DETAILED ACTION
Claims 1-8, and 11-16 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." The following references have been cited in the specification but have not been listed in the IDS:
Page 2, lines 14, 16, 18-20;
Page 9, lines 25-30;
Page 10, lines 16-19, 21, 23-25, 27, 31-33;
Page 11, lines 1-2;
Page 15, line 26;
Page 17, lines 22, 30;
Page 18, lines 13-14, 22-23, 27, 29;
Page 23, lines 8, 10, 15-21, 28, 30-32;
Page 24, lines 6, 30, 33;
Page 25, lines 33-34;
Page 26, lines 1-4, 10;
Page 31, lines 21, 27, 30,
Page 32, lines 3, 7-8;
Page 34, line 23;
Page 37, line 13.
Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The abstract of the disclosure is objected to because the sentence beginning on line 6 (“This either as monotherapy …”) is a sentence fragment that lacks clarity. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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. The examiner has noted that page 17, line 33 of the specification contains a hyperlink.
The disclosure is objected to because of the following informalities:
“10’000 KPC cells” should read “10,000 KPC cells” (page 34, line 8);
“20’000 g” should read “20,000 g” (page 36, line 3);
“rans-Blot” should read “Trans-Blot” (page 36, line 24);
“Trans-Blot. TurboTM” should read “Trans-Blot TurboTM” (page 36, line 24);
“sacrifice” should read “sacrificed” (page 38, line 28);
“PercPcy5.5” should read “PerCP-Cy5.5” (page 39, line 3);
“DynabeadsTM” should read “DynabeadsTM” (page 39, line 14; page 39, line 34).
“FACS Canto” should read “FACSCanto” (page 40, line 2).
Appropriate correction is required.
The use of the term AlphabodyTM, Nanobody®, DARPin®, Affibody®, Anticalin®, PROTAC®, UltiMateTM, DionexTM, Q Exactive®, XcaliburTM, TritonTM X-100, phosSTOPTM, MiniPROTEAN®, Trans-Blot® Turbo, Tween®, ImageQuant®, HyperSense®, NucleoFectorTM, FACSAriaTM, FlowJoTM, FACSCantoTM, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such with the appropriate notation:
Alphabody: pages 3 and 13
Nanobody: pages 3, 13, 38
DARPin: pages 3, 13-14, 20, 24
Affibody: pages 3 and 13
Anticalin: pages 3, 13-14, 20, 25
PROTAC: pages 3, 13-14, 25
Dionex (page 36, line 5);
UltiMate (page 36, line 5);
Q Exactive (page 36, line 6);
Xcalibur (page 36, line 16);
Triton X-100 (page 36, line 21);
phosSTOP (page 36, line 22);
MiniPROTEAN (page 36, line 22);
Trans-Blot Turbo (page 36, line 24);
Tween (page 36, line 25);
ImageQuant (page 36, line 31);
HyperSense (page 37, line 18);
Nucleofector (page 38, lines 16-18);
FACSAria (page 38, line 25);
FlowJo (page 38, line 26; page 39, lines 5, 28; page 40, line 2);
FACSCanto (page 39, line 5; page 39, line 28; page 40, line 2).
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities:
“Carrir” should read “Carrier”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 6 is rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus
Instant claim 6 claims a specific inhibitor of SLC4A4, wherein the specific inhibitor of SLC4A4 is a pharmacological inhibitor. Additionally, the claim limits the pharmacological inhibitor to a group consisting of a polypeptide comprising an immunoglobulin variable domain, a monoclonal antibody or a fragment thereof, an AlphabodyTM, a Nanobody®, an intrabody, an aptamer, a DARPin®, an Affibody®, an affitin, an Anticalin®, a monobody, a bicyclic peptide, a PROTAC®, or a LYTAC.
