological sample involves obtaining a biological sample (e.g. a tumor sample) from a test subject and contacting the biological sample with a compound or an agent capable of detecting the polypeptide or nucleic acid (e.g., mRNA, genomic DNA, or cDNA). The detection methods of the invention can thus be used to detect mRNA, protein, cDNA, or genomic DNA, for example, in a biological sample in vitro as well as in vivo… In vitro techniques for detection of a polypeptide corresponding to a marker of the invention include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence" (column 22, lines 20-36).
This teaching reads on claim 6 comprising detecting a gene encoding the marker; claim 8 comprising detecting the marker protein; claim 9 wherein the marker protein is detected via performing an immunoassay; and claim 14 wherein the biological sample is a tumor biopsy.
Relevant to claim 7, Bryant et al. teaches "Any and all such nucleotide variations and resulting amino acid polymorphisms or variations that are the result of naturally occurring allelic variation and that do not alter the functional activity are intended to be within the scope of the invention" (column 35, lines 53-57).
Relevant to claim 10, Bryant et al. teaches "and tumors of the nervous system including glioma, meningoma, medulloblastoma…" (column 8, lines 23-24).
This teaching reads on claim 10 wherein the cancer is a glioblastoma or medulloblastoma.
Relevant to claim 12, Bryant et al. teaches "The chemotherapeutic agents generally employed in chemotherapy treatments are listed below in Table A" (column 32, lines 31-22). Bryant et al. Table A includes etoposide, teniposide, and doxorubicin.
These teachings read on claim 12 wherein the TOP2 poison compound is selected from amsacrine, etoposide, etoposide phosphate, teniposide, and doxorubicin.
Relevant to claim 13, Bryant et al. teaches "For example, if the method is being used to determine whether a patient's cancer can be treated with an agent, or a combination of agents, then the preferred source of sample will be cancer cells obtained from a tumor from the patient, e.g., a tumor biopsy (including a solid or a liquid tumor), a blood sample, a plasma sample, a urine sample, a saliva sample, a lymph sample or other sample can be used" (column 21, lines 2-9).
This teaching reads on claim 13 wherein the biological sample is blood or a blood product.
Relevant to claim 15, Bryant et al. Abstract teaches "The present invention is directed to the identification of predictive markers that can be used to determine whether patients with cancer are clinically responsive or non-responsive to a therapeutic regimen prior to treatment. In particular, the present invention is directed to the use of certain individual and/or combinations of predictive markers, wherein the expression of the predictive markers correlates with responsiveness or non-responsiveness to a therapeutic regimen. Thus, by examining the expression levels of individual predictive markers and/or predictive markers comprising a marker set, it is possible to determine whether a therapeutic agent, or combination of agents, will be most likely to reduce the growth rate of tumors in a clinical setting."
Further relevant to claim 15, Bryant et al. teaches "In one aspect, one or more of the markers listed in any one of Table 1A, Table 18, Table 2A, Table 2B, and/or Table 3, can be used to identify candidate agents for use in a treatment regimen which will produce a response in a patient" (column 31, lines 28-31). Table 1A includes RPS11, RPS16, and RPS18.
Further relevant to claim 15, Bryant et al. teaches "In certain aspects, determining the level of expression of a predictive marker comprises detection of mRNA" (column 12, lines 34-35).
Further relevant to claim 15, Bryant et al. teaches "Determining the level of expression of a predictive marker is compared to a reference expression level. For example, a reference expression level can be a predetermined standard reference level of expression in order to evaluate if expression of a marker or marker set is informative and make an assessment for determining whether the patient is responsive or non-responsive" (column 12, lines 45-51).
Further relevant to claim 15, Bryant et al. teaches "The level of expression of a marker or markers may be determined as having increased expression in certain aspects" (column 12, lines 65-66).
Further relevant to claim 15, Bryant et al. teaches “However, if the expression profile of one or more marker sets identified in Table 1A, Table 1B, Table 2A, Table 2B, and/or Table 3 demonstrates increased non-responsiveness in the presence of the agent, then the cancer may have become resistant to proteasome inhibition therapy and/or glucocorticoid therapy, and another treatment protocol should be initiated to treat the patient” (column 44, lines 16-22). Upregulated RPS11, RPS16, and RPS18 demonstrate increased non-responsiveness in Table 1A, and would thus be treated with “another treatment protocol” such as the chemotherapeutic agents included in the Bryant et al. teaching that “Further to the above, the language, proteasome inhibition therapy regimen and/or glucocorticoid therapy regimen can include additional agents in addition to proteasome inhibition agents, including chemotherapeutic agents. A ‘chemotherapeutic agent’ is intended to include chemical reagents which inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable. Chemotherapeutic agents such as… Topoisomerase II inhibitors, e.g., VW-26, topotecan and Bleomycin, strand-breaking agents, e.g., doxorubicin…" (column 32, lines 12-23).
