DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/21/2026 has been entered.
No claims are amended or new. Claims 3-6, 8, 13-20, 25-26, 30-32, and 37-43 are cancelled. Claims 1-2, 7, 9-12, 21-24, 27-29, and 33-36 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 05/17/2023, is a continuation of application 16/758,474, filed 04/23/2020, which is a 371 filing of PCT/US2018/057058, filed 10/23/2018, and claims domestic benefit to provisional applications 62/688,002, filed 06/21/2018, and 62/576,001, filed 10/23/2017.
Withdrawn Rejections
In the office action of 07/22/2025, claims 1, 2, 7, 21-24, 27, 33, and 36 were rejected under 35 USC 103 over Ritter in view of Barrero as evidenced by WO’282; claims 9, 12, 28-29, and 34-35 were rejected under 35 USC 103 over Ritter in view of Barrero and Mohammad; and claims 9-10 and 12 were rejected under 35 USC 103 over Ritter in view of Barrero and Shao. The arguments submitted in the response filed 01/21/2026 have been considered and are persuasive, particularly arguments concerning the difference in the cancers studied between Ritter and Barrero and reasonable expectation of success.
Upon further consideration, new grounds of rejection are provided below.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In the specification amendment of 09/09/2024, the following hyperlink was identified in the paragraph at page 66, line 22 that comprises non-top-level domain browser executable code:
david.ncifcrf.gov/summary.jsp
Appropriate correction is required. It is also noted that the hyperlink does not appear to connect to a functioning web page.
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 t;’he claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 7, 9-12, 21-24, 27-29, 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/035112 A1 (Baylin, S.B., et al) 12 MAR 2015 in view of WO 2017/114497 A (Motz, G., et al) 06 JULY 2017 and Toh, T.B., et al (2017) Epigenetics in cancer stem cells Molecular cancer 16(29); 1-20.
WO’112 teaches methods for the treatment of cancer in which an epigenetic agent is administered before or concurrently with an immune modulating agent (page 1, lines 14-18; page 2, lines 20-26).
WO’112 teaches that epigenetic modulation was observed to alter tumor gene expression and induce an immune signature. This finding, in combination with the ability of demethylating agents to induce de novo expression of tumor-specific antigens, and tumors to induce immune checkpoint ligands to protect themselves from anti-tumor immune responses, led to the identification that a combination of epigenetic modulation and blockade of immune checkpoint pathways, such as PD-1, could provide a synergistic anti-tumor response. Such identification was validated through observation of clinical outcomes of advanced, chemotherapy refractory lung cancer patients treated with antibodies that block the PD-1 checkpoint pathway after tumors of these subjects had progressed during epigenetic modulation. Three of five patients treated sequentially with epigenetic modulation followed by PD-1 blockade, developed objective clinical responses with dramatic tumor shrinkage. The other two patients developed stable disease lasting longer than 6 months. These findings demonstrate an unexpected anti-neoplasia synergistic activity between epigenetic modulation and immune modulation (page 2, lines 5-19). WO’112 teaches therapeutic implications for PD-1 pathway blockade of adaptive resistant models in Figure 11, which is duplicated below:
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As shown in figure 11, WO’112 teaches that cancers with weak endogenous anti-tumor immune response have no PD-L1 up-regulation on tumor/TAM and; therefore, no response to single agent anti-PD-1 (second row). However, in cancers with weak endogenous anti-tumor immune response, epigenetic modulation can be added inducing anti-tumor immunity and endogenous anti-tumor immune response. Such response upregulates PD-L1 expression on the tumor/TAM and allowing for a response to anti-PD-1 therapy (third row).
WO’112 teaches that a likely reason for the lack of responsiveness observed for certain tumors administered single agent anti-PD-1 therapies is related to the fact that such tumors elicit a weak endogenous anti-tumor immune response, versus a strong endogenous anti-tumor immune response, which would have responded to single agent anti-PD-1. The administration of an epigenetic modulator preceding or concomitant with administration of an anti-PD-1 agent provokes an anti-tumor response, even in a tumor that would otherwise elicit weak endogenous anti-tumor response. The epigenetic modulation therapy upregulates the endogenous anti-tumor response and, thereby PD-L1 expression on the tumor/TAM, increasing the susceptibility of such a tumor to anti-PD-1 therapy (page 46, lines 18-29). WO’112 further teaches that the generation of anti-tumor response leads to immune cell infiltration into tumors (page 30, lines 6-8), suggesting that the tumors with weak endogenous immune response are non-T cell infiltrating cancers.
