DETAILED ACTION
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 .
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 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.
Priority
The instant application, filed 11/18/2020, claims domestic benefit to provisional application 62/936,867, filed 11/18/2019.
Status of Application, Amendments, and/or Claims
Applicant’s response of 07/23/2026 is acknowledged. Claim 1 is amended and claims 2, 4, 6-7, 13-14, and 16-19 are cancelled. Claims 1, 3, 5, 8-12, and 15 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 04/24/2026,
Claims 1, 3, 5, 8-12, and 15 were rejected under 35 USC 112(b). Applicant’s amendment to claim 1 to recite that the high expression of checkpoint kinase 2 is relative to non-tumor brain tissue has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are modified as necessitated by applicant’s amendment to the claims.
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 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 1, 3, 8-9, 11-12, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Chen, R.Q., et al (2019) The prognostic and therapeutic value of PD-L1 in glioma Frontiers in Pharmacology 9(1503); 1-13 in view of Sen, T., et al (2019) Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer Discov 9(5); 646-661, Bartkova, J., et al (2010) Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signaling in human gliomas Oncogene 29; 5095-5102, Campagne, O., et al (2020) CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model European Journal of Pharmaceutical Sciences 142(105106); 1-10 and Prexasertib HCl (LY2606368) Datasheet (2018) from Selleckchem.com (online 15 Dec 2018), as evidenced by Dent, P., et al (2011) CHK1 inhibitors in combination chemotherapy; Thinking beyond the cell cycle Molecular interventions 11(2); 133-140.
Chen teaches that Gliomas are the most common type of primary brain tumor and that, after standard treatment regimens, the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1, has achieved breakthrough in many cancers, but still not in glioma. Chen provides a review summarizing PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures and also summarizes the relationship between PD-L1 and immune cell infiltration in glioma. Chen also discusses therapeutic results from the use of anti-PD-1/PD-L1 antibodies or PD-L1 knockdown in glioma (abstract).
Chen teaches that PD-1 and PD-L1 are two major negative regulatory molecules at the immune checkpoint axis. PD-1, a cell surface receptor belonging to the extended CD28/CTLA-4 family of T cell regulators, is predominantly expressed on activated T cells, B cells, and macrophages. PD-L1 and PD-L2, both PD-1 ligands, belong to the B7 family. PD-L1 is most widely expressed in almost all tumor cells as well as many normal cells and can be upregulated in cancer cells upon IFN-γ stimulation and some activated immune cells. The binding of PD-L1 to PD-1 delivers strong inhibitory signals to suppress the proliferation, activation, and infiltration of cytotoxic T-lymphocytes, which was proved to be the major negative regulation of CTL in the cancer microenvironment (paragraph bridging columns, page 2). In previous studies, flow cytometry detected PD-L1 expression in 12 glioma cell lines, most primary cultures of glioma cells, and glioma cells from a great number of human glioma specimens, demonstrating the presence of PD-L1 on the cell surface of most glioma cells. In addition, many results of immunohistochemistry show much higher PD-L1 expression in human glioma tissues than that in their surrounding or distant normal tissues (page 2, right column, paragraph 2).
Chen teaches that most clinical studies of PD-1/PD-L1 inhibition remain recruiting and inconclusive. Several studies reported that glioma or GBM patients may benefit from PD-1 antibody therapy with treatments including pembrolizumab or nivolumab (page 9, right column, paragraph 2). Chen also discloses that animal studies have also supported that PD-L1 antibodies may be effective in the treatment of gliomas (page 10, paragraph bridging columns).
Chen further teaches that PD-L1 antibody had cumulative therapeutic effects on C57 mice/GL261 orthotopic glioma when in combination with other drugs or anti-CTLA-4 antibodies. Other results have reported that PD-L1 in combination with CTLA-4 antibodies significantly increased survival time of mice with intracranial glioma models (page 10, right column, paragraph 2). Chen reports studies in glioma in which the PD-1 antibody nivolumab was combined with the CTLA-4 antibody ipilimumab (page 10, Table 3). The studies discussed by Chen demonstrates the relevance of checkpoint blockade in gliomas, including intracranial glioma.
Chen further teaches that it is well-known that the engagement of PD-1 and PD-L1 promotes apoptosis of PD-1+ CTL. In various types of cancer, including glioma, PD-L1 plays a major inhibitory role in modulating infiltration of immune cell such as CTL, tumor infiltrating lymphocytes (TIL), and regulatory T cells (Treg) (page 5, right column, paragraph 3). PD-L1 plays opposite regulatory roles in the functions of CTL and Treg (paragraph bridging pages 5 and 7).
Chen concludes that PD-L1 is not only associated with decreased CTL and increased Treg in glioma lesions but also has intrinsic oncogenic roles by interacting with Ras. Intrinsic PD-L1, as well as its related signaling pathways, may also serve as therapeutic targets. PD-1 antibody has limited therapeutic effects on glioma patients while PD-L1 experimentally shows therapeutic effects in animal glioma models. The combination of PD-1/PD-L1 antibodies with other molecule targeting anti-cancer drugs is prospective (paragraph bridging columns, page 11).
