CTNF 18/531,312 CTNF 90090 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Claims 1-3, 8, 11, 15, 16, 18, 22, 24, 26-31, 38, 43, 52, and 53 are pending. Claims 1-3, 8, 11, 15, 16, 18, 22, 24, 26-31, 38, 43, 52, and 53 are under examination on the merits. Priority Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-3, 8, 11, 15, 16, 18, 22, 24, 26-31, 38, 43, 52, and 53 have an effective filing date of 12/16/2014, corresponding to PRO 62/092,783. Information Disclosure Statement The information disclosure statement (IDS) submitted on 10/22/2025 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Claim Objections 07-29-01 AIA Claim 11 objected to because of the following informalities: The claim depends from claim 10, which is canceled. For the purposes of examination, it will be assumed that claim 11 depends from claim 1 . Appropriate correction is required. 07-29-01 AIA Claim 38 objected to because of the following informalities: The claim recites an “anti-CTLA-1 antibody,” and it appears that this is a typographical error that should read “anti-CTLA-4 antibody.” Appropriate correction is required. Claim Rejections 35 U.S.C. 102(a)(1) 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA Claim 1 is rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Freeman et al. (US PG PUB 2013/0291136, publication date 10/31/2013, IDS) . At [0005], Freeman et al. disclose that “[t]he importance of the B7:CD28/CTLA4/ICOS costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this costimulatory pathway results in the development of antigen specific tolerance in murine and human systems… Conversely, expression of B7 by B7-negative murine tumor cells induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge… Therefore, manipulation of the costimulatory pathways offers great potential to stimulate or suppress immune responses in humans.” At [0006], Freeman et al. disclose that “[t]he discovery of more members of the B7-1 and CD28 families has revealed additional pathways that provide costimulatory and inhibitory second signals to T cells. One of the newer pathways is represented by the programmed death 1 (PD-1; also known as CD279) receptor and its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). PD-1 is a member of the CD28/CTLA4 family that is expressed on activated, but not resting T cells… Ligation of PD-1 by its ligands mediates an inhibitory signal that results in reduced cytokine production, and reduced T cell survival…” At [0254], Freeman et al. disclose that “[i]n another embodiment, the immune response can be stimulated by the methods described herein, such that preexisting tolerance is overcome. For example, immune responses against antigens to which a subject cannot mount a significant immune response, e.g., to an autologous antigen, such as a tumor specific antigens can be induced by administering an antibody that blocks the interaction of a PD-1 ligand with PD-1.” Freeman et al. disclose an antibody or antigen-binding fragment that binds a PD-1 protein and inhibits a PD-1-mediated signal. See [0019]. At claims 42 and 43, Freeman et al. disclose that anti-PD-1 antibodies may be used to treat cancer, including glioma. Therefore Freeman et al. disclose a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, thus meeting the limitations of claim 1. Therefore all of the limitations of claim 1 are met by the disclosure Freeman et al . 07-15 AIA Claim s 1, 8, 11, 18, 22, and 43 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) . At [0004], Cogswell et al. disclose that “Programmed Death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1... Unlike CTLA-4, PD-1 primarily functions in peripheral tissues where activated T-cells may encounter the immunosuppressive PD-L1 (B7-H1) and PD-L2 (B7-DC) ligands expressed by tumor and/or stromal cells... Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models…, and the use of Ab inhibitors of the PD-1/PD-L1 interaction for treating cancer has entered clinical trials.” At [0006], Cogswell et al. disclose “a method for immunotherapy of a subject afflicted with cancer, which method comprises administering to the subject a composition comprising a therapeutically effective amount of an agent that reduces or suppresses signaling from an inhibitory immunoregulator. In preferred embodiments, the agent is an Ab. In other preferred embodiments, the inhibitory immunoregulator is a component of the PD-1/PD-L1 signaling pathway. In further preferred embodiments, the Ab disrupts the interaction between PD-1 and PD-L1. In certain embodiments, the Ab is an anti-PD-1 Ab of the invention or an anti-PD-L1 Ab of the invention. In preferred embodiments, the anti-PD-1 Ab of the invention is nivolumab…” At [0003], Cogswell et al. disclose that “[h]uman cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system... Although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as ‘self’ and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively suppress the host immune response... Among these mechanisms, endogenous ‘immune checkpoints’ that normally terminate immune responses