WO’112 teaches that the epigenetic modulating agent is a demethylating agent. In a related embodiment, the epigenetic modulating agent is a DNMT inhibitor or an HDAC inhibitor or a combination thereof (page 2, lines 27-30).
WO’112 further teaches immune modulating agents for administration with the epigenetic modulating agent, including cancer vaccines, anti-CTLA-4 antibodies, anti-LAG-3 antibodies, anti-TIM3 antibodies, or anti-OX40 antibodies (page 14, lines 5-19).
WO’112 further teaches that the therapy is effective to achieve eradication, removal, or control of primary, regional, and/or metastatic cancer (page 15, line 29 – page 16, line 11). WO’112 also teaches that the cancer treated can be acute myelogenous leukemia (AML), breast cancer, Ewing’s sarcoma, head and neck cancer, squamous cell carcinoma, gastric cancers, melanoma, bladder cancer, prostate cancer, lung cancer, including NSCLC, and renal cell carcinoma (page 4, line 19 – page 5, line 11).
WO’112 further teaches that that the therapeutically effective amount of the epigenetic modulating agent depends on the agent. In some embodiments, the compositions can be administered from one or more times per day to one or more times per week; including every other day (page 38, lines 15-29) and can be administered parenterally e.g., intravenously, subcutaneously, orally, or via rectal administration (page 35, lines 13-16).
WO’112 also teaches that the patient can have previous cancer treatment, teaching that, more surprising than the responses to epigenetic modulation alone, was that several patients treated experienced major objective responses to subsequent line of therapy, despite being heavily pretreated (page 30, line 22 – page 31, line 3).
WO’112 teaches that the impact of anti-PD-1 treatment following epigenetic therapy was particularly striking in one subject who entered the clinical trial at stage 4 NSCLC, yet then exhibited reduction of tumor size over the course of more than eight months of such treatment (page 47, lines 5-8), demonstrating a reduction in tumor volume. WO’112 teaches that an effective amount of an epigenetic modulatory agent and/or an immunomodulatory agent can inhibit further tumor growth, cause a reduction in size or even completely halt tumor growth, shrink the sizes of tumor, even complete regression of tumor, and reduce clinical symptoms associated with the tumor. The therapy can also delay the development of a tumor, delay further growth of the tumor, or slow the course of cancer progression. (page 10, line 20 – page 11, line 26).
WO’112 teaches that the cancer therapy can include chemotherapeutic agents (pages 7-9).
WO’112 teaches that, beyond cell-autonomous effects, a combination of published and unpublished data has offered three non-mutually exclusive mechanisms by which epigenetic modulation of tumors can enhance anti-tumor immunity. First, epigenetic modulation induces a vast array of new antigens by the tumor that are potential targets for T cell and antibody responses; second, re-expression is induced at silenced promoters of key cytokine genes in T cells, such as interferon gamma (IFNγ) and IL-2 – critical effector cytokines in antitumor responses; and, third, an induction of a “pathogen response” pattern of gene expression characterized in part by a type I interferon response. WO’112 teaches that examples of immunologic genes that are induced by pharmacologic demethylation of DNA by treating of tumor cells in vitro include IRF7, a major driver of the interferon pathway, certain toll-like receptors, cytoplasmic sensors of DNA such as IF127, inflammatory cytokines and interferon induced genes such as OAS1 and HLA-A. The epigenetic modulation in patients cancer induces anti-tumor immune responses (page 29, line 23 – page 30, line 5).
WO’112, however, does not disclose that the demethylating agent used for epigenetic modulation is a LSD1 inhibitor.
WO’497 teaches the use of LSD1 inhibitors in connection with the use and/or manufacture of immune effector cells, for example, immune effector cells engineered to express a CAR to treat a disease, e.g., a disease associated with the expression of a cancer associated antigen (or tumor marker). WO’497 teaches that inhibition of LSD1 is effective in improving the function of immune effector cells (page 1, lines 20-27). WO’497 teaches that the approaches disclosed can be used to optimize the performance of immune effector cells, e.g., T cells, in the subject. It is believed that the performance of endogenous, non-modified immune effector cells, e.g., T cells, is improved (page 4, lines 15-25).
