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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/24/2025 has been entered.
Response to Amendment
The rejection of claims 9-14 and 29 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn in view of the amendment to the claims limiting the HAT activator to oxaliplatin.
The rejection of claim 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment removing “ICI”. Note a new rejection under 35 USC 112(b) appears below.
The rejection of claim(s) 9-14 under 35 U.S.C. 103 as being unpatentable over US 2017/0112894 A1 (Kawabe), Shalapour et al., (Nature 521:94-98 and suppl. material, 26 pages, 7 May 2015) Nehme et al. (Eur J Cancer 30A(4): 520-525, 1994) and Ni et al. (Canc. Lett. 336:174-184, 2013) is withdrawn in view of the amendment to the claims limiting the HAT-inducer to oxaliplatin. Note a new rejection under 35 USC 103 appears below.
Claim Objections
Claims 29 and 41 are objected to because of the following informalities: there is a comma between “hepatocellular” and “carcinoma”. In the interest of compact prosecution, it is being assumed that not all carcinomas are encompassed and that only hepatocellular carcinomas are. This is consistent with instant claim 11. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9, 10 and 12-14 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 9, 10 and 12-14 are indefinite because they recite the term “CTLA”, which is not itself a well-known art-recognized term and the specification does not define it. There is no clear context within the claims so as to further define it. The specification recites only “CTLA-4” (e.g., [0006]-[0008]).
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
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 –
(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 9, 10, 12 and 14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Perrot et al. (Poster w/Abstract 2718, Am. Assoc. Canc. Res., Canc. Res. 78(13_Supplement):2718, July 2018)
Perrot et al. teaches in Fig. 1B that anti-PD-1 antibody with oxaliplatin (10 mg/kg each agent, Fig. 1 legend) administered to MCA205 tumor-engrafted mice had more antitumor activity than anti-PD-1 alone as shown by tumor growth inhibition and survival.
Claim(s) 9-12, 14 and 29 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shalapour et al., (Nature 521:94-98 and suppl. material, 26 pages, 7 May 2015, cited in the PTO-892 mailed 4/2/2025).
Shalapour et al. treated mice bearing tumors from subcutaneously injected Myc-CaP (MC) prostate tumor cells with oxaliplatin plus anti-PD-L1 antibody or with anti-PD-L1 antibody alone. It showed that the combination but not anti-PD-L1 antibody alone inhibited tumor growth, increased GrzB (granzymeB) expression by effector T cells, reduced PD-L1 expression on IgA+ cells and reduced serum IgA (p. 94, col. 1, last paragraph, Fig. 7i, and p. 96, col. 1, middle). It was also found that oxaliplatin induced PD-L1 in about 50% of IgA+ plasmocytes (Fig. 3j). It is concluded (p. 98, col. 1, end of second paragraph), “Immunogenic chemotherapy may also enhance response rates to PD-1 or PD-L1 blockade in other malignancies, including bladder cancer and cutaneous melanoma in which only 35% of the patients exhibit a response28.” The dose of oxaliplatin used was 6 mg/kg, designated as “low-dose” (e.g., p. 2 of Suppl., Methods: Treatment with chemotherapy and antibodies”, col. 1 p. 96, col. 1, last paragraph, and first sentence after Abstract).
Claim(s) 9, 10, 12 and 14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Song et al. (Nat. Commun. 9:2237 and Suppl. Material, 25 pages, Jun. 2018).
Song et al. teach that in a murine orthotopic colorectal tumor model, treatment with oxaliplatin (OxP) induced immunogenic cell death (ICD; p. 2, col. 1, start of third paragraph, and col. 2, start of second paragraph). It is reported (p. 4, col. 1) that treatment of the mice with both OxP (6 mg/kg) and anti-PD-L1 monoclonal antibody led to significant tumor inhibition compared to other treatments (Fig. 3d and Suppl. Fig. 4), “suggesting the synergistic effect of combining ICD and checkpoint inhibitor in MSS/MMR-proficient colorectal cancer therapy.” Similar highly efficient tumor inhibitory results are disclosed using an expressed PD-L1 trap made of the extracellular domain of PD-1 fused to a trimerization domain (Fig. 4a and paragraph beginning on p. 5, col. 2). It was also effective in mice with orthotopic B16F10 melanoma tumors (p. 7, col. 1).
