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 .
Claim Status
Applicant’s amendments and remarks, filed 10/15/2025, are acknowledged.
Claims 2-5, 7-9, and 15-34 are canceled.
Claims 1, 10-11, and 14 are amended.
Claims 1, 6, and 10-14 are pending.
As such, claims 1, 6, and 10-14 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/6/25 has been entered.
Withdrawn Rejections
Applicant’s arguments, see pages 6 and 7, filed 10/15/2025, with respect to claims 1, 4-6, 8-14, and 25-34 rejected under 35 USC 112(a) as allegedly lacking written description have been fully considered and are persuasive. The issue regarding the specification failing to disclose Applicant’s possession of treating neuroblastoma or melanoma with the large genera of Myc, PD-1, PD-L1, or CTLA-4 inhibitors has been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claims 4, 5, 8, 9, and 25-34 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(a) is withdrawn.
Applicant’s remarks, see pages 7 and 8, filed 10/15/2025, with respect to claims 1, 4-6, 8-9, and 12-14 rejected under 35 USC 103 as allegedly unpatentable over Chakrabarti in view of Wyce; and, claims 1, 4-5, 8-10, and 12-14 rejected under 35 USC 103 as allegedly unpatentable over Srinivasan in view of Chakrabarti and Wyce have been fully considered and are persuasive. Examiner acknowledges that claims 4, 5, 8, and 9 are canceled, thus rendering the rejection moot. Further, Examiner acknowledges that claim 1 was amended to recite “wherein the Myc inhibitor is an inhibitor of Bromodomain and Extra-terminal motif (BET) proteins, wherein the BET inhibitor is JQ1 or I-BET726” and “wherein said PD-Li inhibitor is atezolizumab, avelumab, or durvalumab, and wherein said CTLA-4 inhibitor is ipilimumab” which is not disclosed by the art. As such, the rejections under 35 USC 103 are withdrawn.
New Rejection Necessitated by Amendment
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, 6, and 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al (PLoS Med 15(1): e1002497 (2018); previously submitted with the Office Action mailed 02/10/2025), and further in view of Chakrabarti et al (PLoS ONE 10(6): e0129237(2015); previously submitted with the Office Action mailed 02/10/2025), Wyce et al (PLoS ONE 8(8): e72967 (2013); previously submitted with the Office Action mailed 02/10/2025), Nallasamy et al (Seminars in Cancer Biology 52 (2018) 53–65), Melaiu et al (Clin Cancer Res 2017; 23(15); 4462–72), Kelley et al (JPET Fast Forward. Published on September 8, 2016 as DOI: 10.1124/jpet.116.235283), and Merchant et al (Clin Cancer Res 2015; 22(6); 1364–70).
In regard to instant claims 1, 10, 12, and 14, Srinivasan et al disclose of PD-L1 checkpoint inhibition and anti-CTLA-4 whole tumor cell vaccination counter adaptive immune resistance in a mouse neuroblastoma model (see Title). Adaptive immune resistance induces an immunosuppressive tumor environment that enables immune evasion which results in tumor escape with progression and metastasis (see Abstract). Srinivasan et al disclose of a potent vaccine strategy in a mouse neuroblastoma model (see pg. 4). Srinivasan et al disclose of neuro2a cell lines (N2a) derived from AJ mice and the aggressive subclone of Neuro2a (AgN2a) cells were produced by repeated in vivo passaging of the cells (see pg. 4). The cells were transduced with Id2-shRNA expressing lentiviral particles containing a Puromycin resistance gene (see pg. 4). These cells, also referred to as Id2-kd N2a cells, were injected into the mice models (see pg. 5). An anti-PD-L1 antibody and an anti-CTLA-4 antibody was also administered intra-peritoneally (see pg. 5). The tumors were excised either when they reached 10 mm or when they started to shrink following vaccine therapy (see pg. 5). Srinivasan et al disclose that PD-L1 is detected on the mouse N2a cell line, and its surface expression levels increase in a dose-dependent manner after 24 hours of stimulation with IFNγ (see pg. 7). Similarly, the expression of PD-L1 rises markedly in response to increasing doses of IFNγ in the SK-NSH and SH-SY5Y human cell lines (non-MYCN amplified cell lines) (see Fig. 1A). Srinivasan et al disclose that tumor necrosis was most prevalent in the group that recited Id2kd vaccine plus anti-CTLA-4 antibody, which also displayed the highest level of T-cell infiltrates compared to mice from the other cohorts indicating that the combination of immune priming (Id2kd-N2a vaccine) with immune modulation (anti-CTLA-4 antibody) potently boosts T-cell immunity (see pg. 7). Srinivasan et al found a dramatic increase in PD-L1 expression around tumor-infiltrating lymphocytes in the mouse tumors following Id2kd plus anti-CTLA-4 treatment (see pg. 7). Blockade of both CTLA-4 and PD-L1 might lead to improved immunotherapy by virtue of their differential targets on T-cell expansion and adaptive tumor cell resistance, respectively (see pg. 9). When the vaccine was combined with both CTLA-4 and PD-L1 inhibition, all mice were cured of their tumors and remained tumor free for 6 months in follow-up (see pg. 10 and Figs. 2B-2D). Average tumor growth curves also showed significant differences for treatment when the combination of vaccine with anti-PD-L1 and anti-CTLA-4 was compared to control (see Fig. 2D).