WO’497 teaches a method of treating and promoting an immune response in a subject comprising administering a LSD1 inhibitor and teaches that the LSD1 inhibitor inhibits a negative immune response mediated by the engagement of PD-1 with PD-L1 or PD-L2, and increases the number of T cells capable of proliferation, cytotoxic function, and secreting cytokines, or activation. WO’497 further teaches that the inhibitor increases the amount of cytokine secretion including interferon gamma and/or IL-2, in response to stimulation and/or activation of the T cell (page 5, lines 1-13). WO’497 teaches the administration of an LSD1 inhibitor in vivo prior to administration of immune effector cells for a time sufficient for an increase in the proliferation of immune effector cells and an increase in the production of cytokines (page 5, line 14 – page 6, line 12).
WO’497 teaches that the subject has cancer and the method comprises promoting the subject’s immune response. In an embodiment, the subject was selected on the basis of having cancer. WO’497 also teaches that a cell of the cancer or a cell in the cancer microenvironment expresses PD-L1/PD-L2 (page 9, lines 24-27).
WO’497 further teaches that the LSD1 inhibitor may be a gene editing system targeted to one or more sites of the LSD1 gene or its corresponding regulatory elements; a nucleic acid, e.g., an siRNA, shRNA, or antisense oligonucleotide; a protein; or a small molecule (page 21, lines 1-6). WO’497 teaches that the LSD1 inhibitor can be a small molecule, including GSK2699537 (page 22, lines 4-7).
WO’497 teaches that the methods disclosed can be used to treat cancer including AML, renal cell carcinoma, NSCLC, melanoma, cancer of the head or neck, stomach cancer, Hodgkin’s disease, cancer of the bladder, cancer of the kidney, squamous cell cancer, Ewing sarcoma, breast cancer, or prostate cancer (page 23, line 12 – page 24, line 6; page 296, lines 1-2; page 290, lines 17-19). WO’497 teaches that the cancer can be these, and metastatic lesions thereof (page 371, lines 6-7).
Toh teaches that recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contributes to cancer progression and provides a review of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis. This information, together with promising clinical and preclinical trials of epigenetic modulating drugs offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall (abstract).
Toh demonstrates that LSD1 inhibitors, like HDACi and DNMTi, were recognized epigenetic modifiers for use in cancer and teaches that LSD1 inhibitors including tranylcypromine, ORY-1001, and GSK2879552 were in clinical studies for the treatment of AML and SCLC (pages 8-9, Table 1).
Toh also teaches that cancer cells can evade cytotoxic T cells by down-regulating HLA to avoid tumor antigen presentation. Hypermethylation of HLA promoters was frequently observed in gastric cancer and esophageal squamous cell cancers. Treatment with DNMT and HDAC inhibitors were found to be capable of reversing this hypermethylation and increasing HLA expression, thus priming these cells for immunotherapy. In addition, it has been shown that azacitidine treatment was able to enhance immunomodulatory pathways, such as antigen processing/presentation and interferon signaling in breast cancer, colorectal cancer, and ovarian cancers. These preclinical data highlight the promising potential of combining epigenetic and immunotherapies to improve cancer treatment efficacy (paragraph bridging pages 12-13).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by WO’112 by substituting the DNMTi and HDACi disclosed with an LSD1 inhibitor as taught by WO’497 and further supported by Toh. It would have been obvious to substitute the DNMTi and HDACi with an LSD1 inhibitor as WO’497 teaches that the administration of an LSD1 inhibitor promotes the subject’s immune response to cancer, increases the number of T cells capable of proliferation, and increases the production of cytokines from immune effector cells, including interferon gamma and/or IL-2, which WO’112 teach are critical effector cytokines in antitumor responses. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’112 teaches the use of an epigenetic modulator and, as demonstrated by Toh, LSD1 inhibitors were art recognized as epigenetic modulators, like DNMTi and HDACi. Additionally, WO’112 teaches the use of an epigenetic modifier as a means to induce an anti-tumor immune response and WO’497 teaches that LSD1 inhibition promotes anti-tumor immune responses while increasing the number of T cells capable of proliferation. WO’497 also teaches the use of LSD1 inhibitors to promote efficacy of an immunotherapy to treat cancers including cancers that overlap with the cancers taught by WO’112.
