DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The amendment filed on 11/14/2025 has been entered. Claims 1-8, 12, and 13 are cancelled. Claims 9-11 and 14-23 are pending in this application. Claims 10 and 16-20 are withdrawn. Claims 9, 11, 14, 15, and 21-23 are currently examined.
Priority
This application is a DIV of 17/098,177 filed on 11/13/2020, now PAT 11786542, and claims benefit of US PRO No. 62/936,139 filed on 11/15/2019.
Withdrawn Claim Objections/Rejections
The objection of claim 9, as set forth on page 3 of the Non-Final Rejection mailed on 08/14/2025, is withdrawn in view of previously amended claim.
The rejection of claims 9, 11, 14, 15, and 21-23 under 35 U.S.C. 112(a), as set forth on pages 3-4 of the Non-Final Rejection mailed on 08/14/2025, is withdrawn in view of previously amended claims.
The rejection of claims 9, 11, 14, and 15 are rejected under 35 U.S.C. 112(a), as set forth on pages 4-6 of the Non-Final Rejection mailed on 08/14/2025, is withdrawn in view of previously amended claims.
The rejection of claims 9, 11, 14, and 15 under 35 U.S.C. 102(a)(1) as being anticipated by Seok et al. as evidenced by Jacobs et al., Shireman et al., and Wang et al., as set forth on pages 7 to 8 of the Non-Final Rejection mailed on 08/14/2025, is withdrawn in view of debatable three-subtype or four-subtype classification of glioblastoma, as indicated in Applicant’s Arguments/Remarks with cited references (p. 6, last para.; p. 7, para. 1) filed on 11/14/2025. In response, these arguments are persuasive because the Seok et al. did not teach specific subtype of glioblastoma.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 9, 11, 14, 15, and 21-23 remain rejected under 35 U.S.C. 103 as being unpatentable over Seok et al. (Korean Society of Internal Medicine Fall Conference 2018.1 (2018): 456; hereinafter referred to as Seok ‘2018, cited in the previous office action) in view of Jacobs et al. (US 2019/0015423, Jan. 17, 2019, hereinafter referred to as Jacobs ‘423, cited in the previous office action), Shireman et al. (Neuro Oncol. 2018 Nov 5;20(Suppl 6):vi75, hereinafter referred to as Shireman ‘2018, cited in the previous office action), and Wang et al. (Cancer Cell 32, 42–56, July 10, 2017, hereinafter referred to as Wang ‘2017).
Seok ‘2018 disclosed a rare case of kidney transplantation recipient with abrupt neurologic symptom, who was finally diagnosed with intracranial glioblastoma. The patient received immunosuppressive therapy with cyclosporine, prednisolone and mycophenolate mofetil for 7 years and then has still treated with prednisolone and mycophenolate mofetil. Concomitant temozolomide-based chemotherapy and radiotherapy (6000 Gy/30 fx) was performed for 30 days and the patient was discharged without any focal neurologic deficit (page 456, para. 1).
Seok ‘2018 did not explicitly disclose the limitations “a therapeutic agent that down-regulates expression of ARL13B or that inhibits biological activity of ARL13B”, and “the ARL13B-mediated proliferative cell disease or disorder is mesenchymal subtype glioblastoma, classical subtype glioblastoma, or proneural subtype glioblastoma”, required by claims 9 and 21-23.
Jacobs ‘423 disclosed Table 4, Compounds increasing both cilia length and cilia incidence, including inosine-5’-monophosphate dehydrogenase (IMPDH) inhibitor: mycophenolate mofetil. Arl13b is a protein that is naturally trafficked exclusively to the primary cilium. Many diseases are attributed to cilia formation and/or functional defects, which affect organs, such as kidney, brain, limb, eye, ear, liver and bone (page 71/85, row 8; page 59/85, [0302]; page 48/85, [0153]).
