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 .
Claims Status
Claims 1, 3, and 6 are amended.
Claims 1-8, and 11-16 are pending and are being examined on the merit.
Objections Withdrawn
All objections to the claims with regard to drawings and specification are withdrawn in view of Applicant’s amendments.
Rejections Withdrawn
Rejection of claim 6 under 35 U.S.C. §112(a) is withdrawn with Applicant amendment of the claim.
Rejection of claims 3 and 6 under 35 U.S.C. §112(b) are withdrawn with Applicant amendment of the claim.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Ganesh (Ganesh et al, Nat Rev Gastroenterol Hepatol (Author Manuscript), March 18, 2019, 16(6):361-375 (actual pages on uploaded version: 1-33); hereinafter Ganesh) and further in view of Pilon-Thomas (Pilon-Thomas et al, Cancer Res, 2016, 76(6):1381-1390; hereinafter Pilon-Thomas), Parks (Parks and Pouyssegur, J. Cell. Physiol., 2015, 230:1954-1963, IDS entered on 11/10/2023; hereinafter Parks), and McIntyre (McIntyre et al, Cancer Res, 2016, 76(13):3744-3755, IDS entered on 11/10/2023; hereinafter McIntyre).
Regarding instant claims 1, 4, and 5, Ganesh teaches that in colorectal cancer (CRC), current immune checkpoint inhibitors (ICIs) are ineffective in tumors that are mismatch-repair-proficient (pMMR) and are microsatellite-stable (MSS) or have low levels of microsatellite instability (MSI-L) (termed pMMR–MSI-L tumors) due to the low tumor mutation burden and lack of immune cell infiltration, leading to immune resistance (page 2, lines 6-11; Fig. 2). However, Ganesh discloses that a subset of CRCs, mismatch-repair-deficient and microsatellite instability-high (dMMR–MSI-H) CRC, which comprises approximately 15% of all CRCs, have shown positive responses, wherein the objective response rate and disease control rate were 60% and 84%, respectively, 7% of patients had a complete response, and PFS and overall survival values at 12 months were 77% and 83%, respectively, when patients were treated with a combined therapy of nivolumab (targeting PD1) and low dose ipilimumab (targeting CTLA-4) (page 3, second paragraph; page 5, first paragraph).
However, Ganesh does not teach a method of treating comprising administering an inhibitor of SLC4A4 wherein the cancer is resistant to immunotherapy and the inhibitor of SLC4A4 is a specific inhibitor of SLC4A4, wherein the specific inhibitor of SLC4A4 is an inhibitory oligonucleotide specifically targeting SLC4A4.
The deficiency is resolved by Pilon-Thomas, McIntyre, and Parks.
Pilon-Thomas teaches that cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. In this context, Pilon-Thomas discloses that solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. Notably, Pilon-Thomas teaches that neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration, overall demonstrating that raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation (page 1381, Abstract; page 1381, right column, last paragraph – page 1382, left column, first paragraph; Figures 4-6).
McIntyre teaches that in general, tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes (page 3744, Abstract). One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth, wherein McIntyre discloses that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result (page 3744, Abstract). McIntyre also discloses that the most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression (page 3748, left column, second paragraph; Figure 2), wherein the expression of SLC4A4 was driven by hypoxic conditions in several cancer cell lines, including colorectal, breast cancer and head and neck cancer cell lines (page 3744, Abstract; page 3745, left column, fourth paragraph; page 3747, Figure 1). McIntyre further teaches that in cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth, suggesting that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy (page 3744, Abstract).
Finally, Parks teaches a method comprising administering independent shRNA sequences specifically targeting SLC4A4 to inhibit SLC4A4 via shRNA knockdown in LS174 colon adenocarcinoma cell lines (page 1955, left column, third paragraph; page 1956, left column, first paragraph; page 1957, left column, lines 26-32). Additionally, Parks teaches that hypoxia increases SLC4A4 expression in the LS174 colon cancer cell line (page 1955, Figure 1; page 1957, left column, first paragraph) and demonstrated that knockdown of SLC4A4 showed a recovery of intracellular pH from an intracellular acid load (page 1957, Figure 2; page 1958, left column, first paragraph) and increased cell mortality under acidic conditions (page 1958, Figure 3; page 1958, left column, second paragraph). Parks further teaches that the knockdown of SLC4A4 in LS174 cells reduced cell proliferation in both standard culture conditions as well as 3-dimensional spheroid growths and showed a trend towards increased cell death (page 1958, left column, second paragraph; Figure 3). Parks also discloses that the same results were achieved in SLC4A4-knockdown MDA-MB-231 triple-negative breast cancer cells (page 1958, left column, third paragraph – page 1959, left column, first paragraph; Figures 4 and 5).