Chen differs from the instantly claimed invention in that Chen does not disclose the additional administration of a checkpoint kinase 2 inhibitor, specifically prexasertib HCl, or that the glioma subjects have high expression of checkpoint 2 kinase relative to non-tumor brain tissue. Chen also does not disclose the claimed outcomes when prexasertib and PD-1/PD-L1 antibodies are used in combination.
Sen teaches that immunotherapies that harness or enhance a patient’s own immune system to target and kill cancer cells have been developed, with common targets including immune checkpoints PD-1, PD-L1, and CTLA4 (page 647, left column, paragraph 1). Although these ICB agents are promising, their activity varies across cancer types and there is increasing evidence of primary and adaptive resistance to ICB in multiple cancer types. Thus, efforts are underway to develop new therapeutic strategies with novel drug combinations to enhance the antitumor efficacy of ICB (paragraph bridging columns, page 647). Recent studies have demonstrated the potential of targeting the DNA damage response (DDR), including CHK1 inhibitors and PARP inhibitors, and several DDR inhibitors had been developed and were either approved for the treatment of cancers or were in clinical trial. Although best known for its functions in repairing DMA damage and controlling the cell cycle, the DDR pathway has also been shown to be involved in the antitumor immune response. For example, PARP inhibitor Olaparib was recently reported to show synergistic effects with PD-L1 blockade in triple-negative breast cancer in preclinical models. However, at the time, little was known about the mechanistic interactions between DDR targeting and response to ICB, as well as the immune activating properties of DDR targeting (page 647, right column, paragraph 2).
In the studies provided by Sen, a role of DDR targeting through CHK1 and PARP inhibition in modulating T-cell action via regulation of the innate response pathway was identified. Using multiple models of SCLC, Sen demonstrates that the pharmacologic inhibition of CHK1 or PARP increased levels of tumor-infiltrating T lymphocytes and synergized with anti-PD-L1 therapy. Sen teaches that, taken together, the results elucidate a mechanism of action for DDR inhibitors in antitumor immunity and suggest that treatment with DDR inhibitors may increase the effectiveness of ICB in patients with SCLC (paragraph bridging pages 647-648).
In the studies performed by Sen, a panel of human SCLC lines were treated with either prexasertib or a PARP inhibitor for 72 hours (3 days) and protein expression was analyzed by reverse phase protein array (RPPA), immunoblot, and flow cytometry. DDR targeting was found to significantly increase the total level of PD-L1 protein in all cell lines tested with the greatest PD-L1 fold change, up to 5-fold, with prexasertib (page 648, left column, paragraph 1; FIG 1A-D). Sen further teaches that prexasertib was administered by subcutaneous injection (page 660, left column, paragraph 3), which is a form of systemic administration.
Sen teaches that, in studies, the CHK1i, prexasertib, alone was not sufficient to eradicate tumors despite reduced tumor growth, increased T-cell infiltration, and abrogated T-cell exhaustion in vivo, so the ability of CHK1i to sensitize tumors to PD-L1 blockade was then tested. Sen teaches that anti-PD-L1 alone showed no anti-tumor response in the model but that remarkable tumor regression was observed in the combination treated group. Of the 10 mice treated with the combination of prexasertib and anti-PD-L1, 6 had a complete response with 100% reduction (page 648, right column, paragraph 3).
Combination treatment significantly increased CD3+ total T-cell infiltration and CD8+ cytotoxic T-cell infiltration. In addition, the single agent prexasertib treatment increased CD44+ memory/effector T cells populations, which was further enhanced in the combination treatment. Prexasertib and anti-PD-L1 treatment furthermore reduced the CD62+ naïve T cell population (page 648, right column, paragraph 4). IHC staining score confirmed the flow cytometry observations with higher CD8 staining intensity and percentage of CD9+ cells in prexasertib treated groups as compared with vehicle or anti-PD-L1 alone and further enhancement of this population was observed in combination treated tumors. Sen teaches that CHK1 targeting by prexasertib significantly augments the antitumor immune response of anti-PD-L1 and causes cytotoxic T-cell infiltration and activation in an IC in vivo model of SCLC (page 651, left column, paragraph 2).
Sen further teaches that CHK1i plus PD-L1 blockade resulted in complete tumor regression in 60% of treated animals and FACs profiling of TILs from day 21 resected tumors revealed that prexasertib and anti-PD-L1 treatment induced CD8+ but not CD4+ T cell infiltrate. Sen further demonstrated that the responses were mediated through CD8+ immune cells (page 651, left column, paragraph 3).
It is noted that, although Sen refers to prexasertib as a checkpoint kinase 1 inhibitor, prexasertib inhibits both checkpoint kinase 1 and 2 as evidenced by both the prexasertib HCL data sheet, which teaches inhibition of both CHK1 and CHK2, as well as Campagne, which teaches that prexasertib is a potent inhibitor of CHK1 and CHK2 protein kinases (abstract). The inhibition of checkpoint kinase 2 is a property of prexasertib and a compound and its properties are inseparable. See MPEP 2112.01 II, which states “’Products of identical chemical composition can not have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.“
Furthermore, the inhibition of CHK2 would flow naturally from the use of prexasertib as it is a property resulting from the structure of the therapeutic itself. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.” Additionally, although the reference does not explicitly disclose that prexasertib potentiates an ERK pathway, this would also flow naturally from the administration of prexasertib and is a mechanistic outcome of the structure of the therapeutic as evidenced by Dent, which teaches that CHK1 inhibitors were known to result in compensatory, rapid, and sustained activation of ERK1/2 pathways.
