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 .
Priority
The instant application is a 371 of PCT/US2021/038880 filed on 06/24/2021, which claims priority to the US Provisional application 63/043,163 filed on 06/24/2020. The instant application is examined under an effective filing date of 06/24/2020.
Status of the Claims/Application
Claims 8-11, 14-16 and 18 are currently amended. Claims 1-9 are currently pending and are herein under examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on is acknowledged and is in compliance with the provisions of 37 CFR 1.97. It has been considered by the examiner.
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.
The factual inquiries 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.
Claims 1-6, 8-13 and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/133809 A1, and further in view of Martin et al. Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology. Front Immunol. 2020 Apr 30;11:745, Di Pilato et al. Targeting the CBM complex causes Treg cells to prime tumors for immune checkpoint therapy. Nature 570, 112–116 (2019), herein after referred to as Mempel, Martin and Di Pilato respectively.
Regarding claim 1-6, 8-13 and 15-19, Mempel teaches a method for treating cancer where the cancer can be a solid tumor such as adrenocortical tumor or a melanoma (Mempel para 0007 - 0008) by administering a combination treatment comprising an agent that inhibits the activity of a CBM signalosome complex and a second therapeutic such as an immune checkpoint inhibitor to the subject (Mempel Abstract and Fig. 4H). Mempel further teaches that the disruption of a fraction of the CBM signalosome complex in a fraction of Treg by a MALT1 inhibitor avoided systemic autoimmunity thereby sufficient to produce anti-tumor effect and indicating that gain of effector activity by Treg dominantly initiates tumor control. Treg production of IFN-y was accompanied by macrophage activation and up-regulation of MHC-I on tumor cells, reflecting enhanced tumor immune-reactivity. Tumor cells also up-regulated expression of PD-L1, indicating activation of adaptive immune resistance. Consequently, a PD-1 blockade concomitant with disruption of the CBM signalosome complex caused rejection of tumors that otherwise do not respond to anti-PD-1 monotherapy. Experimental findings described herein demonstrate, in part, that partial disruption of the CBM signalosome complex and induction of IFN-y-secretion in the self-reactive Treg pool does not cause systemic autoimmunity but is sufficient to prime the tumor environment for successful immune checkpoint therapy (Mempel pg. 1-2 para 5). Mempel also teaches that the immune checkpoint inhibitor includes antibodies to PD-L1, PD-L2, VISTA, TIM-3, LAG-3, TIGIT, PD-1 wherein the PD-1 comprises Pembrolizumab (Keytruda), Nivolumab, AUNP-12, and Pidilizumab, or the PD-L1 comprises Atezolizumab, MPDL3280A, Avelumab, or Durvalumab (Mempel pg. 2 para 0011 -0012). Mempel also teaches that the MALT1-inhibitor can be a small molecule MI-2 or analogs thereof, pyrazolo pyrimidine derivative, a phenothiazine derivative, and tetrapeptide Z-VRPR-FMK wherein the MALT1-inhibitor is mepazine, thioridazine or promazine (Mempel para 15). Mempel also teaches that the MALT1-inhibitor can be (S)-mepazine (Mempel para 0097).
Mempel does not specifically teach an intermittent dosing method of MALT1 inhibitor wherein the MALT1-inhibitor was administered to the subject for up to 7 days, withholding the administration of MALT10inhibitor for at least 2 days and then administering a second dose of the MALT-1 inhibitor after the withholding step.
Martin teaches that despite the effectiveness of MALT1 protease inhibitors in preclinical models of autoimmunity and B cell malignancies, there is a severe reduction in Tregs and associate IPEX-like pathology occurring upon long term congenital disruption of the MALT1 protease in mice and that these factors should be considered before using MALT1-inhibitor in the clinic (Martin Abstract). Martin also teaches that to assess the effect of MLT-943 (at MALT1-inhibitor) on Treg frequency in blood, naïve rats were treated for 10 consecutive days with an effective dose of MLT-943 or suboptimal doses and Treg frequency was assessed over time and the result showed that the effective inhibition of MALT1 protease activity using the effective dose of MLT-943 resulted in progressive reduction in the frequency of Foxp3+CD25+ Treg cells in circulating CD4+ T cells, which was maximal after 7 days of treatment about reached about 50% of the original value (Martin pg. 7 col 1 para 2). Martin further teaches that the reduction in circulating Treg frequency is a hallmark of effective MALT1 protease inhibition and that this reduction can be reverted upon treatment cessation (Martin pg. 7 col 1 para 4 and Fig. 1). Martin also teaches that prolonged treatment with MALT1 inhibitor at various doses can induce severe immune-mediated pathology in rats (Martin pg. 7 col 2 and Fig. 2-3). Martin further suggest that an alternative strategy for using MALT1-inhibitors such as MLT-943 maybe intermittent dosing of the MALT1-inhibitor (Martin pg. 17 col 1 para 2).