These teachings read on claim 15 A method for treating a subject having cancer, the method comprising: (a) detecting one or more mRNAs encoding one or more of RPS11, RPS16, and RPS18 in a biological sample from the subject; (b) quantifying the amount of detected mRNAs relative to one or more control mRNAs; and (c) administering a topoisomerase 2 (TOP2) poison compound to the subject when the amount of detected mRNAs encoding at least one of RPS11, RPS16, or RPS18 is increased relative to the one or more control mRNAs.
Relevant to claim 16, Bryant et al. teaches "The chemotherapeutic agents generally employed in chemotherapy treatments are listed below in Table A" (column 32, lines 31-22). Bryant et al. Table A includes etoposide, teniposide, and doxorubicin.
These teachings read on claim 16 wherein the TOP2 poison compound is selected from amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin.
Relevant to claim 18, Bryant et al. teaches "and tumors of the nervous system including glioma, meningoma, medulloblastoma…" (column 8, lines 23-24).
This teaching reads on claim 18 wherein the cancer is glioblastoma or medulloblastoma.
(ii) Bryant et al. is silent to TOP2 poison compound concentrations relevant to claims 1-2, 15, and 17. However, this limitation was known in the prior art and taught by Genomics of Drug Sensitivity in Cancer (GDSC) – Doxorubicin IC50 data in Glioblastoma multiforme.
Relevant to claims 1 and 15, the IC50 data shows doxorubicin administration at < 6 µM for all but one glioblastoma cell line.
This teaching reads on claim 1 wherein the TOP2 poison compound is administered at a dose that delivers a concentration of 6 µM or less to the cancer; and claim 15 wherein the TOP2 poison compound is administered at a dose that delivers a concentration of 6 µM or less to the cancer.
Relevant to claims 2 and 17, the IC50 data shows doxorubicin administration at < 1 µM for all but four glioblastoma cell lines.
This teaching reads on claim 2 wherein the TOP2 poison compound is administered at a dose that delivers a concentration of 1 µM or less to the cancer; and claim 17 wherein the TOP2 poison compound is administered at a dose that delivers a concentration of 1 µM or less to the cancer.
(iii) Although Bryant et al. does not explicitly teach the GDSC TOP2 poison compound concentrations, it would have been prima facie obvious to the skilled artisan. Bryant et al. and GDSC are analogous disclosures to the instant cancer biology field.
The skilled artisan would have been motivated to combine the analogous art. The skilled artisan would recognize that increased expressions of RPS11 would result in TOP2 poison compound treatment responsiveness.
Yong et al. teaches that “Recently, multiple lines of evidence have shown that a number of RPs are mouse double minute 2 homolog (MDM2)-binding partners, and it is suggested that, under nucleolar stress conditions, free RPs are released to the nucleoplasm where they interact with MDM2, leading to blockage of its E3 ligase function and resulting in the stabilization and activation of p53… Thus, upregulation of RPS11 in quiescent TRGC [treatment-resistant glioblastoma stem cell clones] or in tumors may be associated with maintenance of a stem-like, stress-resistant phenotype. This may also explain that the association of upregulation of RPS11 with poor prognosis is more pronounced in patients with newly diagnosed primary GBM [glioblastoma], a GBM subtype that more often lacks p53 mutations than secondary GBM… Like RPS11, RPS20 is one of the RPs that can also bind to MDM2 and activate p53…” (page 14, paragraph 2).
Valkov et al. teaches "Usually, wild-type p53 expression predisposes cells (normal or slightly transformed) to a more rapid rate of cell death after DNA damage. That is why mutations in p53 are postulated to confer drug resistance to genotoxic agents… Tumors with p53 mutations were found to be significantly resistant to a chemotherapy regimen that included two topo II inhibitors (etoposide and epirubicin)" (page 34, column 1, paragraph 2).
Valkov et al. additionally teaches “It may be that wild-type p53 status expression is needed to prevent the excessive recombinational activity induced by topo II-based chemotherapy, and perhaps reduce the frequency of secondary malignancies” (page 31, column 2, last sentence of paragraph 2).
Taken together, the skilled artisan would recognize that the Yong et al. teachings (upregulated RPS11 and association with a GBM subtype “often [lacking] p53 mutations” and p53 activation) and Valkov et al. teachings (activated and wild-type expression of p53) would confer responsiveness to topoisomerase II poison compounds. The skilled artisan would further recognize that the GDSC TOP2 poison compound concentrations have been successfully administered to glioblastoma cells, and would thus consider those concentrations as appropriate administrative doses.
Given these teachings, the skilled artisan would have been motivated to administer a TOP2 poison compound when ribosomal proteins are enriched because the skilled artisan would have known to take advantage of the disruption of ribosome biogenesis-p53 pathway in order to “reduce the frequency of secondary malignancies.”
The skilled artisan would have a reasonable expectation of success based on the disclosures of Bryant et al. in view of Genomics of Drug Sensitivity in Cancer (GDSC) – Doxorubicin IC50 data in Glioblastoma multiforme, Yong et al., and Valkov et al. as discussed in the preceding paragraphs.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682