to mitigate collateral tissue damage can be co-opted by tumors to evade immune destruction. Intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of the anti-CTLA-4 antibody (Ab), ipilimumab…” At [0128], Cogswell et al. disclose that the administration of nivolumab may be combined with ipilimumab. At [0135], Cogswell et al. disclose that glioma may be treated using anti-PD-1 antibody therapy. At [0030], Cogswell et al. disclose that the antibodies of the invention may be administered via an intravenous route. Therefore Cogswell et al. disclose a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, further comprising administering an additional anti-cancer therapy concurrently with, prior to, or after the administration of said antibody or antigen-binding portion thereof that binds to a PD-1, wherein said antibody or antigen-binding portion thereof that binds to a PD-1 is nivolumab, wherein said additional anti-cancer therapy is an anti-CTLA-4 antibody, such as ipilimumab, thus meeting the limitations of claims 1, 8, 11, 18, 22, and 43. Therefore all of the limitations of claims 1, 8, 11, 18, 22, and 43 are met by the disclosure of Cogswell et al. 35 U.S.C. 103 07-06 AIA 15-10-15 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. 07-20-02-aia AIA 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-21-aia AIA Claim s 1-3, 24, 26-30, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Freeman et al. (US PG PUB 2013/0291136, publication date 10/31/2013, IDS) in view of Berghoff et al. (Neuro Oncol, 16(Suppl 2), September 2014) . At [0005], Freeman et al. teach that “[t]he importance of the B7:CD28/CTLA4/ICOS costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this costimulatory pathway results in the development of antigen specific tolerance in murine and human systems… Conversely, expression of B7 by B7-negative murine tumor cells induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge… Therefore, manipulation of the costimulatory pathways offers great potential to stimulate or suppress immune responses in humans.” At [0006], Freeman et al. teach that “[t]he discovery of more members of the B7-1 and CD28 families has revealed additional pathways that provide costimulatory and inhibitory second signals to T cells. One of the newer pathways is represented by the programmed death 1 (PD-1; also known as CD279) receptor and its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). PD-1 is a member of the CD28/CTLA4 family that is expressed on activated, but not resting T cells… Ligation of PD-1 by its ligands mediates an inhibitory signal that results in reduced cytokine production, and reduced T cell survival…” At [0254], Freeman et al. teach that “[i]n another embodiment, the immune response can be stimulated by the methods described herein, such that preexisting tolerance is overcome. For example, immune responses against antigens to which a subject cannot mount a significant immune response, e.g., to an autologous antigen, such as a tumor specific antigens can be induced by administering an antibody that blocks the interaction of a PD-1 ligand with PD-1.” Freeman et al. teach an antibody or antigen-binding fragment that binds a PD-1 protein and inhibits a PD-1-mediated signal. See [0019]. At claims 42 and 43, Freeman et al. teach that anti-PD-1 antibodies may be used to treat cancer, including glioma. Therefore Freeman et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, thus meeting the limitations of claim 1. Although Freeman et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, Freeman et al. do not teach or suggest a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said glioma is a glioblastoma, such as O-6-methylguanine DNA methyltransferase (MGMT) glioblastoma. These deficiencies are remedied by Berghoff et al. Berghoff et al. teach that “[i]mmune checkpoint inhibitors targeting programmed cell death (PD)1 and PD-ligand (L)1 show promising clinical activity in various solid extracranial cancers. Expression of PD1 on tumor infiltrating T lymphocytes and PD-L1 expression on tumor cells were postulated to have predictive value for the response to PD1/PD-L1 targeting immune checkpoint inhibitors. METHODS: 135 specimens of 117 patients (median age 60, range 21-80); median KPS 90 (range 10-100) with glioblastoma were included… Analyses of PD1, PD-L1, CD3 and CD8 expression were performed by immunohistochemistry and previously published semiquantitative evaluation criteria. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was analyzed using pyrosequencing and a cut-off at 8%. RESULTS: Sparse to moderate density of tumor-infiltrating lymphocytes (TILs) in a total of 100/135 (74.1%) cases (CD3+ 92/135, 68.1%; CD8+ 64/135, 47.4%) was observed. PD1 expression was found on scattered TILs, both within the tumor tissue and in the perivascular compartment, in 20/135 (14.8%) cases. PD-L1 expression was evident on tumor cells and macrophages/microglial cells throughout the tumor tissue with occasional focal accentuation in 116/135 (85.9%) specimens, with 44.5% showing PD-L1 staining of more than 50% of the viable tumor tissue. MGMT methylation was found in 37/99 (37.4%) analyzed specimens … CONCLUSION: PD1 and/or PD-L1 are immunohistochemically detectable in a majority of glioblastoma samples. A clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.” Based upon the teachings of Berghoff et al., one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Freeman et al. and Berghoff et al. to develop a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said glioma is a glioblastoma, such as MGMT glioblastoma. One of ordinary skill in the art would have been motivated to do so, because Freeman et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore as indicated above, based upon the teachings of Berghoff et al., one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of Freeman et al. to MGMT glioblastoma patients having tumors that express PD-L1, because there would have been a reasonable expectation that the anti-PD-1 antibody of Freeman et al. would bind the PD-1 protein on activated anti-tumor T cells and inhibit PD-1-mediated signaling by blocking the interaction of PD-1 on T cells with tumor cells that express PD-L1. This effect would be expected to improve the function of said anti-tumor T cells, thereby providing a therapeutic benefit to glioblastoma patients having PD-L1-expressing tumors. With respect to claims 24 and 26-30, as set forth in MPEP 2144.05(II)(B), section entitled “There is a Motivation to Optimize Result-Effective Variables”: In In re Antonie , 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc ., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR , the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, claims 24 and 26-30 are drawn to different dosages and administration times for the claimed anti-PD-1 antibody. One of ordinary skill in the art would appreciate that the ability of said antibody to treat cancer is a function of these variables, and therefore dosages and administration times are variables that achieve a recognized result. Accordingly the different dosages and administration times recited in claims 24 and 26-30 are result-effective variables that achieve a recognized result, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the limitations recited in claims 24 and 26-30 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention. Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references . 07-21-aia AIA Claim s 1, 8, 11, 18, 22, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Freeman et al. (US PG PUB 2013/0291136, publication date 10/31/2013, IDS) and Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) . At [0005], Freeman et al. teach that “[t]he importance of the B7:CD28/CTLA4/ICOS costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this costimulatory pathway results in the development of antigen specific tolerance in murine and human systems… Conversely, expression of B7 by B7-negative murine tumor cells induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge… Therefore, manipulation of the costimulatory pathways offers great potential to stimulate or suppress immune responses in humans.” At [0006], Freeman et al. teach that “[t]he discovery of more members of the B7-1 and CD28 families has revealed additional pathways that provide costimulatory and inhibitory second signals to T cells. One of the newer pathways is represented by the programmed death 1 (PD-1; also known as CD279) receptor and its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). PD-1 is a member of the CD28/CTLA4 family that is expressed on activated, but not resting T cells… Ligation of PD-1 by its ligands mediates an inhibitory signal that results in reduced cytokine production, and reduced T cell survival…” At [0254], Freeman et al. teach that “[i]n another embodiment, the immune response can be stimulated by the methods described herein, such that preexisting tolerance is overcome. For example, immune responses against antigens to which a subject cannot mount a significant immune response, e.g., to an autologous antigen, such as a tumor specific antigens can be induced by administering an antibody that blocks the interaction of a PD-1 ligand with PD-1.” Freeman et al. teach an antibody or antigen-binding fragment that binds a PD-1 protein and inhibits a PD-1-mediated signal. See [0019]. At claims 42 and 43, Freeman et al. teach that anti-PD-1 antibodies may be used to treat cancer, including glioma. Therefore Freeman et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, thus meeting the limitations of claim 1. Freeman et al. do not teach or suggest a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of 1) an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said anti-PD-1 antibody is nivolumab, and 2) an anti-CTLA-4 antibody, wherein said anti-CTLA-4 antibody is ipilimumab. These deficiencies are remedied by Cogswell et al. At [0006], Cogswell et al. teach that “[t]he present disclosure provides a method for immunotherapy of a subject afflicted with cancer, which method comprises administering to the subject a composition comprising a