Regarding instant claims 1, 4, and 5, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method comprising administering independent shRNA sequences specifically targeting SLC4A4 to inhibit SLC4A4 via shRNA knockdown in LS174 colon adenocarcinoma cell lines to reduce cell proliferation and increase cell death as taught by Parks and modify it to include that since colon cancer is a cancer that poorly responds to immunotherapy as taught by Ganesh, an inhibitor targeting SLC4A4, which is one of the most robust and frequently induced sodium-driven bicarbonate transporters as taught by McIntyre, will disrupt pH homeostasis by blocking bicarbonate import, raising intratumoral pH and improving responses to immunotherapy as taught by the combined teachings of Parks, Pilon-Thomas and McIntyre. This is obvious because, Ganesh teaches that in CRC, current immune checkpoint inhibitors are mostly ineffective due to the low tumor mutation burden and lack of immune cell infiltration, leading to immune resistance, Pilon-Thomas teaches that solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity, therefore, neutralizing tumor acidity with bicarbonate monotherapy can improve responses to immunotherapy, McIntyre teaches that one of the most robust and frequent inductions was of the sodium-driven bicarbonate transporter SLC4A4, wherein the expression of SLC4A4 was driven by hypoxic conditions in several cancer cell lines, including colorectal, breast cancer and head and neck cancer cell lines wherein SLC4A4 disruption by either genetic or pharmaceutical approaches reduced cell growth, suggesting that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy, and Parks teaches a method comprising administering independent shRNA sequences specifically targeting SLC4A4 to inhibit SLC4A4 via shRNA knockdown in LS174 colon adenocarcinoma cell lines, wherein the knockdown of SLC4A4 in LS174 cells reduced cell proliferation, increased cell death, increased recovery of intracellular pH from an intracellular acid load, and increased cell mortality under acidic conditions. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to form the instant method of treating cancer comprising administering an inhibitor of SLC4A4, wherein the cancer in the instant application is resistant or poorly responds to immunotherapy and the inhibitor of SLC4A4 is a specific inhibitor of SLC4A4, wherein the specific inhibitor of SLC4A4 in the instant application is an inhibitory oligonucleotide specifically targeting SLC4A4.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Ganesh (Ganesh et al, Nat Rev Gastroenterol Hepatol (Author Manuscript), March 18, 2019, 16(6):361-375 (actual pages on uploaded version: 1-33); hereinafter Ganesh), Pilon-Thomas (Pilon-Thomas et al, Cancer Res, 2016, 76(6):1381-1390; hereinafter Pilon-Thomas), Parks (Parks and Pouyssegur, J. Cell. Physiol., 2015, 230:1954-1963, IDS entered on 11/10/2023; hereinafter Parks), and McIntyre (McIntyre et al, Cancer Res, 2016, 76(13):3744-3755, IDS entered on 11/10/2023; hereinafter McIntyre) as applied to claim 1 above, and further in view of Bauer (Bauer et al, Cancer Letters, October 10, 2016, 381(1): 259-268 IDS entered on 8/16/2023; hereinafter Bauer).
The combined teachings of Ganesh, Pilon-Thomas, Parks, and McIntyre are discussed above.
The combined teachings of Ganesh, Pilon-Thomas, Parks, and McIntyre do not teach a method of treating cancer comprising administering an inhibitor of SLC4A4 to inhibit the progression or metastasis of cancer, wherein the cancer poorly responds to immunotherapy wherein the cancer is pancreatic cancer.
The deficiency is resolved by Bauer.