Bartkova teaches that malignant gliomas show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Bartkova reports on gross, aberrant constitutive activation of DNA damage signaling in low- and high- grade human gliomas, and analyze the sources of endogenous genotoxic stress. Based on analysis of human glioblastoma multiforme (GBM) cell lies, normal astrocytes, and clinical specimens form grade II astrocytomas and grade IV GBM, it was concluded that DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Markers indicative of ongoing DNA replication stress, including Chk1 activation, were also present in GBM cells under high-or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors (abstract).
In Figure 1, page 5097, Bartkova provides staining of normal brain (N.Brain), astrocytoma grade II (Astro.II), and glioblastoma multiforme (GBM) for the indicated markers of activated DNA damage response (DDR). Fig. 1c demonstrates the presence of phosphorylated Chk2 (p-Chk2) and phosphorylated Chk1 (p-Chk1) in both astrocytoma grade II and glioblastoma compared to the normal brain. Similarly, Fig. 2 demonstrates that DDR is constitutively activated in human glioma cell lines as documented for the indicated markers by immunoblotting and confocal immunofluorescence microscopy images. In (a), whole cell extracts demonstrate increased expression of Chk1 and Chk2 in glioblastoma cell lines compared to normal human astrocytes (NHA) (page 5098).
Bartkova further teaches that the data presented is relevant for efforts to design individualized treatments by radiation or chemotherapy combined with checkpoint or DNA repair inhibitors (page 5101, right column, paragraph 1).
Campagne teaches that prexasertib is a potent and selective small molecule inhibitor of cell cycle checkpoint CHK1 and CHK2 protein kinases and was currently under clinical evaluation for the treatment of pediatric malignancies (abstract). As a candidate for medulloblastoma treatment, it is essential to understand the central nervous system (CNS) penetration of prexasertib and its ability to attain adequate exposure at the target site, which is limited by selective permeability of the blood-brain-barrier. Cerebral microdialysis allows sampling of the brain extracellular fluid (ECF) samples and the measurements of unbound drug concentrations in the ECF over time. Campagne used this technique combined with pharmacokinetic modeling and simulation in preclinical studies to further characterize drug brain penetration (page 2, left column, paragraph 3). In the cerebral microdialysis studies performed by Champagne, mice received a 10 mg/kg dose of prexasertib subcutaneously and dialysate samples were collected over 1-hour intervals for up to 24 hours (page 3, left column, 2.8). Campagne teaches that the results show that prexasertib can penetrate both the mouse CNS and G3MB tumor at an adequate exposure for target engagement after a clinically relevant and tolerable dose paving the way for further preclinical studies using prexasertib to treat pediatric CNS malignancies (page 9, left column, paragraph 4).
Campagne further teaches that to translate the preclinical findings to the clinical setting, it was important to use clinically relevant dosages of drugs in the cerebral microdialysis experiments, which would lead to drug exposure in target tissues comparable to those obtained in the clinic. Campagne teaches that the recommended phase II dosage of prexasertib was 105 mg/m2 (page 6, right column, paragraph 2).
Campagne further teaches that administration was performed via subcutaneous or intravenous administration (page 2, right column, paragraph 3).
The prexasertib HCl datasheet demonstrates that prexasertib HCl (LY2606368) is commercially available and has biological activity against CHK1 (Ki value of 0.9 nM). The datasheet also teaches that prexasertib HCl has biological activity in the inhibition of CHK2 (8 nM) (page 1, “biological activity”).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of treating glioblastoma, including intracranial glioblastoma, with anti-PD-1/PD-L1 therapies as taught by Chen by further including prexasertib as taught by Sen, particularly in subjects with gliomas that have high expression of CHK1 and CHK2 compared to normal brains as taught by Bartkova. It would have further been obvious to administer prexasertib systemically, for instance via subcutaneous or intravenous administration, as taught by Sen and Campagne and to use the prexasertib HCl salt form of prexasertib as taught by the prexasertib HCl datasheet.
One of ordinary skill in the art would have been motivated to further administer prexasertib in the methods of Chen as Sen demonstrates that adding prexasertib to immune checkpoint blockade, including PD-1/PD-L1, can lead to complete tumor regression by augmenting the antitumor immune response of the checkpoint inhibitor and causing cytotoxic T cell infiltration and activation. An ordinarily skilled artisan would have had a reasonable expectation of success as both Chen and Sen teach methods of modulating the tumor microenvironment to support antitumor immunity using checkpoint inhibitors. Additionally, Bartkova demonstrates that gliomas, including glioblastoma, have high expression and activation of both CHK1 and CHK2 compared to normal brains, and implicates DDR in glioma pathogenesis and treatment failure, demonstrating the relevance of prexasertib in glioma and providing a reasonable expectation of success in targeting CHK1 and CHK2 expression in glioma patients with prexasertib. It is noted that, while Sen performed studies in SCLC, not glioblastoma, a person of ordinary skill in the art would have nevertheless had a reasonable expectation of success as modulating the immune environment would be expected to result in antitumor effects across cancer types, particularly those which express CHK1 and CHK2 and PD-1/PD-L1. For instance, Chen teaches that PD-L1 binding to PD-1 delivers inhibitory signals that suppress the proliferation, activation, and infiltration of cytotoxic lymphocytes in the glioma microenvironment and Sen teaches that the addition of prexasertib to checkpoint inhibitors further enhances T cell infiltration and activation.