Claim(s) 9, 10 and 12-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov ID. NCT02625610 v.20 (https://clinicaltrials.gov/study/NCT02625610?term=NCT02625610&limit=10&sort=@relevance&rank=1&tab=history&a=20#version-content-panel>, 11-30-2017).
NCT02625610 teaches a phase III clinical trial for treatment of adenocarcinoma of the stomach or gastro-esophageal function by administration with anti-PD-L1 antibody avelumab and chemotherapy (Official Title and Arms and Interventions:Assigned Interventions:Drug:Avelumab). The Study Description: Brief Summary states, “The purpose of this study is to demonstrate superiority of treatment with avelumab versus continuation of first-line chemotherapy.” The chemotherapy is oxaliplatin (85 mg/m2 ) and either 5-fluorouracil (5-FU) or capecitabine (Arms and Interventions: ARMS and Assigned Interventions). Avelumab and oxaliplatin are administered sequentially or at the same time (Arms and Interventions: Assigned Interventions:Drug:Avelumab and Drug:Oxaliplatin).
Claim(s) 9-14 and 29 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent 10,722,523 B2 (Karin).
Karin teaches in Fig. 16 that treatment of a murine hepatocellular carcinoma tumor model with an anti-PD-L1 antibody combined with oxaliplatin showed significantly better tumor regression than either alone (col. 12, lines 46-54). Oxaliplatin causes “immunogenic cell death” (col. 14, lines 65-66). It is taught that (col. 16, lines 25-28), “Unlike cisplatin, oxaliplatin induces immunogenic cell death that augments CTL [cytotoxic T lymphocyte] activation and consequent tumor eradication5,28.” Anti-PD-L1 antibodies, such as atezolizumab, can reduce the number and function of immunosuppressive plasmocyte cells (col. 17, lines 54-63). It was shown in mouse models of prostate cancer that combining low-dose oxaliplatin can sensitize prostate cancer cells to anti-PD-L1 antibody and allow CTL-dependent eradication, and combining oxaliplatin with anti-PD-L1 decreases the number of liver tumors (col. 19, lines 11-67). Oxaliplatin was administered to mice weekly at 6 mg/kg (col. 61, lines 10-11). Claim 1 is drawn to a method of treating an epithelial cancer in a mammal by administering a therapeutically effective amount of a) oxaliplatin in an amount that causes immunogenic cell death of said epithelial cancer cells and that is non-myelosuppressive and b) an anti-PD-L1 antibody, such that the combined administration produces a greater inhibition of said cancer than administering either a) or b) alone. Epithelial cancer includes prostate cancer, liver cancer and lung cancer (col. 2, lines 40-42).
Note that the instant application tested the effect of oxaliplatin on histone acetyltransferase (HAT) activity only in vitro. As shown in Example 5, 2 pM Oxali increased HAT enzymatic activity in Myc-CaP cells (Example 5). This dose is designated as an in vitro low-dose at the start of [0084]. The specification points to Shalapour et al. (2015) as defining low-dose oxaliplatin ([0077]). As evidenced above, Shalapour et al. used 6 mg/kg/mouse and designated that dose as low for mice in vivo. In line with this, the 85 mg/m2 dose in humans administered for ClinicalTrials.gov ID. NCT02625610 v.20 (supra) corresponds to 2.3 mg/kg dose for an average human with a body surface of 1.6 m2 weighing 60 kg (see US HHS, FDA, CDER, Guidance for Industry, 2005, Table 3).
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.
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.
Claim(s) 9-14 and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 10,722,523 B2 (Karin) as applied to claims 9-14 and 29 above, and further in view of Shalapour et al., (Nature 521:94-98 and suppl. material, 26 pages, 7 May 2015, cited in the PTO-892 mailed 4/2/2025), Castro et al. (Front. Immunol. 9:847, 19 pages, May 2018) and Ni et al. (Canc. Lett. 336:174-184, 2013, cited in the PTO-892 mailed 4/2/2025).