Bauer teaches that pancreatic ductal adenocarcinoma (PDAC) reacts poorly to most therapies, including immunotherapy (page 260, left column, third paragraph). Bauer further teaches that although there has been some promising data obtained from murine syngeneic tumor models wherein checkpoint inhibition demonstrated some efficacy, published results from clinical trials that included patients with PDAC have been only minimally effective (page 264, left column, sixth paragraph – right column, first paragraph; Table 1).
Regarding instant claim 2, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method comprising administering independent shRNA sequences to knockdown SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4—a robust sodium-driven bicarbonate transporter—disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, thus improving immunotherapy response as taught by the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre and modify the method to substitute colon cancer with pancreatic cancer as taught by Bauer. This is obvious because, the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre teach a method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4 disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, improving immunotherapy response, and Bauer teaches that pancreatic cancer responds poorly to immunotherapy, and several clinical studies have been minimally effective when different immunotherapeutic agents were used. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating cancer comprising administering an inhibitor of SLC4A4, wherein the cancer in the instant application is resistant or poorly responds to immunotherapy, wherein the cancer in the instant application is pancreatic cancer.
Claims 3, 7-8, and 11-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ganesh (Ganesh et al, Nat Rev Gastroenterol Hepatol (Author Manuscript), March 18, 2019, 16(6):361-375 (actual pages on uploaded version: 1-33); hereinafter Ganesh), Pilon-Thomas (Pilon-Thomas et al, Cancer Res, 2016, 76(6):1381-1390; hereinafter Pilon-Thomas), Parks (Parks and Pouyssegur, J. Cell. Physiol., 2015, 230:1954-1963, IDS entered on 11/10/2023; hereinafter Parks), and McIntyre (McIntyre et al, Cancer Res, 2016, 76(13):3744-3755, IDS entered on 11/10/2023; hereinafter McIntyre) as applied to claim 1 above, and further in view of Fiegle (Fiegle et al, Neoplasia, 2019, 21(9): 932-944, IDS entered on 8/16/2023; hereinafter Fiegle).
The combined teachings of Ganesh, Pilon-Thomas, Parks, and McIntyre are discussed above.
The combined teachings of Ganesh, Pilon-Thomas, Parks, and McIntyre do not teach a method of treating cancer comprising administering an inhibitor of SLC4A4 and immunotherapy to inhibit the progression or metastasis of cancer, wherein the cancer poorly responds to immunotherapy and the immunotherapy comprises therapy with two immune checkpoint inhibitors, wherein the two immune checkpoint inhibitors are each inhibiting a different immune checkpoint. The combined teachings of Ganesh and Parks also do not teach a composition or medicine comprising a combination of an inhibitor of SLC4A4 and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises at least one immune checkpoint inhibitor and inhibits the progression of a cancer, wherein the cancer is resistant to immunotherapy.
The deficiency is resolved by Fiegle.
Fiegle teaches the effects of sole and dual cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and Programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor blockade in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer as well as in CT26 colon carcinoma cells (page 933, right column, second paragraph – page 934, left column, first paragraph), wherein dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis (page 932, Abstract; page 936, left column, “Combination Therapy with Anti-CTL4 and PDL-1…” Section; Figure 1). Fiegle also teaches that dual immune checkpoint blockade and sole CTLA-4 inhibition significantly increased intratumoral CD8+ and CD4+ T cells and reduced FOXP3+/CD4+ Treg cells, which was associated with increased expression levels of the pro-inflammatory Th1/M1-related cytokines IFN-γ, IL-1α, IL-2, and IL-12 (page 932, Abstract; page 936, right column – page 937 left column, “Sole CTLA-4 and Dual Blockade…” Section; page 937 left column, “Combination Blockade …” Section; page 937, right column – page 939, left column, first paragraph, “Combination Therapy Leads to Alterations…” Section; Figures 2,3, and 5). Moreover, Fiegle teaches that tumors treated with combined immune checkpoint blockade showed the strongest increase in intratumoral iNOS+ macrophages, reduction of PD-L1+ and Tie2+ macrophages and the lowest expression of M2/Th2-related IL-4, TARC and COX-2, and further assessment of microenvironmental changes by DCE-MRI and immunohistology revealed no alterations in functional tumor vascularization upon combined immune checkpoint blockade, but a significant increase in intratumoral fibroblasts and collagen I deposition (page 932, Abstract; page 937, right column, “Dual CTL4 and PD-L1 Blockade…” Section; page 939, left column, second paragraph – page 940, left column, first paragraph; Figures 4, and 5). Thus, Fiegle discloses that the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade (page 932, Abstract; page 942, right column, last paragraph).