It would have been obvious to administer prexasertib using systemic delivery routes, such as subcutaneous or intravenous administration, as Sen demonstrates subcutaneous administration of prexasertib and Champagne demonstrates that, following subcutaneous or intravenous administration, prexasertib can penetrate the CNS as well as brain tumors with adequate exposure for target engagement.
It would have been obvious to use prexasertib HCl as it is a commercially available salt of prexasertib. An ordinarily skilled artisan would have had a reasonable expectation of success in using prexasertib HCl as Sen demonstrates that the active component, prexasertib, is effective for use in potentiating the effects of immunotherapy based on its ability as a checkpoint kinase inhibitor
With regards to the claimed outcomes that the administration results in activated CD8 T cell pools in the brain of the subjects, localized to the brain and not observed in peripheral tissues, and that the administration of both Prexasertib HCl and the anti-PD-1/PD-L1 therapy demonstrate a statistically significant longer (days) survival rate on Kaplan-Meier curves, these outcomes would have been reasonably expected in view of the combined teachings of the prior art.
For instance, Sen teaches that DDR targeting leads to higher expression of CXCL10 and CCL5, dependent on the STING pathway activation, leading to the recruitment of CD8+ T lymphocytes and antitumor immunity (page 656, right column, paragraph 3). Sen further teaches that the combination treatment causes cytotoxic T cell infiltration and activation (page 651, left column, paragraph 2) demonstrating that the administration of prexasertib increases activated CD8 T cell pools in the tumor microenvironment, which in the case of the glioblastoma taught by Chen, is the brain.
Furthermore, it is noted that increases in activated CD8 T-cell pools in the brain of the subject, localized to the brain and not observed in peripheral tissues, would flow naturally from administration of prexasertib and is a mechanistic outcome resulting from the administration of prexasertib. As stated in MPEP 2145 II, recognition of a latent property in the prior art does not render nonobvious an otherwise known invention.
With regards to the statistically significant longer survival rate of the subject demonstrated by Kaplan-Meier survival curves, an ordinarily skilled artisan would have reasonably expected such an outcome based on the teachings of Sen. Sen studied the combination of PD-L1 blockade with PARP (olaparib) or DDR (prexasertib) inhibiting therapies. Sen provides a Kaplan Meier survival plot comparing anti-PD-L1 combined with olaparib to controls and monotherapies and demonstrates significantly longer survival when the PAPR olaparib is added to anti-PD-L1 therapy (page 653, Fig. 4B). The plot is duplicated below and has been annotated for clarity:
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While Sen provides survival data for olaparib and anti-PD-L1, not prexasertib and anti-PD-L1, Sen compared the effects of olaparib combinations and prexasertib combinations in tumor volume response and demonstrates that both combinations have similar outcomes. For instance, see Sen page 653, Figure 4G and H, which are duplicated below and have been annotated for clarity.
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As combinations of prexasertib and anti-PD-L1 result in tumor reduction similar to those of olaparib and anti-PD-L1, an ordinarily skilled artisan would reasonably expect that the combination of prexasertib and anti-PD-L1 would result in similar statistically significant longer survival rates to those of olaparib and anti-PD-L1.
While these results are in studies of small cell lung cancer, not glioblastoma, an ordinarily skilled artisan would nevertheless have expected similar increases in survival rate in glioblastoma based on these teachings and the teachings of the applied references in combination, which demonstrate that the outcomes reported are the result of modulating the tumor microenvironment leading to increases in the anti-tumor immune response. Furthermore, Chen demonstrates that checkpoint expression, particularly the PD-1/PD-L1 pathway, was known to contribute to immunosuppression and reduced proliferation and infiltration of tumor specific cytotoxic T cells in glioblastoma (page 471, introduction). Campagne teaches the use of prexasertib as a means of treating brain cancer and demonstrates that systemic administration of prexasertib can penetrate the CNS as well as brain tumors with adequate exposure for target engagement. Sen teaches that inhibition of DDR inhibitors potentiates the anti-tumor immune response of checkpoint blockade through T-cell mediated effects. Based on these teachings, an ordinarily skilled artisan would reasonably expect that the further administration of prexasertib in the methods of Chen, would result in the potentiation of the checkpoint inhibitor through improved T cell mediated effects resulting in improved survival in glioblastoma.
Claims 5 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Chen, R.Q., et al (2019) The prognostic and therapeutic value of PD-L1 in glioma Frontiers in Pharmacology 9(1503); 1-13 in view of Sen, T., et al (2019) Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer Discov 9(5); 646-661, Bartkova, J., et al (2010) Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signaling in human gliomas Oncogene 29; 5095-5102, Campagne, O., et al (2020) CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model European Journal of Pharmaceutical Sciences 142(105106); 1-10 and Prexasertib HCl (LY2606368) Datasheet (2018) from Selleckchem.com (online 15 Dec 2018), as applied to claim 1 above, and in further view of Brown, J.S., et al (2017) Combining DNA damaging therapeutics with immunotherapy: more haste, less speed British Journal of Cancer 118; 312-324.