Response to Arguments
Applicant’s arguments in the response filed 01/21/2026 concerning the applied references have been fully considered in so far as they apply to the rejections of the instant office action, but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant further provides arguments that appear to be unexpected result arguments. Applicant argues that the present application establishes that LSD1 inhibition overcomes tumor PD-1/PD-L1 resistance. Applicant argues that the inventors tested the role that LSD1 inhibition had in antitumor activity in numerous cell lines including those known to be resistant to PD-1 inhibitor or PD-L1 inhibitor treatment. For example, applicants showed that in a mouse model featuring B16 tumors with high expression of PD-L1 but poor immunogenicity that are known to be non-responsive to PD-1/PD-L1 blockade in the absence of vaccination, PD-1 blockade alone had no effect. However, data showed that LSD1 inhibition sensitized the B16 tumors to PD-1/PD-L1 blockade and showed a dramatic effect on controlling LSD1 KO B16 tumors that was independent of tumor size. Moreover, this profound delay in tumor growth was achieved with a late initiation of PD-1 blockade as well as low dose of blocking antibody and demonstrated a strong synergy between LSD1 inhibition and PD-1 blockade in controlling tumor growth as shown in Fig. 11B, which is duplicated in the response. Applicant argues that, given the unpredictability of the chemical and pharmaceutical arts, one of ordinary skill in the art could not have predicted the results shown in instant Examples 7-9.
While the results presented by applicant do demonstrate that LSD1 KO in combination with anti-PD-1 inhibitor provides a synergistic increase in the percent survival of mice with B16 (melanoma) tumors that have poor immunogenicity, these results would have been expected in view of the newly applied art.
MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
As discussed in detail in the rejections of the instant office action, the prior art, specifically WO’112, teaches that tumors that have weak endogenous anti-tumor immune responses do not display PD-L upregulation on the tumor/TAM and have no response to single agent PD-1 inhibitors. WO’112 further teaches that if an epigenetic modulator that enhances anti-tumor immunity is added to the treatment, endogenous anti-tumor immune responses are achieved allowing for response to anti-PD-1 therapy. Based on this, WO’112 teaches methods of treating cancers combining epigenetic modulating agents with immune modulating agents for improved treatment (abstract; Fig. 11). WO’112 teaches that the cancers that can be treated include melanoma. WO’112 also teaches that a combination of epigenetic modulation and blockade of immune checkpoint pathways, such as the PD-1 pathway can provide synergistic anti-tumor responses (page 2, lines 10-12). While WO’112 does not teach that the epigenetic modulator is a LSD1 inhibitor, the reference WO’497 is applied to demonstrate that LDS1 inhibitors had been considered as a means for promoting tumor immune responses in cancers prior to immunotherapy with an adoptive cell therapy. WO’497 also teaches that such a method can be used in the treatment of melanoma, demonstrating a nexus among the cancers treated in the art and in the instant disclosure. The reference Toh is also applied to demonstrate that LSD1 inhibitors were art recognized as epigenetic modulating agents along with DNMT and HDAC inhibitors. Based on these teachings, an ordinarily skilled artisan would have reasonably expected that the combination of an epigenetic modulating agent, such as a LSD1 inhibitor, in combination with an anti-PD-1 inhibitor, would synergize to treat PD-1/PD-L1 resistant melanoma by inducing an endogenous anti-tumor immune response allowing for more effective response to the immunotherapy.
Additionally, applicant does not provide a comparison to a closest prior art. MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
The results provided by applicant compare controls with anti-PD-1 alone, LSD1 KO alone, and a combination of LSD1 KO and anti-PD-1. However, this comparison is not a comparison to the closest prior art which, in this case, could be considered to be WO’112, which teaches the combination of epigenetic modulators including HDACi and DNMTi with immunotherapy for enhanced treatment of cancers with weak endogenous anti-tumor immune responses.
Furthermore, even if the results presented were identified as being unexpected, the results are not commensurate with the entire scope of the claims. MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
Independent claim 1 encompasses the treatment of any type of cancer in a patient that is identified as being resistant to PD-1 or PD-L1 inhibitor treatment comprising administering to the patient any LSD1 inhibitor. Independent claim 2 encompasses the treatment of any type of cancer in a patient that is identified as being resistant to PD-1 or PD-L1 inhibitor treatment comprising administering to the patient any LSD1 inhibitor and at least one immunotherapy.
The example presented in the response, however, only demonstrates synergistic results in the treatment of a melanoma tumor model that has PD-L1 expression but reportedly poor immunogenicity. It is noted that Example 8 further tests the response in another “cold” tumor model of melanoma (D4m) and Example 12 studied LLC cells, and Renca cells, which are models of lewis lung carcinoma, which is commonly used to study NSCLC, and renal adenocarcinoma, respectively.
These cancers, however, are not commensurate in scope with the claimed genus in which any cancer is claimed.
In the response, applicant argues that, because of the unpredictability of the chemical and pharmaceutical arts, one of ordinary skill in the art could not have predicted the results provided. In the case that the art is unpredictable, there is no demonstration that the results shown would extend to any and all other forms of cancer. This is also further suggested by applicant’s arguments concerning the teachings of the previously applied references Ritter and Barrero in which it is suggested that cancers respond differently to epigenetic modulators.