Karin teaches in Fig. 16 that treatment in a murine hepatocellular carcinoma tumor model with an anti-PD-L1 antibody combined with oxaliplatin showed significantly better tumor regression than either alone (col. 12, lines 46-54). Oxaliplatin causes “immunogenic cell death” (col. 14, lines 65-66). It is taught that (col. 16, lines 25-28), “Unlike cisplatin, oxaliplatin induces immunogenic cell death that augments CTL [cytotoxic T lymphocyte] activation and consequent tumor eradication5,28.” Anti-PD-L1 antibodies, such as atezolizumab, can reduce the number and function of immunosuppressive plasmocyte cells (col. 17, lines 54-63). It was shown in mouse models of prostate cancer that combining low-dose oxaliplatin can sensitize prostate cancer cells to anti-PD-L1 antibody and allow CTL-dependent eradication, and combining oxaliplatin with anti-PD-L1 decreases the number of liver tumors (col. 19, lines 11-67). Oxaliplatin was administered to mice weekly at 6 mg/kg (col. 61, lines 10-11). ”Data herein show that successful eradication of large tumors in prostate (Examples 1-7) and liver (Example 8) by immunogenic chemotherapy requires removal of immunosuppressive plasmocytes that are present both in mouse and human PC.” (col. 16, lines 18-22) Prostate cancer Myc-Cap (MC) cells were used in some PC models established with s.c. MC cell transplantation (e.g., col. 22, lines 32-37). Claim 1 is drawn to a method of treating an epithelial cancer in a mammal by administering a therapeutically effective amount of a) oxaliplatin in an amount that causes immunogenic cell death of said epithelial cancer cells and that is non-myelosuppressive and b) an anti-PD-L1 antibody, such that the combined administration produces a greater inhibition of said cancer than administering either a) or b) alone. Epithelial cancer includes prostate cancer, liver cancer and lung cancer (col. 2, lines 40-42). The mammal may be a human (col. 14, line 33). Karin is silent with respect to administration of exogenous Interferon-gamma (IFN-γ).
Shalapour et al. found that treatment of mice bearing tumors from subcutaneously injected MC prostate tumor cells with oxaliplatin plus anti-PD-L1 antibody, but not anti-PD-L1 antibody alone, inhibited tumor growth, increased GrzB (granzymeB) expression by effector T cells, reduced PD-L1 expression on IgA+ cells and reduced serum IgA (p. 96, col. 1, middle, and Fig. 7i). It was also found that oxaliplatin induced PD-L1 in about 50% of IgA+ plasmocytes (Fig. 3j). It is concluded (p. 98, col. 1, end of second paragraph), “Immunogenic chemotherapy may also enhance response rates to PD-1 or PD-L1 blockade in other malignancies, including bladder cancer and cutaneous melanoma in which only 35% of the patients exhibit a response28.” The dose of oxaliplatin used was 6 mg/kg, designated as “low-dose” (p. 7/26, last paragraph and, e.g., p. 1/26, first sentence after Abstract).
Castro et al. discusses the role of IFN-γ in cancer and its treatment or endogenous inhibition of cancer. It states (p 7, col. 2, third paragraph), “Consistently, immunotherapy using immune checkpoint blockers (anti-CTLA-4 and/or anti-PD-1) combined with anticancer vaccines, clearly associate inhibition of tumor growth with increased proportion of IFN-γ-producing effector T cells (236, 237)... In other way, it was recently shown that IFN-γ-induced Treg cell fragility (loss of suppressive function) is required for response to anti-PD-1 therapy (240).” Several clinical trials have shown the positive effect of IFN-γ on cancer therapy for a variety of cancers (paragraph bridging pp. 7-8). Castro et al. concludes (p. 10, col. 2, second paragraph), “The outcome of IFN-γ signaling depends on the tumor-specific context, the magnitude of the signal, and the microenvironmental cues. Nevertheless, IFN-γ or IFN-γ inducers remain promising agents to include in combined therapies against cancer…. In addition, these strategies would profit from the combination with conventional treatments and with anti-PD-L1 and anti-CTLA-4 therapies to overcome the regulatory effects of IFN-γ.”