therapeutically effective amount of an agent that reduces or suppresses signaling from an inhibitory immunoregulator. In preferred embodiments, the agent is an Ab. In other preferred embodiments, the inhibitory immunoregulator is a component of the PD-1/PD-L1 signaling pathway. In further preferred embodiments, the Ab disrupts the interaction between PD-1 and PD-L1. In certain embodiments, the Ab is an anti-PD-1 Ab of the invention or an anti-PD-L1 Ab of the invention. In preferred embodiments, the anti-PD-1 Ab of the invention is nivolumab…” At [0003], Cogswell et al. teach that “[h]uman cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al., 2006). Although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as ‘self’ and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively suppress the host immune response (Topalian et al., 2011; Mellman et al., 2011). Among these mechanisms, endogenous ‘immune checkpoints’ that normally terminate immune responses to mitigate collateral tissue damage can be co-opted by tumors to evade immune destruction. Intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of the anti-CTLA-4 antibody (Ab), ipilimumab…” Based upon the teachings of Cogswell et al., one of ordinary skill in the art would appreciate that nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) may be used in cancer immunotherapy. At [0030], Cogswell et al teach that antibodies of the invention may be administered intravenously. One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Freeman et al. and Cogswell et al. to develop a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of 1) an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said anti-PD-1 antibody is nivolumab, and 2) an anti-CTLA-4 antibody, wherein said anti-CTLA-4 antibody is ipilimumab. One of ordinary skill in the art would have been motivated to do so, because Freeman et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore based upon the teachings of Cogswell et al., one of ordinary skill in the art would appreciate that nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) may be used in cancer immunotherapy. Therefore one of ordinary skill in the art would have been motivated to modify the method of Freeman et al. to comprise the administration of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), because the resultant method would reasonably be expected to provide a therapeutic benefit to glioma patients. Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references . 07-21-aia AIA Claim s 1-3, 8, 11, 18, 22, 24, 26-31, 38, 43, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) in view of Berghoff et al. (Neuro Oncol, 16(Suppl 2), September 2014) . At [0004], Cogswell et al. teach that “Programmed Death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1... Unlike CTLA-4, PD-1 primarily functions in peripheral tissues where activated T-cells may encounter the immunosuppressive PD-L1 (B7-H1) and PD-L2 (B7-DC) ligands expressed by tumor and/or stromal cells... Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models…, and the use of Ab inhibitors of the PD-1/PD-L1 interaction for treating cancer has entered clinical trials.” At [0006], Cogswell et al. teach “a method for immunotherapy of a subject afflicted with cancer, which method comprises administering to the subject a composition comprising a therapeutically effective amount of an agent that reduces or suppresses signaling from an inhibitory immunoregulator. In preferred embodiments, the agent is an Ab. In other preferred embodiments, the inhibitory immunoregulator is a component of the PD-1/PD-L1 signaling pathway. In further preferred embodiments, the Ab disrupts the interaction between PD-1 and PD-L1. In certain embodiments, the Ab is an anti-PD-1 Ab of the invention or an anti-PD-L1 Ab of the invention. In preferred embodiments, the anti-PD-1 Ab of the invention is nivolumab…” At [0003], Cogswell et al. teach that “[h]uman cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system... Although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as ‘self’ and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively suppress the host immune response... Among these mechanisms, endogenous ‘immune checkpoints’ that normally terminate immune responses to mitigate collateral tissue damage can be co-opted by tumors to evade immune destruction. Intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of the anti-CTLA-4 antibody (Ab), ipilimumab…” At [0128], Cogswell et al. teach that the administration of nivolumab may be combined with ipilimumab. At [0135], Cogswell et al. teach that glioma may be treated using anti-PD-1 antibody therapy. At [0030], Cogswell et al. teach that the antibodies of the invention may be administered via an intravenous route. Therefore Cogswell et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Cogswell et al. do not teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said glioma is a glioblastoma, such as O-6-methylguanine DNA methyltransferase (MGMT) glioblastoma. These deficiencies are remedied by Berghoff et al. Berghoff et al. teach that “[i]mmune checkpoint inhibitors targeting programmed cell death (PD)1 and PD-ligand (L)1 show promising clinical activity in various solid extracranial cancers. Expression of PD1 on tumor infiltrating T lymphocytes and PD-L1 expression on tumor cells were postulated to have predictive value for the response to PD1/PD-L1 targeting immune checkpoint inhibitors. METHODS: 135 specimens of 117 patients (median age 60, range 21-80); median KPS 90 (range 10-100) with glioblastoma were included… Analyses of PD1, PD-L1, CD3 and CD8 expression were performed by immunohistochemistry and previously published semiquantitative evaluation criteria. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was analyzed using pyrosequencing and a cut-off at 8%. RESULTS: Sparse to moderate density of tumor-infiltrating lymphocytes (TILs) in a total of 100/135 (74.1%) cases (CD3+ 92/135, 68.1%; CD8+ 64/135, 47.4%) was observed. PD1 expression was found on scattered TILs, both within the tumor tissue and in the perivascular compartment, in 20/135 (14.8%) cases. PD-L1 expression was evident on tumor cells and macrophages/microglial cells throughout the tumor tissue with occasional focal accentuation in 116/135 (85.9%) specimens, with 44.5% showing PD-L1 staining of more than 50% of the viable tumor tissue. MGMT methylation was found in 37/99 (37.4%) analyzed specimens … CONCLUSION: PD1 and/or PD-L1 are immunohistochemically detectable in a majority of glioblastoma samples. A clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.” Based upon the teachings of Berghoff et al., one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Cogswell et al. and Berghoff et al. to develop a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said glioma is a glioblastoma, such as MGMT glioblastoma. One of ordinary skill in the art would have been motivated to do so, because Cogswell et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore as indicated above, based upon the teachings of Berghoff et al., one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of Cogswell et al. to MGMT glioblastoma patients having tumors that express PD-L1, because there would have been a reasonable expectation that the anti-PD-1 antibody of Cogswell et al. would bind the PD-1 protein on activated anti-tumor T cells and inhibit PD-1-mediated signaling by blocking the interaction of PD-1 on T cells with tumor cells that express PD-L1. This effect would be expected to improve the function of said anti-tumor T cells, thereby providing a therapeutic benefit to glioblastoma patients having PD-L1-expressing tumors. With respect to claims 24, 26-31, and 38, as set forth in MPEP 2144.05(II)(B), section entitled “There is a Motivation to Optimize Result-Effective Variables”: In In re Antonie , 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc ., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR , the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, claims 24, 26-31, and 38 are drawn to different dosages and administration times for the claimed anti-PD-1 antibody and/or anti-CTLA-4 antibody. One of ordinary skill in the art would appreciate that the ability of said antibodies to treat cancer is a function of these variables, and therefore dosages and administration times are variables that achieve a recognized result. Accordingly the different dosages and administration times recited in claims 24, 26-31, and 38 are result-effective variables that achieve a recognized result, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the limitations recited in claims 24, 26-31, and 38 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention. Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references . 07-21-aia AIA Claim s 1, 8, 11, 15, 16, 18, 22, 43, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) in view of Friedman et al. (Clinical Cancer Research: 6: 2585-2597, 2000) . At [0004], Cogswell et al. teach that “Programmed Death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1... Unlike CTLA-4, PD-1 primarily functions in peripheral tissues where activated T-cells may encounter the immunosuppressive PD-L1 (B7-H1) and PD-L2 (B7-DC) ligands expressed by tumor and/or stromal cells... Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models…, and the use of Ab inhibitors of the PD-1/PD-L1 interaction for treating cancer has entered clinical trials.” At [0006], Cogswell et al. teach “a method for immunotherapy of a subject afflicted with cancer, which method comprises administering to the subject a composition comprising a therapeutically effective amount of an agent that reduces or suppresses signaling from an inhibitory immunoregulator. In preferred embodiments, the agent is an Ab. In other preferred embodiments, the inhibitory immunoregulator is a component of the PD-1/PD-L1 signaling pathway. In further preferred embodiments, the Ab disrupts the interaction between PD-1 and PD-L1. In certain embodiments, the Ab is an anti-PD-1 Ab of the invention or an anti-PD-L1 Ab of the invention. In preferred embodiments, the anti-PD-1 Ab of the invention