Regarding instant claims 3, 7, and 8, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4—a robust sodium-driven bicarbonate transporter—disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, thus improving immunotherapy response as taught by the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre and modify the method to further comprise immunotherapy, wherein the immunotherapy comprises two immune checkpoint inhibitors, wherein the two immune checkpoint inhibitors are anti-CTLA-4 and anti-PD-L1 antibodies that inhibit different immune checkpoints as taught by Fiegle. This is obvious because the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre teach a method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4 disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, improving immunotherapy response, and Fiegle teaches the effects of dual CTLA-4 and PD-L1 immune checkpoint inhibitor blockade in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer, wherein dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis, wherein the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating cancer comprising administering an inhibitor of SLC4A4 and immunotherapy, wherein the cancer in the instant application is resistant or poorly responds to immunotherapy, wherein the instant immunotherapy comprises therapy with two immune checkpoint inhibitors, wherein the instant two immune checkpoint inhibitors each inhibit different immune checkpoints.
Regarding instant claims 11-16, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the SLC4A4 inhibitor as taught by Parks and combine the SLC4A4 inhibitor with an immunotherapeutic agent to form a composition or medicine, wherein the immunotherapeutic agent comprises at least one immune checkpoint inhibitor to inhibit the progression or metastasis of cancer as taught by Fiegle, wherein the cancer is colon cancer that poorly responds to immunotherapy as taught by Ganesh. This is obvious because, Ganesh teaches that in CRC, current immune checkpoint inhibitors are mostly ineffective due to the low tumor mutation burden and lack of immune cell infiltration, leading to immune resistance, Parks teaches a method comprising administering independent shRNA sequences specifically targeting SLC4A4 to inhibit SLC4A4 via shRNA knockdown in LS174 colon adenocarcinoma cell lines, and Fiegle teaches the effects of dual CTLA-4 and PD-L1 immune checkpoint inhibitor blockade in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer, wherein dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis, wherein the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition or medicine to inhibit the progression or metastasis of a cancer, wherein the cancer in the instant application poorly responds to immunotherapy, and the instant composition comprises a combination of an SLC4A4 and an immunotherapeutic agent, wherein the instant immunotherapeutic agent comprises at least one immune checkpoint inhibitor.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Ganesh (Ganesh et al, Nat Rev Gastroenterol Hepatol (Author Manuscript), March 18, 2019, 16(6):361-375 (actual pages on uploaded version: 1-33); hereinafter Ganesh), Pilon-Thomas (Pilon-Thomas et al, Cancer Res, 2016, 76(6):1381-1390; hereinafter Pilon-Thomas), Parks (Parks and Pouyssegur, J. Cell. Physiol., 2015, 230:1954-1963, IDS entered on 11/10/2023; hereinafter Parks), and McIntyre (McIntyre et al, Cancer Res, 2016, 76(13):3744-3755, IDS entered on 11/10/2023; hereinafter McIntyre) as applied to claim 1 above, and further in view of Khang (Khang and Park, PGPUB No. US20210008118 A1, priority to July 11, 2019; hereinafter Khang).
The combined teachings of Ganesh, Pilon-Thomas, Parks, and McIntyre are discussed above.
However, the combined teachings of Ganesh, Pilon-Thomas, Parks, and McIntyre do not teach a method of treating cancer comprising administering an inhibitor of SLC4A4 to inhibit the progression or metastasis of cancer, wherein the cancer poorly responds to immunotherapy and the inhibitor of SLC4A4 is a specific inhibitor of SLC4A4 wherein the specific inhibitor of SLC4A4 is a pharmacological inhibitor (e.g. a monoclonal antibody) specifically inhibiting SLC4A4.
The deficiency is resolved by Khang.