Shireman ‘2018 disclosed that knockdown of ciliary protein ARL13B in patient derived xenograft cells significantly increased survival of mice in an orthotropic glioblastoma (GBM) model. An ARL13B pulldown during temozolomide (TMZ) therapy identified inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in de-novo guanine nucleotide biosynthesis, as a significant binding partner of ARL13B during TMZ chemotherapy. When ARL13B is lost, GBM cells are forced into salvage pathway synthesis thus becoming sensitized to TMZ therapy due to increased incorporation of alkylated purines (page 1/2).
Wang ‘2017 disclosed when comparing the clustering result with the previously defined proneural (PN), neural (NE), classical (CL), and mesenchymal (MES) classification, the three subtypes were strongly enriched for MES, PN, and CL GBMs, respectively. None of the three subtypes were enriched for the NE subtype, suggesting the NE phenotype is non-tumor specific (page 44, right col., para. 1; page 45, left col., para. 1). Temozolomide (TMZ) treatment of gliomas can induce hypermutation. Patients with hypermutated tumors may have a more immunological reactive microenvironment that may be responsive to immune checkpoint inhibitors (page 50, right col., para. 3; page 52, left col., para. 1).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the glioblastoma treated with mycophenolate mofetil as IMPDH inhibitor or knockdown of ARL13B along with temozolomide (TMZ) as taught by Seok ‘2018 in view of Jacobs ‘423 and Shireman ‘2018 with glioblastoma subtype (either mesenchymal subtype, classical subtype, or proneural subtype) in view of Wang ‘2017 for increasing both cilia length and cilia incidence and inhibiting glioblastoma or subtype glioblastoma because either mycophenolate mofetil or knockdown of ARL13B inhibits the binding of ARL13B to IMPDH and temozolomide promotes binding of (IMPDH2) to ARL13B or hypermethylation, described above. Thus, one of skill in the art would have a reasonable expectation that by substituting the glioblastoma treated with mycophenolate mofetil as IMPDH inhibitor or knockdown of ARL13B along with temozolomide (TMZ) as taught by Seok ‘2018 in view of Jacobs ‘423 and Shireman ‘2018 with glioblastoma subtype (either mesenchymal subtype, classical subtype, or proneural subtype) in view of Wang ‘2017, one would achieve Applicant’s claims 9, 11, 14, 15, and 21-23. "Exemplary rationales that may support a conclusion of obviousness include: (B) Simple substitution of one known element for another to obtain predictable results". See MPEP § 2143 [R-01.2024] [I].
Applicant’s Arguments/Remarks filed on 11/14/2025 have been fully considered. Applicant argued “Nothing in the cited references provides evidence that any one or, more particularly, that each of the subtypes could be effectively treated by the same treatment” (p. 8, para. 3) and “Evidence presented in Shireman et al. Brain, Volume 144, Issue 4, April 2021, Pages 1230-1246… provides clear and experimentally validated proof that different glioblastoma molecular subtypes exhibit distinct therapeutic responses to IMPDH2 inhibition and alkylating chemotherapy… Collectively, the data from Shireman 2021 provide direct experimental proof of differential therapeutic efficacy across GBM molecular subtypes. Specifically, distinct survival outcomes across GBM5 (mesenchymal), GBM6 (classical), and GBM43 (proneural) are reported for combined IMPDH2 inhibition (MMF) and TMZ therapy. Additionally, ARL13B loss differentially impairs tumor initiation in mesenchymal versus proneural and classical PDX lines” (p. 9, para. 2; p. 10, para. 2).
In response, these arguments are not persuasive because of the following reasons. First, claim 9 recites “treating an ARL13B-mediated proliferative cell disease or disorder in a subject in need thereof” in the preamble and thus an intended result. Second, the “treating” is not specifically defined and does not commensurate with provided evidence. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., cited evidence) are not recited in the rejected claim(s). 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). To overcome this 103 rejection, Applicant may insert the clause “; and the administering (a) and (b) extends survival of the subject compared with untreated control” at the end of claim 9. Such proposed amendment is supported by specification and Figs. 2E, 2F, 5C, and 5D of this Application, and Figs. 3F, 3G, 3H, 4A, 4B, 4C, 6G, 6H, 6I, and 6J of the Shireman 2021. Any amendment after Final may not be entered if new issue arises and/or extensive search is needed.
Conclusion
No claims are 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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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691