is nivolumab…” At [0003], Cogswell et al. teach that “[h]uman cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system... Although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as ‘self’ and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively suppress the host immune response... Among these mechanisms, endogenous ‘immune checkpoints’ that normally terminate immune responses to mitigate collateral tissue damage can be co-opted by tumors to evade immune destruction. Intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of the anti-CTLA-4 antibody (Ab), ipilimumab…” At [0128], Cogswell et al. teach that the administration of nivolumab may be combined with ipilimumab. At [0135], Cogswell et al. teach that glioma may be treated using anti-PD-1 antibody therapy. At [0030], Cogswell et al. teach that the antibodies of the invention may be administered via an intravenous route. Therefore Cogswell et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Cogswell et al. do not teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said subject is also treated with an additional anti-cancer therapy that is an alkylating agent, such as temozolomide. These deficiencies are remedied by Friedman et al. Friedman et al. teach that temozolomide is an alkylating agent that may be used in the treatment of malignant glioma - “Temozolomide is a new and effective p.o. administered anticancer agent that demonstrates a broad spectrum of activity in various solid tumors and distribution to all tissues, including the brain. It spontaneously converts to an active methylating agent with activity against a number of refractory cancers, including malignant glioma, metastatic melanoma, and other solid tumors. Temozolomide is well tolerated, with minimal myelosuppression that is noncumulative and with nonhematological toxicity that is easily managed with standard antiemetic agents.” See Abstract and Summary/Conclusions sections. One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Cogswell et al. and Friedman et al. to develop a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity, wherein said subject is also treated with an additional anti-cancer therapy that is an alkylating agent, such as temozolomide. One of ordinary skill in the art would have been motivated to do so, because Cogswell et al. teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore as indicated above, Friedman et al. teach that temozolomide is an alkylating agent that may be used in the treatment of malignant glioma. One of ordinary skill in the art would have been motivated to combine the teachings of Cogswell et al. and Friedman et al., because there would have been a reasonable expectation that the resultant method is effective in the treatment of glioma. Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references. Nonstatutory Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp. 08-36 AIA Claim s 1-3, 8, 11, 18, 22, 24, 26-31, 38, 43, and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1 and 2 of U.S. Patent No. 10,668,152 in view of Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) and Berghoff et al. (Neuro Oncol, 16(Suppl 2), September 2014) . Both the instant claims and the conflicting claims recite methods of treating cancer (glioma) comprising the administration of an anti-PD-1 antibody. The teachings of Cogswell et al. and Berghoff et al. are detailed above. Based upon these references, one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of the conflicting claims to MGMT glioblastoma patients having tumors that express PD-L1, because there would have been a reasonable expectation that the anti-PD-1 antibody of the conflicting claims would bind the PD-1 protein on activated anti-tumor T cells and inhibit PD-1-mediated signaling by blocking the interaction of PD-1 on T cells with tumor cells that express PD-L1. This effect would be expected to improve the function of said anti-tumor T cells, thereby providing a therapeutic benefit to glioblastoma patients having PD-L1-expressing tumors. Furthermore based upon the teachings of Cogswell et al., it would have been prima facie obvious to modify the conflicting claims to comprise the concurrent administration of the anti-PD-1 antibody nivolumab and the anti-CTLA-4 ipilimumab to glioma patients. With respect to claims 24, 26-31, and 38, as set forth in MPEP 2144.05(II)(B), section entitled “There is a Motivation to Optimize Result-Effective Variables”: In In re Antonie , 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc ., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR , the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, claims 24, 26-31, and 38 are drawn to different dosages and administration times for the claimed anti-PD-1 antibody and/or anti-CTLA-4 antibody. One of ordinary skill in the art would appreciate that the ability of said antibodies to treat cancer is a function of these variables, and therefore dosages and administration times are variables that achieve a recognized result. Accordingly the different dosages and administration times recited in claims 24, 26-31, and 38 are result-effective variables that achieve a recognized result, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the limitations recited in claims 24, 26-31, and 38 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention. Therefore the instant claims are prima facie obvious over the conflicting claims in view of Cogswell et al. and Berghoff et al . 