The combination of Chen, Sen, Bartkova, Campagne, and prexasertib HCl datasheet teach the method of claim 1 as discussed above.
As discussed above, Bartkova suggests the combination of chemotherapy with checkpoint or DNA repair inhibitors (page 5101, right column, paragraph 1). This addition of chemotherapy to the method disclosed by the combination of applied references is further supported by the prior art.
The combination of applied references does not teach that the method further comprises administration of at least one of the checkpoint kinase inhibitors recited in claim 5.
Brown provides a review discussing the preclinical rationale for combining immune checkpoint inhibitors with DNA damaging agents and focuses on the immunomodulatory effects of chemotherapy, as well as the newer DNA repair inhibitors (page 312, left column, paragraph 2; page 314, left column, paragraph 2). Brown teaches that DNA repair inhibitors include CHK1 inhibitors and PARP inhibitors (page 315, Box 2). Brown teaches examples of CHK1 inhibitors including MK8776 and LY2603618, which is rabusertib (page 315, Box 2). Brown further teaches that the host immune system actively protects itself against tumor development and evasion and the evasion of cancer is due to immunosuppression within the tumor microenvironment (TME) (page 312, right column, paragraph 1).
Brown further teaches that the idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumor immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumor microenvironment, and/or stimulate neoantigen production, thereby activating an anti-tumor response (abstract). Brown teaches that combining DNA damaging chemotherapy with immune checkpoint inhibitors has the potential to reverse immunoevasive strategies used by tumors and that combined treatment with PD-1/PD-L1 inhibitors and DNA damaging chemotherapy has been demonstrated to be superior to chemotherapy alone (page 321, left column, paragraph 3; page 321, left column, paragraph 1). Brown also teaches that DNA damage can be enhanced using inhibitors of DDR signaling (page 317, right column, paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the method taught by the combination of Chen, Sen, Bartkova, Campagne, and prexasertib HCl datasheet to further include administration of additional DDR targeting therapies, such as MK8776 and/or LY2603618 and/or to have further administered a chemotherapeutic treatment as taught by Brown.
It would have been obvious to further administer MK8776 and/or LY2603618 as Brown teaches that they, like prexasertib, are CHK inhibitors that have been shown to cause direct cytotoxic effects on cancer cells by promoting immunologic cell death, alteration of the inflammatory milieu of the tumor microenvironment, and/or stimulation of neoantigen production thereby activating an anti-tumor immune response. The addition of other CHK inhibitors is further supported by MPEP 2144.06, which states that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.”
An ordinarily skilled artisan would have been motivated to administer a chemotherapeutic treatment in order to take advantage of the known synergistic effects of immune checkpoint therapies, DDR signaling inhibitors, and chemotherapeutic agents as taught by Brown. An ordinarily skilled artisan would have had a reasonable expectation of success as Brown teaches that chemotherapeutics can reverse the immunoevasive tumor microenvironment and activate an anti-tumor response (page 321, left column, paragraph 3).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Chen, R.Q., et al (2019) The prognostic and therapeutic value of PD-L1 in glioma Frontiers in Pharmacology 9(1503); 1-13 in view of Sen, T., et al (2019) Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer Discov 9(5); 646-661, Bartkova, J., et al (2010) Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signaling in human gliomas Oncogene 29; 5095-5102, Campagne, O., et al (2020) CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model European Journal of Pharmaceutical Sciences 142(105106); 1-10 and Prexasertib HCl (LY2606368) Datasheet (2018) from Selleckchem.com (online 15 Dec 2018), as applied to claim 1 above, and in further view of Kamran, N., et al (2018) Current state and future prospects of immunotherapy for glioma Immunotherapy 10(4); 317-339.
The combination of Chen, Sen, Bartkova, Campagne, and prexasertib HCl datasheet teach the method of claim 1 as discussed above.
While the combination of applied references suggests the use of an anti-PD-L1 antibody therapy, the combination of applied references does not teach that the anti-PD-L1 antibody is one of those recited in instant claim 10.
Kamran provides a review highlighting the wide array of immunotherapeutic interventions currently being tested in glioma patients (abstract).
Kamran teaches that a reduction in CD4 and CD8 T cells has been reported in the tumor and circulation of GBM patients and that PD-L1 expression has been identified on tumors of GBM patients. Thus, approaches targeting T cell exhaustion could provide clinical benefit in glioma. Kamran teaches that CTLA-4 and PD-1 have been identified as two major inhibitory receptors/checkpoints involved in T-cell exhaustion and monoclonal antibodies targeting CTLA-4 (ipilimumab and tremelimumab) and PD-1 (nivolumab, and pembrolizumab) have been studied in cancer treatment (page 322, T cell exhaustion in glioma).