Ni et al. examined label-retaining cancer cells (LRCCs), which are stem-like cancer cells with slow cell cycling. Ni et al. found that LRCCs are especially sensitive to apoptosis from IFNγ treatment in vitro and in vivo because they have higher levels of IFNγ receptor levels compared to non-LRCCs (Abstract). Primary colon cancer cells were stained with PKH26/27, which preferentially labels quiescent cancer cells such that only PKHhi are LRCC (p. 174, col. 2, first paragraph). No specific approach to eradicate LRCCs is known (p. 175, first full sentence). “CSCs [cancer stem cells] escape immune surveillance through the low expression of MHC molecules, resulting in the inhibition of anti-tumor immune cell activation and the inhibition of regulatory T (Treg) cell induction [13,14].” (p. 175, col. 1, start of first full paragraph) To test the effect of IFNγ and a chemotherapeutic drug, oxaliplatin (Oxa), on xenografted mice with PKHhi, PKHlow or PKHneg tumors, mice were injected i.p. with recombinant human (rh) IFNγ and/or Oxa (2 mg/kg/wk), with treatment lasting 4 weeks (p. 176, col. 1, paragraphs 5-6). Of PKHhi, PKHlow or PKHneg cells, PKHhi were significantly more able to form tumors xenografts in mice (Fig. 1E). When each subpopulation was treated with Oxa, the PKHhi population was enriched while viable PKHlow and PKHneg cell populations decreased, suggesting “that PKHhi cells are especially resistant to conventional chemotherapy.” (p. 175, col. 2, third paragraph) In culture, almost all primary colon cancer cells in the G0 cell cycle phase were PKHhi cells (Fig. 1C). IFNγ had much higher cell killing ability for PKHhi cells than PKHlow or PKHneg cells (paragraph bridging pp. 177-178). PKHhi cells were also more sensitive to IFNγ (p. 179, col. 1, first paragraph). In vivo, IFNγ treatment significantly reduced the number of viable PKHhi cells, but not PKHlow or PKHneg cells (p. 179, col. 1, third paragraph). IFN-γ was shown to exert synergistic effects with oxaliplatin on cancer cells in vitro, but presence of IFN-γ was required for high Oxa cytotoxic activity as shown by changing the orders of treatment of cells from the different PKH populations with Oxa (10 μg/ml) and rhIFN-γ (1000 μ/ml; p. 181, col. 2, first full paragraph). Treatment with rhIFN-γ followed by Oxa led to preferential killing of Oxa-resistant PKHhi cells; however, most of the PKHlow and PKHneg cells were viable during the IFN-γ incubation and not killed until the Oxa treatment (Fig. 3B). When the order was reversed, the majority of the PKHhi cells survived after Oxa treatment, but were killed after introduction of IFN-γ (Fig. 3C). When treated with a combination of Oxa and IFN-γ, the PKHhi, PKHlow and PKHneg cells were eliminated simultaneously (Fig. 3D). This was shown in vivo in a xenograft model in which administration of Oxa and IFN-γ showed a greater inhibition of tumor growth than either drug alone (paragraph bridging pp. 181-182 and Fig. 5B). In a second xenograft experiment using the same cancer cells transferred from the first xenografted mice (p. 182, col. 1, second paragraph), “[C]ompared with the other groups, the combination therapy significantly reduced the tumor formation ratio and tumor volume (Fig. 5D and E, Table 1). Altogether, these data suggest that IFN-γ treatment combined with chemotherapy could profoundly enhance anti-tumor effects and decrease the capacity for serial tumor formation.” Ni et al. summarizes the findings by stating (p. 175, col. 1, end of second full paragraph), “Furthermore, we report that IFN-γ synergistically combined with oxaliplatin (Oxa), a first-line colon cancer chemotherapy drug, can eradicate both LRCCs and non-LRCCs, which significantly inhibits tumor growth and reduces the risk of serial tumor formation.” Reference 40 of Ni et al. is entitled, “Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma”.