Khang teaches using monoclonal antibodies that specifically bind to SLC4A4 to inhibit SLC4A4 in order to investigate the effect of ion channel activity on the ability of stem cells to migrate into cancer cells, wherein the cancer cells are PANC-1 pancreatic cancer cells (page 31, paragraph [0071] – page 32, paragraph [0072]; Figs. 3 and 4).
Regarding instant claim 6, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4—a robust sodium-driven bicarbonate transporter—disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, thus improving immunotherapy response as taught by the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre and modify it so that the SLC4A4 inhibitor comprises a monoclonal antibody that specifically bind to SLC4A4 as taught by Khang. This is obvious because, the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre teach a method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4 disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, improving immunotherapy response, and Khang teaches using monoclonal antibodies that specifically bind to SLC4A4 to inhibit SLC4A4. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating cancer comprising administering a SLC4A4 inhibitor to inhibit the progression or metastasis of cancer, wherein the cancer in the instant application responds poorly to immunotherapy and the SLC4A4 inhibitor is a specific inhibitor of SLC4A4, wherein the specific inhibitor of SLC4A4 in the instant application is a monoclonal antibody.
Applicant Arguments
Applicant argues the following points:
The amended claims are not obvious over Ganesh in view of Pilon-Thomas, Parks, and McIntyre:
A person or ordinary skill in the art at the time of the present application would have had no reasonable expectation of success that inhibition of SLC4A4 would alter the TME to sufficiently neutralize extracellular pH; and
Neither McIntyre nor Parks, in only reporting on intracellular pH (pHi), teaches or suggests any effect of SLC4A4 knockdown or SLC4A9 knockdown on acidity of the TME (extracellular pH) or, even if it is altered, neutralized sufficiently to restore ICI activity;
The amended claims are not obvious over Ganesh in view of Pilon-Thomas, Parks, McIntyre, and Bauer (regarding claim 2);
Bauer does not predict which combination of checkpoint inhibitors would be successful to overcome therapy resistance in the treatment of pancreatic cancer, and does not hint towards combination with an inhibitor of SLC4A4; and
The amended claims are not obvious over Ganesh in view of Pilon-Thomas, Parks, McIntyre, and Khang (regarding claim 6):
Khang is completely unrelated to the problem of how to restore immune checkpoint inhibitor activity;
Khang teaches away from using SLC4A4 inhibitors;
Khang does not demonstrate that SLC4A4 inhibition can produce a TME neutralization effect that would be sufficient to recapitulate the apparent effect of oral bicarbonate buffer in restoring ICI activity as reported by Pilon-Thomas.
Response to Arguments
Applicant's arguments filed 7/14/2026 have been fully considered but they are not persuasive.
In the interest of a clear record, the Examiner acknowledges Applicant’s observation that Pilon-Thomas reports neutralization of extracellular pH (pHe) rather than intracellular pH (pHi), and that McIntyre and Parks report measurements of pHi following transporter disruption. To the extent the prior Office Action used these terms interchangeably, the terminology is clarified here. However, this clarification does not disturb the rejections. The rejection of claim 1 does not depend on showing that SLC4A4 inhibition neutralizes extracellular pH, because claim 1 does not recite any limitation directed to extracellular pH, to neutralization of the tumor microenvironment (TME), or to restoration of immune checkpoint inhibitor (ICI) activity. The pH rationale supplied additional motivation to combine; it is not the predicate for the reasonable expectation of success.
Instant claim 1 requires (1) administering an SLC4A4 inhibitor to a cancer, and (2) that the cancer be one that poorly responds to or is resistant to immunotherapy or to therapy comprising an immunotherapeutic compound or agent. It does not require that immunotherapy be administered, the resistance be overcome, that pHe be neutralized, or that any pH-mediated mechanism take place. Limitations not appearing in the claims cannot be relied upon to establish patentability. See MPEP 2145. Applicant disclosing that the instant application demonstrates pHe neutralization and ICI activity restoration through instant Figures 3D, 5A-B, and 7-9 is a showing of results beyond the scope of what claim 1 requires. Accordingly, Applicant’s arguments are not commensurate with the scope of the claims.