Di Pilato teaches that the partial inhibition of CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumor environment for successful immune checkpoint therapy Di Pilato Abstract). Di Pilato also teaches that when either one or both alleles of CARMA1 was deleted mature Treg cells, levels of CARMA1 was proportionally reduced and mice that had both CARMA1 alleles deleted stopped thriving after 17 days and most died before 4 weeks suggesting that CARMA1 is essential for cell to maintain immune homeostasis, but a reduction in its expression at least up to 50% is tolerated (Di Pilato pg. 112 col 1 para 3 – col 2 para 1).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Mempel in view of Martin and DI Pilato with a reasonable degree of predictable success so as to administer the immune checkpoint inhibitor and MALT1-inhibitor combination therapy in an intermittent manner so as not to induce an immune mediated pathology in the subject as a result of a severe reduction in Treg caused by the over inhibition of MALT1 protease. As indicated by Martin’s suggestion for using intermittent dosing (Martin pg. 17 col 1 para 2) and in combination with Martins assessment of the effects of MALT1-inhibitor dosage on the levels of Foxp3+CD25+ Treg cells in circulating CD4+ T cells (Martin pg. 7 col 1 para 2), a skilled artisan would have been able to determine the dosage and frequency of administration required for the optimal reduction in Treg required to prime the system for administration of the immune checkpoint inhibitor based on the type of MALT1-inhibitor to be administered and the weight of the subject, and the effective MALT1-inhibition dosage can be calculated by measuring the level of Foxp3+CD25+ Treg cells in circulation CD4+ T cells in the subject in order to determine the number of days require to administer MALT1-inhibitor or withhold MALT1-inhibitor in order for the system revert to the normal levels of Foxp3+CD25+ Treg cells in circulation CD4+ T cells. Therefore, a skilled artisan would have been able to calculate the intermittent dosage and frequency requirements to administer a first dose and then withholding the MALT1-inhibitor for at least 2 days and 14 days or 5 consecutive days so that the Treg level can revert to normal before administering the MALT1-inhibitor a second time.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Mempel, Martin, Di Pilato as applied to claim 3 above, and further in view of Pai-Scherf et al. FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Oncologist. 2017 Nov;22(11):1392-1399, herein further referred to as Pai-Scherf.
Regarding claim 7 and incorporating the analysis of claim 3 above, neither Mempel, Martin or Di Pilato teaches the administration of the anti-P1 antibody once every three weeks.
Pai-Scherf teaches that an anti-PD1 antibody such as pembrolizumab is 200 mg every three week (Q3W) as a standard of care (SOC) or based on the investigator’s choice of care still administered QW3 for first-line therapy and beyond (Pai-Scherf Abstract and pg. 1393 col 2 para 1).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Mempel, Martin and Di Pilato in view of Pai-Scherf with a reasonable degree of predictable success to administer the anit-PD1 antibody once every three weeks given that anti-PD1 antibody such as pembrolizumab is known in the art to be administered every three weeks as the standard of care practice. Therefore a skilled artisan would have been motivated to administer anti-PD1 antibody every three weeks as it is a common practice in the art and at time of filing is the standard of care.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Mempel, Martin, Di Pilato as applied to claim 3 above, and further in view of PubChem Retrieved from <pubchem.ncbi.nlm.nih.gov/compound/Safimaltib> on 02/11/2026, herein further referred to as PubChem.
Regarding claim 14, and incorporating the analysis of claim 1 above, neither Mempel, Martin or Di Pilato teach a MALT1-inhibitor having the structure as claimed.
PubChem teaches a MALT1-inhibitor (safimaltib), a small molecule drug that reduces interleukin and upregulates IFN which then inhibits the Janus kinase/signal transducers and activator of transcription (JAK/STAT) signaling and nuclear factor-kappa (NF-kB) signaling, induces apoptosis and inhibits tumor cell growth of MALT1-expressing tumor cells (PubChem pg. 2).
Therefore, it would have been obvious before the effective filing date for a skill artisan to modify the teachings of Mempel, Martin and Di Pilato in view of PubChem with a reasonable degree of predictable success, to use the MALT1-inhibitor (safimaltib) of PubChem in the combination therapy for the treatment of cancer as claimed. Safimaltib as indicated by PubChem is an MALT1-inhibitor that can inhibit tumor cell growth and is currently in clinical trials, therefore a skilled artisan would have been motivate to use safimaltib as the MALT1-inhibitor in the combination treatment.
Conclusion
No Claims Allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanna Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMMANUEL LED YOUTCHOM PENDIE/ Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647