Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/18/2025 has been entered.
Currently, claims 1-2, 8-20, 23-26, 29-32, 35-38, 41-42 are pending in the instant application. Claims 3-7, 21-22, 27-28, 33-34, 39-41 have been canceled and claims 10-20. 23-26, 29-32, 35-38, 41-42 are withdrawn. This action is written in response to applicant’s correspondence submitted 12/18/2025. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are reiterated from the previous office action. This action is FINAL.
Claims 1-2 and 8-9 are under examination. Claim 8 is under examination with regard to elected MEKi and Claim 9 is under examination with regard to elected selumetinib.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-2 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Flueckinger (Cancer Res 2016, 76, (14_Supplement):300) in view of Vaira (PNAS, 2010, vol 107, pp8352-8356). This rejection was previously presented and is reiterated below.
Flueckinger teaches that BRAFi treatment induces a SOX2 dependent cellular program with features of adaptive drug resistance. Flueckinger teaches analysis of SOX2 expression in a melanoma cell line that was treated with BRAFi and analysis of SOX2 expression before and after treatment. Flueckinger teaches acute inhibition of oncogenic MAPK signaling by BRAFi or MEKi in established and primary patient-derived melanoma cell cultures leads to rapid induction of stem cell maintenance and pluripotency factor SOX2. Flueckinger does not explicitly teach exposing an isolated sampled obtained from a tissue sample ex vivo to MAPKi, determining expression level of SOX2 in one sample exposed to MAPKi and determining expression level of SOX2 in a sample not exposed to MAPKi.
However, it was known in the art to isolate a sample comprising a tissue sample and determine expression before and after treatment in ex vivo patient derived cells. Vaira teaches an ex vivo method that is reproducible, rapid and personalized culture method to investigate antitumoral pharmacological properties (see pg. 8352, 2nd column). Vaira teaches obtaining tissue samples and culturing in a 6 well plate (see pg. 8352, 2nd column). Vaira teaches measuring gene expression in the tissue culture from colon, lung, prostate and adenocarcinoma (see pg. 8353, 2nd column). Vaira teaches ex vivo treatment with a PI3K inhibitor and teaches expression change after treatment (see targeted therapy in ex vivo Tissue culture). Vaira teaches the method is a rapid, reproducible, and personalized method suitable to test therapeutic agents in viable tumor sections (see pg. 8355)
It would have been obvious to modify the method of Flueckinger to include determining expression level of SOX2 in a sample comprising tissue samples exposed to MAPKi ex vivo because Flueckinger teaches patient derived melanoma cell cultures before and after treatment and Vaira teaches obtaining tissue samples and testing therapeutic response and expression analysis ex vivo allows for a rapid test for therapeutic agents in viable tumor sections. The skilled artisan would have been motivated to include analysis of SOX2 by ex vivo analysis of melanoma tissue samples because Flueckinger teaches patient derived melanoma cells and analysis of inhibitor, MAPKi for gene expression and Vaira teaches a reproducible and personalized method using tissue samples from cancer samples to test therapeutic agents with expression analysis which allows a personalized method. The skilled artisan would have further been motivated to include analysis of a sample comprising tissue samples and analysis ex vivo by exposing the sample to MAPKi in the method of Flueckinger because Flueckinger teaches SOX2 expression was determined by exposing to MEKi in patient derived melanoma cell cultures and Vaira ex vivo patient derived tissue cultures and teaches exposing inhibitors to tissue cultures for treatment response. Additionally the skilled artisan would have a reasonable expectation of success that the method of Flueckinger could include ex vivo analysis of SOX2 expression after exposure to MEKi because Flueckinger teaches patient derived cells for the gene expression analysis after exposed to an inhibitor and Vaira teaches tissue derived cultures and expose to an inhibitor followed by expression analysis to determine targeted inhibitors for patients teaching the method allows for a rapid, reproducible, and personalized method suitable to test therapeutic agents in viable tumor sections. Because both Flueckinger and Vaira teach culture medium for analysis of expression before and after exposure to an inhibitor, it would have been obvious to one skilled in the art to substitute the melanoma cell line of Flueckinger with an ex vivo tissue model as taught by Vaira in order to achieve the predictable result of an ex vivo melanoma tissue model for analysis of expression before and after exposure to MAPKi to determined drug resistance.