As stated in the teachings above, Parks teaches administering independent shRNA sequences specifically targeting SLC4A4 to LS174 colon adenocarcinoma cells, and reports that the resulting knockdown reduced cell proliferation in both standard culture and three-dimensional spheroid growth and showed a trend toward increased cell death. The same outcome is reported in SLC4A4-knockdown MDA-MB-231 cells. Ganesh teaches that in colorectal cancer, current ICIs are ineffective in pMMR-MSI-L tumors due to low tumor mutation burden and lack of immune cell infiltration, leading to immune resistance. The claimed step in instant claim 1 is administration of an SLC4A4 inhibitor to a cancer that poorly responds to immunotherapy. Accordingly, Parks teaches direct experimental evidence that inhibiting SLC4A4 reduces proliferation and increases death of colon cancer cells, and Ganesh teaches that colon cancer is a cancer that poorly responds to immunotherapy. Furthermore, Applicant reinforces this combination wherein Applicant quotes Parks as reporting that SLC4A4 knockdown has a strong impact on cellular proliferation while only exhibiting minor effect on pHi recovery from acidosis, and that bicarbonate transporters can play an important role in cellular progression outside of basic pHi regulation (see page 11 of Remarks). Therefore, there is reasonable expectation of success independent of the pH rationale.
Applicant also argues that it is a priori uncertain whether targeted SLC4A4 inhibition would create a TME permitting ICI activity (see page 11 in Remarks), relying on the teachings of Pilon-Thomas as described in page 9 in Remarks. However, obviousness does not require absolute predictability of success; a reasonable expectation of success is sufficient. See MPEP 2143.02. In this context, the Examiner reads the same passage of Pilon-Thomas’s teachings as disclosed in the Applicant’s Remarks as an invitation to investigate agents other than oral bicarbonate for modulating tumor pH and improving immunotherapy response. A disclosure that a result is not yet known is to propose a research direction, not a statement that the direction is unpromising. Thus, Pilon-Thomas provides the motivation to combine with an expectation of success.
In regards to Applicant’s arguments that:
neither McIntyre nor Parks teaches an effect of SLC4A4 knockdown on pHe;
Bauer does not predict which combination would succeed and does not hint toward combination with an SLC4A4 inhibitor;
Fiegle teaches no solution other than dual checkpoint blockade; and
Khang is unrelated to restoring checkpoint inhibitor activity;
these arguments are directed to the references individually, and nonobviousness cannot be shown by arguing each reference individually when the rejections are based on combinations of references. See MPEP 2145 (IV). The rejections do not rely on Bauer for an SLC4A4 combination, on Fiegle for a pH mechanism, or on Khang for an immunotherapy rationale. These secondary references are relied upon for discrete teachings as discussed above in the 103 discussion.
Furthermore, in regards to Applicant’s argument that Khang teaches away from using SLC4A4 inhibitors, a reference teaches away only when it discourages the claimed solution. See MPEP 2145(X)(D). Khang does not discourage the use of anti-SLC4A4 antibodies as anticancer agents. Khang simply pursues a different objective, in which inhibition of stem cell migration is an unwanted outcome. A reference that pursues a different purpose is not teaching away, since prior art is relevant for all it teaches to a person of ordinary skill, not only for the inventor’s preferred embodiment. See MPEP 2123.
Accordingly, for the foregoing reasons, the rejections under 35 U.S.C. 103 of claims 1-8 and 11-16 are maintained.
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.
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Claims 1, 4, and 11-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16 of copending Application No. 19/482,990 (hereinafter ‘990) and further in view of Fiegle (Fiegle et al, Neoplasia, 2019, 21(9): 932-944, IDS entered on 8/16/2023; hereinafter Fiegle), Ganesh (Ganesh et al, Nat Rev Gastroenterol Hepatol (Author Manuscript), March 18, 2019, 16(6):361-375 (actual pages on uploaded version: 1-33); hereinafter Ganesh), Pilon-Thomas (Pilon-Thomas et al, Cancer Res, 2016, 76(6):1381-1390; hereinafter Pilon-Thomas), Parks (Parks and Pouyssegur, J. Cell. Physiol., 2015, 230:1954-1963, IDS entered on 11/10/2023; hereinafter Parks), and McIntyre (McIntyre et al, Cancer Res, 2016, 76(13):3744-3755, IDS entered on 11/10/2023; hereinafter McIntyre). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 16 of ‘990 teach a pharmaceutical composition comprising a carrier and a means for specifically inhibiting electrogenic sodium bicarbonate cotransporter 1 (NBCe1)/solute carrier family member 4A4 (SLC4A4).