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to treat a cancer with low-dose oxaliplatin in combination with IFNγ and an inhibitor of PD-L1, such as an anti-PD-1 or anti-PD-L1 mAb like avelumab, because Karin and Shalapour et al. taught that treatment with oxaliplatin and anti-PD-L1 antibody had antitumor efficacy when neither alone did. It would have been obvious wherein the cancer was prostate cancer, including a Myc-CaP (MC) phenotype, or liver cancer, including hepatocellular carcinoma, as shown to be susceptible to antitumor activity of the combination of oxaliplatin and PD-L1 inhibitor by Karin and Shalapour et al. It further would have been obvious to include administration of IFNγ because Ni et al. showed the combination of oxaliplatin with IFNγ was effective to kill colon cancer cells in vivo and Castro et al. discussed the antitumor effect of IFNγ shown in clinical trials and the mechanisms by which IFNγ produces antitumor effects. Further, Ni et al. provided motivation for combining Oxa and IFNγ or other platinoid with IFNγ in a composition for simultaneous treatment with both drugs because the results using both compared with monotherapy or with sequential administration were superior (e.g., Ni et al. Fig. 6). The in vivo results provided a reasonable expectation of successful tumor cell killing, especially because of the ability to kill stem-like and non-stem-like cancer cells both in vitro and in vivo. Castro also suggests combining IFNγ administration with anti-PD-L1 therapy. It would have been obvious wherein the cancer to be treated was any cancer comprising stem-like cancer cells due to the findings of Ni et al. or was prostate or a liver cancer as taught by Karin or Shalapour et al. It would have been obvious wherein the immune checkpoint inhibitor was a known anti-immune checkpoint inhibitor antibody, such atezolizumab as taught by Karin. For these reasons, the invention is prima facie obvious.
Applicant’s arguments which pertain to the new rejection under 35 USC 103 are addressed here:
Applicant argues (p. 6 of REMARKS, first three paragraphs) that amendment to claim 9 to recite “administration to the subject an effective amount of oxaliplatin sufficient to induce histone acetyltransferase (HAT) activation in a subject” overcomes the rejection because this is something surprising that the inventors discovered. As recited in the specification [0090], 2 μM Oxali (oxaliplatin) led to greater stimulation of HAT activity than 4 μM (Fig. 5B). This increased HAT activation also “increased expression of chromatin modifiers, chromatin accessibility, enhanced p65/NF-kB recruitment to the Ifngr2 promoter, as well as increased p300 recruitment to Ifngr2 and Tapl promoter. Id. Importantly, these effects were not present with other platinoids such as cisplatin. Id. at paragraph [0093]. In fact, treatment with low-dose Oxali, but not Cis, enhanced expression of Ifngr2, Psmb9, Tap1, and Nlrc5 mRNAs in s.c. Myc-CaP tumors (FIGS. 7B and 7C). Id. at [0093].” The argument has been fully considered but is not persuasive. It reasonably appears the function of inducing HAT activity was inherent to the methods of the prior art or would have been obvious in view of the prior art as set forth in the rejection above. Something which is old does not become patentable upon the discovery of a new property. The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 195 USPQ 430, 433 (CCPA 1977). Fig. 5B referenced by Applicant shows that at hours 3, 6 and 12 after treatment of Myc-CaP cells in culture, 2 μM Oxali induced higher HAT activity than 4 μM; however, at hours 3 and 6, 4 μM still showed significant HAT activity induced by Oxali. These experiments are in vitro and the claimed methods require administration to a subject and, therefore, in vivo activity. The only in vivo results referenced in the specification are those of the prior art, which used 6 mg/kg oxaliplatin in mice, illustrative of a “low-dose” (see instant [0077] and Shalapour et al., 2015), and those of Example 7, which neither i) specifies a dose of Oxali that was administered to the mice, saying only that it was “low-dose” ([0093]), or ii) shows the administration induced HAT activity. Therefore, the 6 mg/kg dose used in the prior art relied upon is consistent with a “low-dose” of oxaliplatin that would reasonably have been expected to induce HAT activation in a subject, wherein the subject is a mouse. See Clinicaltrial.gov ID. NCT NCT02625610 v.20 (above) for a human oxaliplatin dose that reasonably appears to meet the limitations of the claim. Applicant is not claiming an in vitro method and has provided no evidence to doubt that the dosage for in vivo administration used in