Response to Arguments
The response traverses the rejection on pages 15-17 of the remarks mailed 12/18/2025. The response asserts Flueckinger neither describes nor suggests a method for determining whether a cancer or tumor cell will develop resistance to a chemical substance or whether a subject previously diagnosed with cancer will develop a resistance to chemical substance. The response asserts Flueckinger does not describe or suggest ex vivo exposure of a sample obtained by a tissue biopsy and points to Flueckinger treating mice with MAPKi in vivo and then immunohistochemical analysis of melanoma sections. This response has been reviewed but not found persuasive. Flueckinger was not cited to describe or suggest ex vivo exposure of a sample obtained by a tissue biopsy. Flueckinger was cited to described SOX2 expression in response to MAPKi and analysis using immunohistochemical analysis of obtained tissue samples. Flueckinger demonstrates SOX2 expression before and after in vivo treatment with BRAFi/MEKi. Flueckinger teaches expression of SOX2 increased after BRAFi/MEKi treatment from drug resistance and decreased SOX2 expression could potentially extend the clinical efficacy of BRAFi/MEKi. Flueckinger teaches increased SOX2 expression is associated with drug resistance. Vaira teaches an ex vivo method to predict response of chemotherapy. Therefore, it would have been obvious to one of ordinary skill in the art to use the methodology of Varia to predict response to MEKi therapy in melanoma tissue samples from a subject by measuring increased SOX2 expression for determining if a subject will develop resistant, because Flueckinger teaches increased SOX2 expression is associated with resistance to MEKi therapy.
The response asserts that Vaira teaches ex vivo culture method may impact predicting response to small molecule inhibitor therapy. The response asserts that PI3k inhibitor decreased proliferation and viability. The response asserts that measuring viability after ex vivo drug exposure of tissue may indicate the cancer cell is responsive and not resistant. The response further asserts another scenario in which the patient is initially responsive to the drug then becomes nonresponsive. The response asserts that Vaira describes determining whether a cell is resistant not whether a subject will develop resistance as claimed. The response asserts that measuring proliferation or viability is not suitable in the method of determining whether a cell will develop resistance. This response has been reviewed but not found persuasive. The rejection is not based on determining proliferation or viability of a cell being exposed to MEKi, the rejection is based on exposing a melanoma cell ex vivo to MEKi inhibitor, measuring SOX2 expression, before and after exposure to MEKi, and elevated expression of SOX2 is indicative of development of resistance to MEKi. The combination of Flueckinger in view of Vaira render the claims obvious. Specifically Flueckinger teaches SOX2 expression is increased in response to resistant to MEKi therapy. Vaira demonstrates an ex vivo assay that allows for predicting tumor sensitivity to drugs in a patient specific manner. Vaira was cited to teach measuring expression before and after treatment in ex vivo patient derived cells. Vaira teaches the method is reproducible, rapid, and personalized culture method to investigate antitumoral pharmacological properties. While Vaira teaches proliferative activity and viability, Vaira also teaches expression analysis before and after treating the ex vivo samples with a therapeutic. Therefore Flueckinger in view of Vaira render the claims obvious for the reasons stated above. For these reasons and reasons of record this rejection is maintained.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Flueckinger in view of Vaira as applied to claim 1-2 and 8 above, and further in view of Ambrosini (WO2015/035146 A2, cited on IDS).
Flueckinger in view of Chung is set forth in section 13 above. Clark in view of Flueckinger does not teach the MAPKi is selumetinib.
Ambrosini teaches obtaining a sample of cancer, determining in the sample whether cells of the cancer contain an increased level relative to a responder cancer cell of mRNA where if the level of gene is increased MEK inhibitor would not have an anti-cancer effect on the cancer (see pg. 10). Ambrosini teaches determining expression level of the same gene before and after selumetinib treatment in patients with melanoma. Ambrosini teaches cells for testing include a biopsy sample and a blood sample (see lines 9-12, pg. 8). Additionally, Ambrosini teaches exposure of cells obtained from melanoma cell line (sample consisting of tumor cells) to selumetinib and teaches cell lines were analyzed for gene expression before and after treatment and over time. Ambrosini teaches expression increased and indicated resistance (see pg. 35-36).
Given the prior art teaches expression levels of genes in cells ex vivo from patients with melanoma before and after MEKi treatment, it would have been prima facie obvious to the ordinary artisan at the time the invention was made to screen and test different MEK inhibitors, including selumetinib. The skilled artisan would have been motivated to include additional MEK inhibitor types because both Flueckinger in view of Varia and Ambrosini teach analysis of gene expression before and after exposure to MEK inhibitors and melanoma cancer cells and Ambrosini teaches MEK inhibitors including selumetinib in patients with melanoma. The skilled artisan would have had a reasonable expectation of success that selumetinib could be analyzed for SOX2 expression because Flueckinger in view of Varia teaches analysis of SOX2 expression with MEK inhibitors and Ambrosini teaches expression analysis with MEK inhibitors including selumetinib for melanoma cancer.
Response to Arguments
The response traverses the rejection on page 18 of the remarks mailed 12/18/2025. The response asserts that claim 1 is not obvious in view of Flueckinger and Vaira and dependent is not obvious over Flueckinger and Vaira in view of Ambrosini. This response has been reviewed but not found persuasive. Claim 1 is obvious over Flueckinger in view of Vaira for the reasons stated above. For these reasons and reasons of record the rejection is maintained.
Conclusion
No claims are allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 SARAE L BAUSCH whose telephone number is (571)272-2912. The examiner can normally be reached M-F 9a-4p.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1634