‘990 does not teach a composition or medicine comprising a combination of an inhibitor of SLC4A4 and an immunotherapeutic compound or agent (instant claims 11, 12, 14), wherein the immunotherapeutic compound or agent is at least one checkpoint inhibitor (instant claim 13), wherein the combination inhibits the progression of a cancer wherein the cancer poorly responds to immunotherapy (instant claims 15 and 16). Furthermore, ‘990 does not teach the composition inhibits the progression of cancer wherein the cancer responds poorly to immunotherapy. Furthermore, ‘990 does not teach a method of treating or inhibiting cancer, or inhibiting the progression, relapse, or metastasis of cancer, where in the method comprises administering an inhibitor of SLC4A4 wherein the cancer poorly responds to immunotherapy and the inhibitor of SLC4A4 is a specific inhibitor of SLC4A4.
The deficiency is resolved by Fiegle, Ganesh, Pilon-Thomas, Parks, and McIntyre.
The teachings of Fiegle, Ganesh, Pilon-Thomas, Parks, and McIntyre are discussed above in the 103 rejection.
Regarding instant claims 1 and 4, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical composition comprising a carrier and a means for specifically inhibiting SLC4A4 as taught by ‘990 and include the composition in a method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4—a robust sodium-driven bicarbonate transporter—disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, thus improving immunotherapy response as taught by the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre. This is obvious because, ‘990 teaches a composition that comprises a carrier and a SLC4A4-specific inhibitor, and the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre teach a method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4 disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, improving immunotherapy response. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating cancer comprising administering an inhibitor of SLC4A4, wherein the cancer in the instant application is resistant or poorly responds to immunotherapy and the inhibitor of SLC4A4 is a specific inhibitor of SLC4A4.
Regarding instant claims 11-16, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical composition comprising a carrier and a means for specifically inhibiting SLC4A4 as taught by ‘990 and combine the SLC4A4 inhibitor with an immunotherapeutic agent to form a composition or medicine, wherein the immunotherapeutic agent comprises at least one immune checkpoint inhibitor to inhibit the progression or metastasis of cancer as taught by Fiegle, wherein the cancer is colon cancer that poorly responds to immunotherapy wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4—a robust sodium-driven bicarbonate transporter—disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, thus improving immunotherapy response as taught by the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre. This is obvious because, ‘990 teaches a composition that comprises a carrier and a SLC4A4-specific inhibitor, the combined teachings of Ganesh, Parks, Pilon-Thomas, and McIntyre teach a method comprising administering independent shRNA sequences to knock down SLC4A4 in colon cancer, thereby reducing proliferation and increasing cell death, wherein since colon cancer responds poorly to immunotherapy, inhibiting SLC4A4 disrupts pH homeostasis by blocking bicarbonate import and raising intratumoral pH, improving immunotherapy response, and Fiegle teaches the effects of dual CTLA-4 and PD-L1 immune checkpoint inhibitor blockade in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer, wherein dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis, wherein the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition or medicine to inhibit the progression or metastasis of a cancer, wherein the cancer in the instant application poorly responds to immunotherapy, and the instant composition comprises a combination of an SLC4A4 and an immunotherapeutic agent, wherein the instant immunotherapeutic agent comprises at least one immune checkpoint inhibitor.
Response to Arguments
Applicant's arguments filed 7/14/2026 have been fully considered but they are not persuasive.
For the reasons discussed above in response to the arguments regarding the 103 rejections, instant claims 1, 4, and 11-16 are not patentably distinct from claim 16 of copending Application No. 19/482,990 in view of Fiegle, Ganesh, Pilon-Thomas, Parks and McIntyre. Thus, the double patenting rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