08-36 AIA Claim s 1, 8, 11, 15, 16, 18, 22, 43, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1 and 2 of U.S. Patent No. 10,668,152 in view of Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) and Friedman et al. (Clinical Cancer Research: 6: 2585-2597, 2000) . Both the instant claims and the conflicting claims recite methods of treating cancer (glioma) comprising the administration of an anti-PD-1 antibody. The teachings of Cogswell et al. and Friedman et al. are detailed above. Based upon these references, one of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of the conflicting claims in combination with temozolomide. One of ordinary skill in the art would have been motivated to do so, because the conflicting claims teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore Friedman et al. teach that temozolomide is an alkylating agent that may be used in the treatment of malignant glioma. One of ordinary skill in the art would have been motivated to combine the teachings of Cogswell et al. and Friedman et al., because there would have been a reasonable expectation that the resultant method is effective in the treatment of glioma. Therefore the instant claims are prima facie obvious over the conflicting claims in view of Cogswell et al. and Friedman et al. Claims 1-3, 8, 11, 18, 22, 24, 26-31, 38, 43, and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over a) claim 1 of U.S. Patent No. 10,392,442 and b) claim 1 of U.S. Patent No. 11,965,031 in view of Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) and Berghoff et al. (Neuro Oncol, 16(Suppl 2), September 2014). Both the instant claims and the conflicting claims recite methods of treating cancer comprising the administration of an anti-PD-1 antibody. The teachings of Cogswell et al. and Berghoff et al. are detailed above. Based upon these references, one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of the conflicting claims to MGMT glioblastoma patients having tumors that express PD-L1, because there would have been a reasonable expectation that the anti-PD-1 antibody of the conflicting claims would bind the PD-1 protein on activated anti-tumor T cells and inhibit PD-1-mediated signaling by blocking the interaction of PD-1 on T cells with tumor cells that express PD-L1. This effect would be expected to improve the function of said anti-tumor T cells, thereby providing a therapeutic benefit to glioblastoma patients having PD-L1-expressing tumors. Furthermore based upon the teachings of Cogswell et al., it would have been prima facie obvious to modify the conflicting claims to comprise the concurrent administration of the anti-PD-1 antibody nivolumab and the anti-CTLA-4 ipilimumab to glioma patients. With respect to claims 24, 26-31, and 38, as set forth in MPEP 2144.05(II)(B), section entitled “There is a Motivation to Optimize Result-Effective Variables”: In In re Antonie , 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc ., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR , the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, claims 24, 26-31, and 38 are drawn to different dosages and administration times for the claimed anti-PD-1 antibody and/or anti-CTLA-4 antibody. One of ordinary skill in the art would appreciate that the ability of said antibodies to treat cancer is a function of these variables, and therefore dosages and administration times are variables that achieve a recognized result. Accordingly the different dosages and administration times recited in claims 24, 26-31, and 38 are result-effective variables that achieve a recognized result, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the limitations recited in claims 24, 26-31, and 38 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention. Therefore the instant claims are prima facie obvious over the conflicting claim in view of Cogswell et al. and Berghoff et al. Claims 1, 8, 11, 15, 16, 18, 22, 43, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over a) claim 1 of U.S. Patent No. 10,392,442 and b) claim 1 of U.S. Patent No. 11,965,031 in view of Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) and Friedman et al. (Clinical Cancer Research: 6: 2585-2597, 2000). Both the instant claims and the conflicting claims recite methods of treating cancer comprising the administration of an anti-PD-1 antibody. The teachings of Cogswell et al. and Friedman et al. are detailed above. Based upon these references, one of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of the conflicting claims in combination with temozolomide. One of ordinary skill in the art would have been motivated to do so, because the conflicting claims teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore Friedman et al. teach that temozolomide is an alkylating agent that may be used in the treatment of malignant glioma. One of ordinary skill in the art would have been motivated to combine the teachings of Cogswell et al. and Friedman et al., because there would have been a reasonable expectation that the resultant method is effective in the treatment of glioma. Therefore the instant claims are prima facie obvious over the conflicting claim in view of Cogswell et al. and Friedman et al . 