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 .
Application Status
Claims 1-3 and 5-20 are pending.
Claims 7-13 and 18-20 are withdrawn.
Claims 1-3, 5-6, and 14-17 are examined on the merits herein.
Grounds of Rejection Withdrawn
Previous objections to the specification are withdrawn in view of amendment.
All previous rejections of claim 4 are rendered moot by claim cancellation.
Previous rejection of claims 1-3, 5-6, and 14-17 under 35 U.S.C. 102 over Fritsch are withdrawn in view of claim amendments.
Previous rejection of claims 1-3, 5-6, and 16-17 under 35 U.S.C. 102 over Svane are withdrawn in view of claim amendments.
Claim Objections
Claims 1-2 are objected to because of the following informalities:
Claims 1-2 recite “wherein BRAF inhibitor-resistant cancer has increased” should read “wherein the BRAF inhibitor-resistant cancer has increased”;
Appropriate correction is required.
Claim Interpretation
Claims 1 and 2 recite wherein BRAF inhibitor-resistant cancer has increased expression of insulin-like growth factor II receptor (IGF2R) relative to a control cancer after the active steps of the method. The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed, therefore the increased expression of IGF2R relative to a control cancer is inherent to the method as it is not an active method step.
Claim Rejections - 35 USC § 112(b)
New Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5-6, and 14-17 are 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.
Claims 1-2 recite “wherein BRAF inhibitor-resistant cancer has increased expression of insulin-like growth factor II receptor (IGF2R) relative to a control cancer”, this phrase renders the scope of the claim as indefinite as this term is not clearly defined. The instant specification does not define “a control cancer” nor are there any examples provided with this type of control. The instant specification teaches: A "control" is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative"(Para 37). The instant specification utilizes DMSO treated cell lines as controls as well as cell lines that have not been genetically manipulated as a basis for comparison for cell lines that have been manipulated to overexpress M6PR (Figure 6).
It is unclear whether the increased expression of IGF2R relative to the control cancer is before administration of the BRAF inhibitor and adoptive cell therapy or after administration of the treatment.
Is the control cancer meant to be BRAF inhibitor resistant with progression but not administered the combination regimen of a BRAF inhibitor and an adoptive cell therapy; or a cancer cell line that does not have increased IGF2R expression but is BRAF inhibitor resistant and has been treated with the a BRAF inhibitor and an adoptive cell therapy?
Regarding 3, 5-6, and 14-17 depend from claim 1 or 2 without correcting the issues identified above and are therefore included in this rejection.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
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 1-3, 5-6, and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Fritsch (US 2018/0153975 A1; IDS entered August 12, 2021) and Kakadia (Onco Targets Ther, 2018 Oct 17, 11:7095-7107; IDS entered August 12, 2021).
Regarding claims 1-2, 5-6, and 17, Fritsch teaches a method of treating or preventing a tumor in a population of subjects in need thereof, comprising administering to a subject an agent comprising an extracellular ligand-binding domain recognizing a tumor-specific neoepitope…wherein agent may be CAR or T cell receptor (para 0050). Fritsch further teaches that the treatment comprises an inhibitor of BRAF, such as Vemurafenib, used as an additional agent and that BRAF inhibition has been shown to be associated with an increase in melanoma antigen expression and T-cell infiltrate and a decrease in immunosuppressive cytokines in tumors of treated patients (para 0666), this would increase the sensitivity of cancer to ACT as required by claim 2. Fritsch further teaches wherein the cancer has tumor specific mutations and the tumor-specific mutations comprise drug resistance mutations (para 0094) wherein at least one tumor-specific mutation is a drug resistance mutation to BRAF/V600E (para 0095) and further that the drug resistance mutation may be induced by treatment with vemurafenib and the subject has a drug resistance mutation before treatment (para 0017).
Regarding claims 3 and 16, Fritsch teaches that the solid tumor may be melanoma (para 0012).
Regarding claim 14, Fritsch teaches herein the population suffering from cancer was treated with, is being treated with, or is selected to be treated with RAF/MEK inhibitor (para 0086).
Fritsch does not teach that the subject has progressed following a previous BRAF inhibitor regimen.