Kamran discusses studies targeting immune checkpoints in glioma including trials evaluating the expression of tremelimumab (anti-CTLA-4) and durvalumab, also known as MEDI4736 (anti-PD-L1) as well as studies using avelumab (page 323, paragraph 3; pages 324-325, Table 1; page 319, Fig. 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Chen, Sen, Bartkova, Campagne, and prexasertib HCl datasheet by using durvalumab or avelumab as the anti-PD-L1 antibody as taught by Kamran. It would have been obvious to use durvalumab or avelumab as both are anti-PD-L1 antibodies and are taught by Kamran as being studied for use in the treatment of gliomas. An ordinarily skilled artisan would have had a reasonable expectation of success because the combination of Chen, Sen, Bartkova, Campagne, and prexasertib HCl datasheet suggest the use of anti-PD-L1 antibodies.
Response to Arguments
Applicant’s arguments in the response filed 07/23/2026 have been fully considered but are not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that the references do not disclose or suggest that systemic delivery of a CHK2 inhibitor increases activated CD8 T-cells pools specifically and exclusively to the brain of glioma-bearing subjects. Applicant argues that the outcome recited is supported by the instant specification, which demonstrates that systemic delivery of prexasertib at 10 mg/kg increased activated CD8 T cell populations specifically in the brains of GL261 glioma-bearing mice, while this increase was not observed in the spleen (i.e., peripheral tissue). Applicant argues that this CNS-localized finding is absent from the cited art.
As discussed in the rejection, increases in activated CD8 T-cell pools in the brain of the subject, localized to the brain and not observed in peripheral tissues, would flow naturally from administration of prexasertib and is a mechanistic outcome resulting from the administration of prexasertib. As stated in MPEP 2145 II, mere recognition of a latent property in the prior art does not render nonobvious an otherwise known invention. Specifically, MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Applicant further argues that the claimed Kaplan-Meier survival outcomes in an intracranial glioma model is not taught or suggested by the art. Specifically, applicant argues that the instant specification [0052]-[0053] and Fig. 15 support the instantly claimed outcome and demonstrates that the combination of prexasertib + anti-PD-1 in GL261-bearing mice with intracranial glioma eradicated tumors in 30% of mice with significantly longer survival time than either agent alone. Applicant argues that Sen’s Kaplan-Meier survival data (Fig. 4B) is for olaparib + anti-PD-L1 (a PARP inhibitor combination), not prexasertib and anti-PD-L1. Applicant also argues that Sen’s entire dataset is from a subcutaneous SCLC model, whereas the claims require intracranial glioma. Applicant argues that it is established in the art that intracranial tumors present different therapeutic challenges compared to subcutaneous tumors and that the survival outcomes in subcutaneous SCLC would not translate to an intracranial glioma setting.
Although the combination of applied references does not experimentally demonstrate the specifically claimed Kaplan Meier survival outcomes, conclusive proof of efficacy is not required in order to establish a prima facie case of obviousness. Rather, the standard for obviousness is a reasonable expectation of success.
As discussed in detail in the rejection, Sen studied the combination of PD-L1 blockade with PARP (olaparib) or DDR (prexasertib) inhibiting therapies. Sen provides a Kaplan Meier survival plot comparing anti-PD-L1 combined with olaparib to controls and monotherapies and demonstrates significantly longer survival when the PAPR olaparib is added to anti-PD-L1 therapy (page 653, Fig. 4B). While the Kaplan Meier survival plots provided by Sen are for the combination of olaparib (PARP) with anti-PD-L1, as stated by applicant in the response, as discussed in detail in the rejection, Sen compared the effects of olaparib + anti-PD-L1 combinations and prexasertib + anti-PD-L1 combinations in tumor volume response studies and demonstrates that both combinations have similar outcomes. For instance, see Sen page 653, Figure 4G and H, which is duplicated and annotated for clarity in the rejection. As combinations of prexasertib and anti-PD-L1 result in tumor reduction similar to those of olaparib and anti-PD-L1, an ordinarily skilled artisan would reasonably expect that the combination of prexasertib and anti-PD-L1 would result in similar statistically significant longer survival rates to those of olaparib and anti-PD-L1.
Sen also teaches that, of the ten mice studied with the combination of prexasertib and anti-PD-L1, six had a complete response (100% reduction) (page 5, paragraph 1).
With regards to applicant’s arguments that Sen’s datasets are from subcutaneous SCLC models, not the claimed intracranial glioma, this discrepancy is directly addressed in the rejection. For instance, as discussed in detail in the rejection, the results reported by Sen are a result of modulating the tumor microenvironment leading to increase in anti-tumor immune response. The other applied references also support the reasonable expectation of success. For instance, Chen demonstrates that the PD-1/PD-L1 pathway was known to contribute to immunosuppression and reduced proliferation and infiltration of tumor specific cytotoxic T cells in glioblastoma; Campagne demonstrates that systemic administration of prexasertib can penetrate the blood brain barrier and brain tumors with adequate exposure for target engagement; and Sen teaches that DDR inhibitors potentiate anti-tumor immune responses of checkpoint blockade through T cell mediated effects. Based on these teachings, an ordinarily skilled artisan would reasonably expect that the further administration of prexasertib in the methods of Chen, would result in the potentiation of the checkpoint inhibitor through improved T cell mediated effects resulting in improved survival in glioblastoma.