State of the Relevant Art
At the time of the filing of the instant application, it was well established in the art that Na+-coupled acid-transporters play essential roles in human biology, wherein their dysfunction has been linked to cancer, heart, and brain disease (page 1, Abstract; Huynh et al, Nature Communications, March 2, 2018, 9(900): 1-9, IDS entered 11/10/2023; hereinafter Huynh). Huynh further teaches that in mammals, solute carrier (SLC) transporters within the amino-acid-polyamine-organocation (APC) protein superfamily regulate blood pressure, ion and metabolite homeostasis, and acid-base chemistry, and play key roles in the maintenance of cell function and growth, wherein the dysregulation of Na+-coupled acid-base SLC transporters in cancer cells has important diagnostic and therapeutic implications (page 2, left column, first paragraph). Parks and Pouyssegur teaches that the hypoxic and acidic tumor environment necessitates intracellular pH (pHi) regulation for tumor progression, wherein carbonic anhydrase IX facilitates CO2 export to generate HCO3- in the extracellular tumor space, wherein HCO3- is then recaptured by the cell to maintain an alkaline pHi for the promotion of tumor cell growth in vitro and in vivo (page 1954, Abstract; page 1954, left column, first paragraph; Parks and Pouyssegur, J. Cell. Physiol., 2015, 230:1954-1963, IDS entered on 11/10/2023; hereinafter Parks). And McIntyre teaches that the most robust and frequent inductions of expression under hypoxic conditions were of the sodium-driven bicarbonate transporters SLC4A4, wherein SLC4A4 disruption by either genetic (e.g. shRNA) or pharmaceutical approaches acidified intracellular pH and reduced cell growth in cancer cells (Figures 1 and 3, page 3744, Abstract; McIntyre et al, Cancer Res, July 1, 2016, 76(13):3744-3755, IDS entered on 8/16/2023).
At the time of the filing of the instant application, there were only a small number of approved drugs or drugs in development, which therapeutically target human SLC transporters. Zimmermann teaches that the main reason behind these shortcomings is the intricate architecture and low thermal stability of the SLC transporters, making it notoriously difficult to work with in early drug delivery stages (page 13, second paragraph; Zimmermann et al, eLife, 2018, 7(e34317):1-32; hereinafter Zimmermann). Van Campenhout teaches that nanobodies targeting SLCs were mainly used as crystallization chaperones (e.g. SLC-26Dg-targeting nanobody) or therapeutic agents (e.g. VGLUT1-targeting nanobodies) to inhibit the function of the SLC (page 12, section 4.5.3 “Porters”; Table 2; Van Campenhout et al, Biomolecules, January 6, 2021, 11(63): 1-19; hereinafter Van Campenhout). Proteolysis-targeting chimeras, or PROTACs, which are a new generation of heterobifunctional small-molecule degraders, have also been used to target SLCs by inducing the selective and rapid degradation of target proteins, e.g. d9A-2, which targets SLC9A1 (page 728, right column, last paragraph – page 729, left column, first paragraph; Figure 4; Bensimon et al, Cell Chemical Biology, June 18, 2020, 27:728-739).
In the context of SLC4A4 inhibition, at the time of the filing of the instant application, SLC4A4 disruption was performed through the use of monoclonal antibodies or pharmacological agents, such as DIDS or S0859. Khang (Khang and Park, PGPUB No. US20210008118 A1, priority to July 11, 2019; hereinafter Khang) teaches using monoclonal antibodies that specifically bind to SLC4A4 for inhibition 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). Nakajima (Nakajima et al, Proc Natl Acad Sci USA, 2013, 110(5):1767-1772; hereinafter Nakajima) teaches that DIDS (4,4′-diisothiocyanatostilbene-2,2′-disulfonate) is an inhibitor commonly used for mammalian SLC-type HCO3- transporters, wherein in Nakajima’s study, DIDS was used to inhibit SLC4 transporters (page 1769, right column, “Inhibition of PtSLC4s” section; Figure 4). And Ch’en (Ch’en et al, Br J Pharmacol, 2008, 153(5):972-982; hereinafter Ch’en) teaches that S0859 inhibited all cardiac NBC activity, wherein at least three isoforms have been detected in humans, wherein all three isoforms are products of the Slc4a gene family, e.g. Slc4A4, Slc4A5, and SLC4A7. Ch’en further discloses that although S0859 appears to be useful as a generic NBC inhibitor in the cardiac cell, it may not be able to resolve functional contributions from specific NBC isoforms (page 979, right column, second paragraph). Regarding the group recited in instant claim 6, there is no prior art at the time of the filing of the instant application where it teaches SLC4A4-specific pharmacological inhibitors comprising an alphabodyTM, a nanobody®, an intrabody, an aptamer, a DARPin®, an affibody®, an affitin, an anticalin®, a monobody, a bicyclic peptide, a PROTAC®, or a LYTAC.