the prior art would not induce HAT activation in a subject. The concomitant increase in expression of chromatin modifiers and accessibility as well as other effects not found with cisplatin are inherent properties of the oxaliplatin activity. The PTO does not have facilities for examining and comparing Applicants' claimed method, particularly the effect of dosage of oxaliplatin in the prior art with induction of HAT activity, and thus Applicant has the burden of persuasion to make some comparison in order to establish unexpected properties for the claimed method. According to MPEP 2114(I), “In re Schreiber, 128 F.3d at 1478, 44 USPQ2d at 1432; In re Swinehart, 439 F.2d 210, 213, 169 USPQ 226, 228 (CCPA 1971) ("where the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on").” It reasonably appears that the prior art dosages used or suggested necessarily or inherently possess characteristics of low-dose oxaliplatin administered in vivo, i.e., induction of HAT activation in the subject. Further, as to the difference between oxaliplatin and cisplatin, Showalter et al. (Cytokine, 97:123-132, 2017) explains (p. 125, col.1, second full paragraph):
Another therapeutic used in cancer therapy is the platinum-based oxaliplatin (OXA), which interrupts DNA replication to prevent cell proliferation. The ability of OXA to cause ICD [immunogenic cell death] was examined in CT26 colon carcinoma cells. After 24 h, CT26 cells treated with 300 μM OXA underwent apoptosis followed by secondary necrosis [29]. CT26 cells treated with OXA displayed membrane-bound CRT by 4 h, while cisplatin, a platinum-based chemotherapeutic that does not induce ICD, was unable to elicit the same response.
Applicant argues (p. 6, last paragraph, through p. 7, third paragraph) that low-dose oxaliplatin sufficient to induce HAT activation administered in combination with PD-L1 blockade agent “significantly and synergistically inhibited tumor growth Id. At FIGS. 7A and 14A-14E.” (emphasis by Applicant) At [0093], it is stated low-dose Oxali had little effect on s.c. MC, B16 or YMM1.7 cell growth. PD-L1 blockade was ineffective to inhibit growth of MC or B16 tumors. However, together they significantly inhibited tumor growth. “Accordingly, Applicant's surprising results are twofold. First, only low dose oxaliplatin - as opposed to higher doses or other platinoids - is necessary for HAT activation. Second, low dose oxaliplatin sufficient to induce HAT activation in combination with immune checkpoint inhibitor (ICI) therapy significantly and synergistically inhibits tumor growth. Moreover, the criticality of low dose oxaliplatin and the synergistic effects with ICI therapy could not have been predicted based on the teachings of the prior art because these effects are qualitatively different than administration of either agent alone or when HAT activation is not present.” (citing Iron Grip Barbell Co. (Fed. Cir. 2004)) “[N]one of the references teach or suggest the importance of effective amount of oxaliplatin sufficient to induce HAT activation.” There would have been no motivation to administer a low-dose of oxaliplatin sufficient to induce HAT activation as an immune checkpoint inhibitor. The argument has been fully considered but is not persuasive. It is noted that in Yumm1.7 tumors, anti-PD-L1 treatment alone was significantly more effective than combined Oxali + anti-PD-L1 treatment (Fig. 14B). As discussed in the preceding paragraph, it reasonably appears that the prior art makes obvious the instant invention. Both Karin and Shalapour et al. teach combined successful antitumor treatment of oxaliplatin, specifically, with an anti-PD-L1 inhibitor. As stated in the rejection under 35 USC 103 above, “Shalapour et al. found that treatment of mice bearing tumors from subcutaneously injected MC prostate tumor cells with oxaliplatin plus anti-PD-L1 antibody, but not anti-PD-L1 antibody alone, inhibited tumor growth, increased GrzB (granzymeB) expression by effector T cells, reduced PD-L1 expression on IgA+ cells and reduced serum IgA (p. 96, col. 1, middle).” “The dose of oxaliplatin used was 6 mg/kg, designated as “low-dose” (e.g., p. 2 of Suppl., Methods: Treatment with chemotherapy and antibodies”, col. 1 p. 96, col. 1, last paragraph, and first sentence after Abstract).” Shalapour