Applicant further argues that the claimed invention is directed to CHK2 inhibition in glioma subjects with high CHK2 expression, and that Sen does not teach or suggest this combination. Applicant argues that Sen expressly identifies prexasertib as a “ChK1i” (CHK1 inhibitor) throughout and is entirely based on CHK1-mediated STING pathway activation. Applicant argues that Sen does not test, measure, or mention CHK2 activity. Applicant further argues that Sen does not disclose “high expression of checkpoint kinase 2” as a criterion for subject selection. Applicant further argues that the Selleckchem datasheet confirms that prexasertib has a Ki of 0.9 nM for CHK1 but an IC50 of 8 nM for CHK2- an approximately 9 fold difference in potency. Applicant argues that the kinetic difference evidences that CHK1 inhibition predominates and that Sen’s observed effects are attributable to CHK1, not CHK2 inhibition.
In the argument, applicant focuses on the teachings of Sen; however, the rejection is based on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. See MPEP 2145 (IV). As such, Sen is not explicitly required to teach the inhibition of CHK2 in order to establish obviousness.
In the rejections, the reference Bartkova is applied to demonstrate that Chk1 and Chk2 are expressed at high levels in glioblastoma compared to the normal brain (Fig. 1, page 5097). Based on this expression, one of ordinary skill in the art would have reasonably expected that the prexasertib taught by Sen could be applied in the treatment methods of Chen with a reasonable expectation of potentiating the immunotherapy treatments, particularly in patient populations that express chk2 and also express Chk1.
While Sen does focus on Chk1, not Chk2, prexasertib is widely recognized in the art as an inhibitor of both Chk1 and Chk2. For instance, as shown in the prexasertib HCl datasheet and Campagne, which teach that prexasertib is a potent and selective small molecule inhibitor of cell-cycle checkpoint Chk1 and Chk2 protein kinase. As such, even if the combination of applied references suggest the targeting of Chk1 in the method of Chen using prexasertib, the inhibition of Chk2 is a property of prexasertib and would flow naturally from the administration. As discussed in detail in the rejection and in MPEP 2112.01 II., a compound and its properties are inseparable. Additionally, MPEP 2145 II states that the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would have otherwise been obvious. Therefore, even if applicant has identified that Chk2 is most likely to impact CD8 T cell response in glioma, such a result would flow naturally from the combination of the prior art, even if the goal was to target Chk1, particularly in gliomas which are disclosed as expressing both Chk1 and Chk2.
With regards to applicant’s arguments that the enzyme kinetics of prexasertib for Chk1 and Chk2 are different and; therefore, it is not reasonable to assume that the administration taught in Sen would inhibit both kinases, applicant does not provide sufficient evidence to demonstrate that the dosages and amounts of prexasertib used by Sen would not be sufficient to inhibit both Chk1 and Chk2; even if Chk2 was inhibited to a lesser degree. For instance, applicant does not provide a comparison to the dosages of Sen to demonstrate that the dosages taught would not be sufficient to potentiate the immunotherapy in the methods disclosed by Chen.
Rather, the examples of the instant disclosure further support the conclusion that the prexasertib administered in Sen would inhibit both Chk1 or Chk2. For instance, the examples of the instant disclosure studied the use of prexasertib in combination with PD-1 antibodies. The disclosure also recognizes prexasertib as a CHEK inhibitor for CHEK1 and CHEK2 (page 14, [0048]). In the example presented in [0052], it is demonstrated that mice treated with a combination of pharmacological inhibition of CHEK1/2 (with prexasertib) and PD-1 immunotherapy in GL261 bearing mice led to eradication of tumors in 30% of mice with significantly longer survival times. While the example does not explicitly disclose the dosage of prexasertib that was used, the other examples suggest that the dosage used was 10 mg/kg (page 15, [0050]).
In the studies performed by Sen combining prexasertib and anti-PD-L1, prexasertib was also administered at 10 mg/kg (page 648, right column, 3).
As the prexasertib dosage used in the instant examples is the same as that studied by Sen, the disclosure further supports the conclusion that inhibition of both Chk1 and Chk2 would have naturally resulted from the methods disclosed by Sen.
With regards to MPEP 2112.01 II (a compound and its properties are inseparable) and MPEP 2145 II (latent properties) and their application in the rejection/response to demonstrate that prexasertib would naturally inhibit CHK2, applicant argues that these doctrines are not relevant to the instant claims. Applicant argues that the invention doesn’t merely recite an inherent property, but, rather, claims a specific therapeutic methods where patients are selected based on high CHK2 expression relative to non-tumor brain tissue, systemic delivery produces localized CD8 T cell activation, and the combination of therapy provides significantly longer survival benefits in intracranial glioma. Applicant argues that these are not latent properties of prexasertib that would flow naturally from Sen’s SCLC model and are glioma specific and only demonstrated in applicant’s specification.
It is noted that, as discussed above, conclusive proof of efficacy is not required in order to establish obviousness and therefore, none of the applied references alone or in combination are required to conclusively demonstrate the claimed outcomes or the claimed method. Additionally, as discussed above, the rejections do not rely on Sen alone, but rather the combination of applied references and what the combination would have suggested to one of ordinary skill in the art.