Summary of Species disclosed in the original specification
The instant specification discloses that for in vivo SLC4A4 inhibition, mice were treated with 15mg/kg of DIDS administered i.p. bi-daily for a period of 10 days (page 34, lines 15-16), wherein for in vitro experiments, cancer cells were transduced with a vector containing a sgRNA targeting the Slc4a4 locus to silence the gene via the inducible CRISPR/Cas9 system (page 37, line31 – page 38, line 8; page 40, Example 2). All examples described in the instant specification either used DIDS for in vivo experiments or the inducible CRISPR-CAS9 system for in vitro examples. Furthermore, the instant specification discloses that immunoglobulin single variable domain (ISVD) antibodies were raised against the SLC4A4 protein, and preliminary results indicated some of the ISVDs were capable of inhibiting SLC4A4 activity (page 44, Example 7). However, the instant specification does not have examples for using the SLC4A4-specific pharmacological inhibitors recited in instant claim 6, wherein the inhibitors are an alphabodyTM, a nanobody®, an intrabody, an aptamer, a DARPin®, an affibody®, an affitin, an anticalin®, a monobody, a bicyclic peptide, a PROTAC®, or a LYTAC. Therefore, the Applicant was not in possession of the pharmacological inhibitors alphabodyTM, nanobody®, intrabody, aptamer, DARPin®, affibody®, affitin, anticalin®, monobody, bicyclic peptide, PROTAC®, and LYTAC that specifically target SLC4A4 as claimed in instant claim 6.
Summary
A genus of species is not present in the instant specification or prior art that demonstrates a structure activity relationship for specifically inhibiting SLC4A4 by a pharmacological inhibitor, wherein the pharmacological inhibitor comprises an alphabodyTM, a nanobody®, an intrabody, an aptamer, a DARPin®, an affibody®, an affitin, an anticalin®, a monobody, a bicyclic peptide, a PROTAC®, or a LYTAC. There is a lack of an appropriate number of species that have SLC4A4 disruption using the pharmacological inhibitors recited in instant claim 6. Therefore, one of skill in the art would reasonably conclude that applicant was not in possession of the required genus of pharmacological inhibitors comprising an alphabodyTM, a nanobody®, an intrabody, an aptamer, a DARPin®, an affibody®, an affitin, an anticalin®, a monobody, a bicyclic peptide, a PROTAC®, or a LYTAC at the time of filing.
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 3 and 6 are 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.
Instant claim 3 is directed to a “method” and depends from instant claim 1. While claim 1 recites the active method step of “administering”, instant claim 3 only recites “further comprising immunotherapy” without a specific active step (e.g. administering) to be performed in the context of the method. Thus, without the active method step, the metes and bounds of “further comprising immunotherapy” is unclear to a person having ordinary skill in the art in the context of what aspect of the method is comprising immunotherapy. For the purpose of expedited prosecution, claim 3 is interpreted as “further comprising administering immunotherapy”.
Instant claim 6 contains the trademark/trade name AlphabodyTM, Nanobody®, DARPin®, Affibody®, Anticalin®, and PROTAC®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a pharmacological inhibitor specifically inhibiting SLC4A4 and, accordingly, the identification/description is indefinite.
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.
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.
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 have been motivated 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 improve responses to immunotherapy as taught by the combined teachings of Parks, Pilon-Thomas and McIntyre 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 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 substitute colon cancer with pancreatic cancer as taught by Bauer 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 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, which improves 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 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 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 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 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 binds to SLC4A4 as taught by Khang 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.
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).
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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 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 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 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 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.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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