et al. used a syngeneic mouse model of prostate cancer (Myc-CaP s.c.) to show that when oxaliplatin was combined with anti-PD-L1, tumor growth was significantly inhibited (Figs. 7i, p. 96, col. 1, middle). When compared to instant Fig. 14D using the same model and same agents, it reasonably appears the results of Shalapour et al. could be considered synergistic. Karin is cited for teaching (supra), “It was shown in mouse models of prostate cancer that combining low-dose oxaliplatin can sensitize prostate cancer cells to anti-PD-L1 antibody and allow CTL-dependent eradication, and combining oxaliplatin with anti-PD-L1 decreases the number of liver tumors (col. 19, lines 11-67). Oxaliplatin was administered to mice weekly at 6 mg/kg (col. 61, lines 10-11).” It reasonably appears absent evidence to the contrary that the prior art not only suggested the claimed method of administering oxaliplatin in an amount effective to induce HAT activity with a PD-L1 inhibitor to treat cancer, but anticipates the claimed invention (see rejections under 35 USC 102). As discussed at the end of the section under 35 USC 102 above:
Note that the instant application tested the effect of oxaliplatin on histone acetyltransferase (HAT) activity only in vitro. As shown in Example 5, 2 pM Oxali increased HAT enzymatic activity in Myc-CaP cells (Example 5). This dose is designated as an in vitro low-dose at the start of [0084]. The specification points to Shalapour et al. (2015) as defining low-dose oxaliplatin ([0077]). As evidenced above, Shalapour et al. used 6 mg/kg/mouse and designated that dose as low for mice in vivo. In line with this, the 85 mg/m2 dose in humans administered for ClinicalTrials.gov ID. NCT02625610 v.20 (supra) corresponds to 2.3 mg/kg dose for an average human with a body surface of 1.6 m2 weighing 60 kg (see US HHS, FDA, CDER, Guidance for Industry, 2005, Table 3).
As discussed in MPEP 716.02(a)(I), “However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991)” It is maintained that the results Applicant points to as surprising, significant and synergistic were not unexpected in view of the prior art as addressed above.
Applicant argues (paragraph bridging pp. 7-8) that new claims 30-32 are patentable for the reasons above and because they are drawn to administration as in claim 9 with the addition of exogenous IFN-γ, “which demonstrated additional synergistic anti-tumor effects when administered with the combination of an effective amount of oxaliplatin sufficient to induce HAT activation and an inhibitor of PD-L1.” It strongly potentiated induction of MHC-1 antigen presentation and HAT activation, “indicating a synergistic effect between the combination oxaliplatin, exogenous IFN-γ, and ICI therapy that was not taught or suggested by the prior art.” The argument has been fully considered but is not persuasive. In view of the teachings of Ni et al. and Castro et al. as set forth in the rejection above, it is not agreed that the addition of IFN-γ would have been nonobvious or that the effect of adding IFN-γ to the low-dose oxaliplatin + anti-PD-L1 treatment would not have been increased. As stated in the rejection above, “Ni et al. summarizes the findings by stating (p. 175, col. 1, end of second full paragraph), “Furthermore, we report that IFN-γ synergistically combined with oxaliplatin (Oxa), a first-line colon cancer chemotherapy drug, can eradicate both LRCCs and non-LRCCs, which significantly inhibits tumor growth and reduces the risk of serial tumor formation.”” Also, Ni et al. referring to in vivo tumor treatment with oxaliplatin and IFN-γ, states, ““[C]ompared with the other groups, the combination therapy significantly reduced the tumor formation ratio and tumor volume (Fig. 5D and E, Table 1). Altogether, these data suggest that IFN-γ treatment combined with chemotherapy could profoundly enhance anti-tumor effects and decrease the capacity for serial tumor formation.” This provides a reasonable expectation of success, as do the antitumor results from IFN-γ administration reviewed by Castro et al. Further, it appears Applicant is referring to the results of Example 7 ([0093]) of the specification shown in Fig. 14E when asserting a synergistic effect for the combination of the three agents of claim 30. However, this