With regards to the properties of prexasertib, MPEP 2112.01 II and MPEP 2145 II are applied in the rejection specifically to establish that the inhibition of CHK1 and CHK2 and the potentiation of an ERK pathway are inherent properties of prexasertib. As discussed in the rejection, the combination of applied references teaches the combination of anti-PD-L1 with prexasertib in the treatment of glioma, including intracranial glioma. The reference Bartkova demonstrate that Chk1 and Chk2 are expressed at high levels in glioblastoma compared to the normal brain, demonstrating that the patient population taught by the combination of references express high levels of Chk1 and Chk2, meeting the instant claim limitations of the subject having a high expression of checkpoint kinase 2 relative to non-tumor brain tissue.
Although applicant’s intention in administering prexasertib is to inhibit Chk2, and the teachings of Sen focus on Chk1, the administration of prexasertib to a patient population overexpressing both Chk1 and Chk2, including those with Glioma, would naturally and inherently inhibit both checkpoints regardless of intention. While the intention and focus of applicant’s invention is on the inhibition of Chk2, this does not structurally change prexasertib or its properties
In response to the response to arguments in the office action of 04/24/2026, and discussion that applicant’s own specification uses prexasertib, applicant disagrees that the use of prexasertib undercuts a kinetics-based rebuttal. Applicant argues that the specification’s use of prexasertib is expressly in the context of CHK2 inhibition in glioma, referencing studies using CRISPR kinome knockout screening; CHK2 knockout in GL261 cells; and prexasertib administered at concentrations directed to CHK2 for glioma sensitization. Applicant argues that the specification establishes that CHK2 targeting, distinct from CHK1, drives the claimed glioma immunotherapy potentiation.
While it is appreciated that the instant application identifies CHEK2 as being the most likely kinase to affect the ability of CD8 T cells to recognize glioma through models using CRISPR kinome knockout screening and CHK2 knockout in GL261 cells, the instant claims are not drawn to CHK2 knockout, or even a small molecule inhibitor that is specific for Chk2 while not inhibiting Chk1, but rather, the administration of prexasertib which inhibits both Chk1 and Chk2.
Furthermore, applicant does not provide any demonstration in the instant disclosure that pharmacological inhibition of only Chk2, such as with one of the Chk2 exclusive small molecule inhibitors identified in the specification, would lead to the claimed outcomes or be effective in potentiating PD-L1 treatment of glioma expressing high levels of Chk2. Rather, the examples of the instant disclosure demonstrate only the use of prexasertib which, as discussed in detail above and acknowledged by applicant in the response, is an inhibitor of both Chk1 and Chk2. Additionally, as discussed by applicant in the response, prexasertib more potently inhibits Chk1, which indicates that in the experiments detailed in the response, both Chk1 and Chk2 would have been inhibited, regardless of what the intent of the inhibitor was. This is particularly the case as applicant does not establish that the glioma models used did not also express Chk1, which would have been expected based on the teachings of the prior art. Applicant does demonstrate longer survival in CHEK2 knockout mice when they are administered anti-PD-1, for instance see Fig. 14; however, applicant does not translate these findings to pharmacological inhibition, for instance through the use of a specific Chk2 inhibitor that does not act on Chk1. If applicant has data that suggests that one of the alternative inhibitors disclosed in the specification, for instance Chk2 Inhibitor II (BML-227), which is specific for Chk2 and does not inhibit Chk1, then such results could be presented in the form of a declaration for consideration.
With regards to Bartkova, applicant argues that the reference does not disclose or suggest using CHK2 expression as a selection criteria for combination immunotherapy. Applicant argues that the general observation that elevated DDR checkpoint kinases in glioma does not render obvious a method of treating glioma in which subjects are selected based on high CHK2 expression, particularly given that Bartkova does not administer any kinase inhibitor and contains no immunotherapy or T cell data.
It is first noted that, as discussed above, conclusive proof of efficacy is not required in order to establish obviousness. Therefore, Bartkova is not required to administer any kind of inhibitor or provide any data in order to establish a prima facie case of obviousness.
That said, the instant claims do not expressly require the active step of selecting a patient based on high CHK2 expression, nor is it apparent that such selection is supported by the originally filed disclosure. Rather, the claim only requires that the subject that is treated have a high expression of Chk2 relative to non-tumor brain tissue; the presence of which is established by Bartkova for glioma.
With regards to Campagne, applicant argues that Campagne contains no immunotherapy data, no CD8 T cell data, no subject selection based on CHK2 expression, and no survival data. Applicant argues that the ability of a compound to penetrate the CNS does not render obvious the specific brain-localized immunological and therapeutic outcomes recited in amended claim 1. Applicant argues that the instant specification uniquely demonstrates these outcomes and that the outcomes could not have been predicted from Campagne’s data alone.
As discussed above, neither Campagne, nor any of the other applied references alone or in combination, are required to experimentally demonstrate the claimed outcomes in order to establish a prima facie case of obviousness as the requirement for obviousness is a reasonable expectation of success. Furthermore, Campagne is not the only applied reference and is, therefore, not required to teach each and every limitation of the claimed invention in order to establish obviousness. Campagne is applied in the rejections of the instant office action in order to demonstrate that, when administered systemically, prexasertib is capable of penetrating the blood brain barrier and penetrating brain tumors with adequate exposure for target engagement.
Conclusion
No claims are allowed.
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.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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