Further, Srinivasan et al disclose that targeting PD-L1 enhanced the effectiveness of whole tumor cell vaccination when combined with CTLA-4 blockade (see pg. 13). There is evidence in the literature suggesting that PD1 inhibition may be more effective than anti-CTLA-4 therapy, but their model and observations suggest that his may only be true for immunogenic tumors in which tumor-infiltrating T cells are already present but rendered incompetent through inhibition of the PD1/PD-L1 pathway (see pgs. 13-14). Srinivasan et al disclose that antibody depletion of CD8+ cells or immune-incompetent mice grow Id2kd tumors avidly, validating the concept that Id2 knockdown confers tumor cell immunogenicity in immune-competent hosts (see pg. 3).
Srinivasan et al fail to disclose of irradiating the cancer cells as recited in claim 13; utilizing an inhibitor of Myc, specifically JQ1 and/or I-BET726, or the PD-L1 and CTLA-4 inhibitors recited in claims 1 and 14. Further, Srinivasan et al fail to disclose of administering an inhibitor of ApoE. This is remedied by Nallasamy, Wyce, Melaiu, Kelley, and Merchant.
While Srinivasan does not explicitly recite administering JQ1 or I-BET726, Melaiu disclose that MYC and MYCN regulate PD-L1 expression in neuroblastoma (see Abstract; pg. 4469). Specifically, Melaiu found that JQ1 treatment significantly reduced PD-L1 surface expression in neuroblastoma cell lines (see pg. 4469; Fig. 5). Further, Wyce et al disclose that BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis (see Abstract). Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways (see Abstract). MYC-family transcription factors, including Myc, N-Myc, and L-Myc, are key regulators of cell growth and survival (see pg. 2, left column). Myc plays an important role in hematologic cancers as well as a number of solid tumors, and the MYCN gene is overexpressed in neuroblastoma (see pg. 2, left column). Wyce et al disclose of a selective small molecule inhibitor, I-BET726, that binds to the acetyl-lysine recognition pocket of BET family proteins (see pg. 2, left column; Fig. 1B). I-BET726 is highly selective for BET family proteins, exhibiting no binding affinity for any bromodomain-containing homolog tested with the exception of CREBBP, for which I-BET726 binds with >1000-fold lower affinity than to BET family proteins (see pg. 2 and Figs. 1D, S1). All neuroblastoma cell lines tested exhibited potent growth inhibition, with a median growth IC50 value equal to 75 nM suggesting that neuroblastoma cell lines are particularly sensitive to BET inhibition (see pg. 2, right column). Potent growth inhibition with I-BET726 was observed irrespective of MYCN amplification status, or level of MYC or MYCN expression (see pg. 2, right column). Further, Wyce et al disclose of consistently observing a potent, concentration-dependent decrease in MYCN expression, independent of MYCN amplification status (see pg. 5, right column; Fig. 5A). High concentrations of I-BET726 almost completely silenced MYCN expression in every cell line tested (see pg. 5, right column). Additionally, Wyce disclose of administering I-BET726 once daily at doses of 5 mg/kg or 15 mg/kg in xenograft models of non-MYCN-amplified and MYCN-amplified neuroblastoma in immunocompromised mice (see pg. 8, right column). The xenograft models following treatment with I-BET726 demonstrated a dose-dependent decrease in MYCN and BCL2 expression (see pg. 11, left column). Wyce et al also disclose that their observations of potent BET inhibitor activity in neuroblastoma are consistent with a report using a different BET inhibitor, JQ1, which was similarly shown to inhibit expression of MYCN and downstream n-myc target genes (see pg. 13, left column).