Kakadia teaches that treatment with a BRAF inhibitor results in a high response rate but that the response is short lived with a median time to progression of 5.1–8.8 months (introduction) and that combining adoptive T cell transfer with BRAF inhibitor treatment improves antitumor activity , in vivo cytotoxic activity and intratumoral cytokine secretion as one way to overcome BRAF inhibitor resistance (page 7099, col 1, para 1).
Regarding claim 14, Kakadia teaches that treatment with BRAF inhibitor and specifically vemurafenib leads to genetic alteration in over 50% of patients that results in reactivation of the MAPK and to a lesser extent the PI3K/Akt pathways which are acquired resistance mechanisms (page 7096, col 1, paras 2-3; summarized in Table 1). Kakadia further teaches that adding a MEK inhibitor to BRAF inhibitor treatment can overcome resistance to BRAF inhibitors and enhance immunosurveillance (page 7098, last para- page 7099, first para). Kakadia further teaches combined BRAF-MEK inhibitor therapy is the standard of care for BRAF V600 mutant advanced melanoma, including vemurafenib combined with cobimetinib (page 7104, col 1, para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to treat BRAF resistant cancer and to add a MEK inhibitor as taught by Kakadia to the method of treatment of melanoma with ACT and a BRAF inhibitor as taught by Fritsch. The ordinary artisan would have been motivated to do so as Kakadia teaches that treatment with a BRAF inhibitor has short term benefits but results in resistance in more than half of patients that are treated and Fritsch teaches use of the method wherein at least one tumor-specific mutation is a drug resistance mutation to BRAF/V600E wherein the subject has a drug resistance mutation before treatment. Kakadia further teaches that adoptive cell transfer combination with BRAF inhibition treatment may overcome BRAF inhibitor resistance as it augments the antitumor activity. Kakadia further teaches that combination treatment with a BRAF inhibitor with a MEK inhibitor is an FDA approved standard of care for BRAF V600 advanced melanoma and a MEK inhibitor can overcome BRAF inhibitor resistance and enhance immunosurveillance. Therefore the ordinary artisan has a reasonable expectation of success to overcome BRAF resistance in cancer therapy with combination therapy comprising ACT and a BRAF inhibitor and further augmenting results with the addition of a MEK inhibitor.
Further, regarding increased expression of IGF2R relative to a control, such expression is an inherent biological or natural feature with no requirement to measure or test for such expression in the claim. See claim interpretation (supra).
Further, Chuang (PLOS ONE 9(10): e109992; PTO-892) teaches that upregulation of mannose-6-phosphate (M6P, which is another name for IGF2R) expression sensitizes tumor cells to cytotoxic T lymphocytes (CTLs) (page 7, col 1).
Response to Arguments
Applicant's arguments filed 03/23/2026 have been fully considered but they are not persuasive.
Applicant submits: It was unexpectedly shown in the present application that, "treatment with [BRAF inhibitor] PLX4720 significantly (p<0.05) increased killing of [IGF2R/M6PR overexpressing] WM983B tumor cells by TILs, whereas this effect was not observed in [IGF2R/M6PR knockout] WM983B-M6PR-KO cells (Fig. 8F)."
In response: As the prior art Chuang teaches that upregulation of mannose-6-phosphate (M6P, which is another name for IGF2R) expression sensitizes tumor cells to cytotoxic T lymphocytes this is not an unexpected result (see updated 103 rejection above).
The remainder of applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Examiner’s Note
The 112 and 103 rejections detailed above can be obviated by requiring a manipulative step to check for IGF2R expression to screen the patients that are BRAF inhibitor resistant for increased IGF2R expression prior to administration of the combination regimen of adoptive cell therapy and BRAF inhibitor.
As an example: Claim 1. A method of treating a BRAF inhibitor-resistant cancer in a subject wherein the subject’s cancer has progressed following a previous BRAF inhibitor administration or a previous MEK inhibitor regimen comprising in the following order:
Measuring the expression of IGF2R in the subject’s cancer wherein the BRAF inhibitor resistant cancer has increased expression of IGF2R relative to a control cancer;
administering a BRAF inhibitor and adoptive T cell therapy to the subject with increased IGF2R expression.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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