experiment did not show that. What it showed was that in tumor cells with genetic ablation of the receptor for IFN-γ (IFNγR2), Oxali + anti-PD-L1 had reduced antitumor activity.” Oxali + anti-PD-L1 induced MHC-I (H-2Kq and H-2Dd) surface expression by tumor cells, which was also abolished by IFNγR2 ablation (Figure 7D).” The advantage of combining oxaliplatin with anti-PD-L1 antibody was shown by Ni et al. (rejection above), “This was shown in vivo in a xenograft model in which administration of Oxa and IFN-γ showed a greater inhibition of tumor growth than either drug alone (paragraph bridging pp. 181-182 and Fig. 5B).” Castro et al. also discussed the importance of combining IFN and PD-L1 inhibition, saying (supra), “[I]t was recently shown that IFN-γ-induced Treg cell fragility (loss of suppressive function) is required for response to anti-PD-1 therapy (240).” As a result, there is no evidence that the combination of the three agents of claim 30 have synergistic activity compared to the combination of two of the agents. There is no in vivo support in the specification for synergistic activity. The prior art supports enhanced antitumor activity when the three agents are combined for the reasons discussed here and in the rejection. It is not agreed the instant results are surprising. It had already been stated in the prior art (Ni et al.) that the combination of oxaliplatin and IFNγ had synergistic antitumor activity and shown that oxaliplatin administered with an immune checkpoint inhibitor such as PD-L1 significantly increased antitumor activity. Therefore, it is maintained for the reasons of record that administration of the combination of a oxaliplatin, exogenous IFNγ and inhibitor of PD-1, PD-L1 or CTLA4 would have been obvious for the treatment of cancer and there would have been a reasonable expectation of synergistic activity with all three, at least in some cancers such as therapy-resistant cancers and/or stem-cell like cancer cells, particularly in view of the synergistic activity of the combination of oxaliplatin and IFNγ shown in the prior art; although, this is not required by the instant claims.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Showalter et al. (Cytokine, 97:123-132, 2017) reviews immunogenic cell death (ICD) and the role of different drugs in ICD. In particular, related to the instant invention, Oxaliplatin (OXA) treatment of mice with colon cancer CT26 tumors significantly slowed tumor growth compared to cisplatin treatment and continued to inhibit tumor growth after subsequent injection of live CT26 cells (p. 125, col.2, end of third paragraph, see also p. 125, col. 1, start of second full paragraph). OXA is in a phase I clinical trial for treatment of metastatic breast cancer (Table 2). It is concluded that (p. 129, col. 2, second full paragraph), “A general trend observed was that most ICD-inducing agents brough about the release of IFN-γ, which is a potent stimulator of TH1 responses and cytotoxic lymphocytes that are beneficial for eliciting anti-tumor immunity.” The advantage of combining ICD-inducing agents with immune checkpoint blockers is considered. “Further, incorporating ICD induction in combination with immunotherapy, such as CTLA-4 blockage [62] could be a promising approach with established agents that already have FDA approval.” (p. 129, col. 2, end of last full paragraph) Also (p. 130, col. 2, second paragraph), “Treatments with anthracyclines, such as DOX or OXA, achieved better efficacy when combined with blockade of immune suppression. Examples are the inhibition of CD73, which enhanced the response of anthracyclines in breast cancer therapy [66], and the synergy with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors that sensitized tumors to ICD inducers [67,68]. Hence the possibility exists that patients with poorly immunogenic tumors could be made responsive to checkpoint inhibitors when used in combination with ICD induction.” This reference is cited to show the advantages of using oxaliplatin to treat cancer and the reasonable expectation of synergy combining anti-PD-1 or anti-PD-L1 antibodies with an ICD-inducing agent, of which oxaliplatin is disclosed as one, in the treatment of tumors.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
February 4, 2026