Additionally, Nallasamy disclose that atezolizumab, an anti-PD-L1 antibody, has been evaluated and found successful for neuroblastoma (see Abstract; pg. 56, left col.). Furthermore, Merchant found that ipilimumab treatment stabilized neuroblastoma in a patient (see Table 2; pg. 1367, right col.).
As such, it would have been obvious to combine the teachings of Srinivasan, Melaiu, Nallasamy, and Merchant to develop a method of treating neuroblastoma comprising administering JQ1, atezolizumab, and ipilimumab. One would be motivated to do so because Srinivasan disclose of treating neuroblastoma with Id2-kd N2a cells, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. Because neuroblastoma cells demonstrate excessively high expression of Id proteins and its function as an effector of n-myc makes it an important target in neuroblastoma (as disclosed by Melaiu), one of skill in the art would have a reasonable expectation that targeting Myc proteins would also provide therapeutic benefit to neuroblastoma cells. This is demonstrated by Wyce who teach that neuroblastoma cells overexpress the MYCN gene, which is associated with Myc, and administering I-BET726 resulted in potent BET family inhibition. Also, one would have a reasonable expectation that administering atezolizumab and ipilimumab, in addition to JQ1 and/or I-BET726, would successfully treat a neuroblastoma patient.
With respect to instant claims 1 and 13, Chakrabarti disclose that live attenuated vaccines induce long-lived cellular and humoral immunity, but safety concerns limit their utilization (see pg. 7). Therefore, in lieu of the potential risk of live albeit attenuated Id2-kd N2a tumor cells Chakrabarti et al sought to determine whether irradiation of these cells would dampen the effects of this tumor cell vaccine strategy (see pg. 7). Chakrabarti et al subsequently tested irradiated (35 Gray) Id2-kd N2a cells as a whole tumor cell vaccine antigen source in combination with anti-CTLA-4 antibody against AgN2a (see Fig. 3A) and found that 60% of mice eradicated established tumors (see Fig. 4D). In contrast, irradiated wild type N2a cells administered in a similar combination fashion, had no effect on growth of the AgN2a aggressive tumor cells (see Fig. 4C). This observation again supports the antigenicity of Id2-kd N2a cells for vaccination, but is also encouraging in that irradiation extends the margin of vaccine safety (see pg. 7). Additionally, Chakrabarti et al disclose that irradiation did not demonstrate favorable nor particularly adverse effects on the antigenic properties of the Id2-kd cells in neuroblastoma despite evoking potent anti-tumor immunity in melanoma and lung cancer models (see pg. 7). In the immune-competent mouse model, Id2-kd N2a failed to grow and subsequently developed immunity against further wild-type N2a tumor cell challenge hence making these cells proliferation incompetent (see Abstract and pg. 14).
Lastly, with respect to instant claim 11, Kelley assessed the anti-tumor effects of APX2009 in neuroblastoma cells (see pg. 5). Kelley found that tumor killing was increased 4.3-8.7-fold when compared to E3330 (APX3330) for the neuroblastoma cell models (see pgs. 16-17).
As such, it would have been obvious to one of ordinary skill in the art at the time of the present invention to administer APX2009 in addition to JQ1/I-BET726, atezolizumab, and ipilimumab to treat neuroblastoma. One would be motivated to do so because the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering JQ1/I-BET726, atezolizumab, and ipilimumab in combination with APX2009 as taught in the references above, one would achieve a method for inhibiting the growth of neuroblastoma cells. The Kerkhoven rationale can also be applied for combined administration of JQ1 and I-BET726 as recited in instant claim 6; one would have a reasonable expectation that administering JQ1 in combination with I-BET726 would successfully treat neuroblastoma cells as taught by the art.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Muralidharan et al (Cell Death and Disease (2017) 8, e2982) disclose that BET bromodomain inhibitors, specifically JQ1, synergize with ATR inhibitors in melanoma.
Shah et al (npj Precision Oncology (2017) 1:19) disclose that APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and is explored in various cancers.
Hodi et al (N Engl J Med. 2010 August 19; 363(8): 711–723) teaches of improved survival with ipilimumab in patients with metastatic melanoma.
Vanella et al (ONCOIMMUNOLOGY 2018, VOL. 7, NO. 1, e1365209) disclose of atezolizumab, durvalumab, and avelumab treatment with various cancers, including melanoma.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674