Double Patenting
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 7, 9-11, 21-24, 28-29, and 33-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. US 11,685,782 B2.
The claims of US’782 are drawn to a method of treating cancer in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a LSD1 inhibitor to thereby treat cancer in the patient, wherein the LSD1 inhibitor comprises an inhibitory nucleic acid comprising SEQ ID NO: 2 (claim 1). US’782 further claims that the cancer is a non-T cell infiltrating cancer, a PD-1 or PD-L1 refractory cancer, or a PD-1 or PD-L1 resistant cancer (claim 13). US’782 further claims a method of treating cancer in a patient comprising administering an LSD1 inhibitor of SEQ ID NO: 2 and at least one immunotherapy selected from an antibody, and adoptive cellular therapy, an antibody-drug conjugate, a toxin, a cytokine therapy, a cancer vaccine, and a checkpoint inhibitor (claims 2 and 7). US’782 further claims that the patient has been identified as having cancer prior to administration, and that the method further comprises administering a PD-1 and/or a PD-L1 inhibitor (claims 3-6, 8-11, 16, 20-21). US’782 further claims that the cancer is selected from melanoma, AML, squamous cell carcinoma, renal cell carcinoma. NSCLC, SCLC, gastric cancer, bladder cancer, kidney cancer, head and neck cancer, Ewing sarcoma, Hodgkin’s lymphoma, Merkel cell carcinoma, breast cancer, and prostate cancer (claim 12). US’782 claims that the LSD1 inhibitor is administered at least once a week and via intravenous, subcutaneous, intraperitoneal, rectal, or oral administration (claims 14-15). US’782 further claims that the method further comprises administering a chemotherapeutic agent (claim 17) and that the treating comprises reducing the volume of the primary tumor in the patient, delaying cancer progression, modifying the tumor microenvironment of the cancer, sensitizing the cancer to a checkpoint inhibitor therapy, decreasing the risk of developing at least one metastatic tumor in the patient, decreasing the rate of tumor growth, or eliciting tumor-intrinsic double stranded RNA stress in a cancer cell (claim 18 and 19).
The claims of US’782 include the limitations of the instantly claimed invention. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the claims of US’782 to arrive at the instantly claimed invention with a reasonable expectation of success.
Claim 12 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. US 11,685,782 B2 as discussed above, and in further view of Mohammad, H.P., et al (2015) A DNA hypomethylation signature predicts antitumor activity against LSD1 inhibitors in SCLC Cancer Cell 28; 57-69 and supplemental material, 33 pages.
The claims of US’782 are as discussed above.
US’782, however, does not claim that the LSD1 inhibitor is a small molecule inhibitor selected from those recited in instant claim 12.
The teachings of Mohammad are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to have modified the claims of US’782 to use a small molecule inhibitor, such as GSK2879552, as disclosed by Mohammad. It would have been obvious to an ordinarily skilled artisan to use a small molecule inhibitor as Mohammad demonstrates treatment of primary tumors using the LSD1 inhibitor GSK2879552 and the inhibitor would be expected to function in inhibiting the same pathways as the shRNA of US’782. An ordinarily skilled artisan would have had a reasonable expectation of success as Mohammad demonstrates that the inhibitor was capable of delaying cancer growth in small cell lung cancer and AML cell lines, which are cancers claimed in US’782.
Claim 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. US 11,685,782 B2 as discussed above, and in further view of WO 2015/035112 A1 (Baylin, S.B., et al) 12 MAR 2015.
The claims of US’782 are as discussed above.
US’782, however, does not claim that the patient had previously received a cancer treatment.
The teachings of WO’112 are as discussed above.
As discussed above, WO’112 teaches that patients treated with epigenetic modulators and antibody blockers of the PD-1 pathway had major objective responses despite being heavily pretreated (page 30, lines 22-24).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the claims of US’782 to treat a patient who had previously received a cancer treatment as taught by WO’112. It would have been obvious to treat this patient population as WO’112 teaches that a combination of an epigenetic modulator and an immunotherapy was capable of causing objective responses in patients, including heavily pretreated patients.
Response to Arguments
In the response of 01/21/2026, applicant requests that the double patenting rejection be held in abeyance until the nonstatutory double patenting rejections are the only remaining rejections.
As the nonstatutory double patenting rejections are not the only remaining rejections, the rejections are maintained.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693