08-37 AIA Claim s 1-3, 8, 11, 18, 22, 24, 26-31, 38, 43, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/025,631 in view of Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) and Berghoff et al. (Neuro Oncol, 16(Suppl 2), September 2014). Both the instant claims and the conflicting claims recite methods of treating cancer comprising the administration of an anti-PD-1 antibody. The teachings of Cogswell et al. and Berghoff et al. are detailed above. Based upon these references, one of ordinary skill in the art would appreciate that in many glioblastoma patients, including MGMT glioblastoma patients, PD-L1 is expressed. One of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of the conflicting claims to MGMT glioblastoma patients having tumors that express PD-L1, because there would have been a reasonable expectation that the anti-PD-1 antibody of the conflicting claims would bind the PD-1 protein on activated anti-tumor T cells and inhibit PD-1-mediated signaling by blocking the interaction of PD-1 on T cells with tumor cells that express PD-L1. This effect would be expected to improve the function of said anti-tumor T cells, thereby providing a therapeutic benefit to glioblastoma patients having PD-L1-expressing tumors. Furthermore based upon the teachings of Cogswell et al., it would have been prima facie obvious to modify the conflicting claims to comprise the concurrent administration of the anti-PD-1 antibody nivolumab and the anti-CTLA-4 ipilimumab to glioma patients. With respect to claims 24, 26-31, and 38, as set forth in MPEP 2144.05(II)(B), section entitled “There is a Motivation to Optimize Result-Effective Variables”: In In re Antonie , 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc ., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR , the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, claims 24, 26-31, and 38 are drawn to different dosages and administration times for the claimed anti-PD-1 antibody and/or anti-CTLA-4 antibody. One of ordinary skill in the art would appreciate that the ability of said antibodies to treat cancer is a function of these variables, and therefore dosages and administration times are variables that achieve a recognized result. Accordingly the different dosages and administration times recited in claims 24, 26-31, and 38 are result-effective variables that achieve a recognized result, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the limitations recited in claims 24, 26-31, and 38 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention. Therefore the instant claims are prima facie obvious over the conflicting claim in view of Cogswell et al. and Berghoff et al . This is a provisional nonstatutory double patenting rejection. 08-37 AIA Claim s 1, 8, 11, 15, 16, 18, 22, 43, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/025,631 in view of Cogswell et al. (US PG PUB 2013/0309250, publication date: 11/21/2013) and Friedman et al. (Clinical Cancer Research: 6: 2585-2597, 2000). Both the instant claims and the conflicting claims recite methods of treating cancer comprising the administration of an anti-PD-1 antibody. The teachings of Cogswell et al. and Friedman et al. are detailed above. Based upon these references, one of ordinary skill in the art would have been motivated to administer the anti-PD-1 antibody of the conflicting claims in combination with temozolomide. One of ordinary skill in the art would have been motivated to do so, because the conflicting claims teach a method for treating a subject afflicted with a glioma comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that binds to a PD-1 and inhibits PD-1 activity. Furthermore Friedman et al. teach that temozolomide is an alkylating agent that may be used in the treatment of malignant glioma. One of ordinary skill in the art would have been motivated to combine the teachings of Cogswell et al. and Friedman et al., because there would have been a reasonable expectation that the resultant method is effective in the treatment of glioma. Therefore the instant claims are prima facie obvious over the conflicting claim in view of Cogswell et al. and Friedman et al . This is a provisional nonstatutory double patenting rejection. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /NELSON B MOSELEY II/Primary Examiner, Art Unit 1642 Application/Control Number: 18/531,312 Page 2 Art Unit: 1642 Application/Control Number: 18/531,312 Page 3 Art Unit: 1642 Application/Control Number: 18/531,312 Page 4 Art Unit: 1642
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