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 1, 3-12, and 15-21, submitted on 22 December 2022, represent all claims currently under consideration. 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. Priority This application is a 371 of PCT/IL2020/050708. The effective filing date is 24 June 2020. Information Disclosure Statement One Information Disclosure Statement (IDS), submitted on 6 February 2023, is acknowledged and has been considered. Claim Objections Claim 21 is objected to because of the following informalities: There is a superfluous “an” in the claim and should be removed. Appropriate correction is required. Claim Rejections - 35 USC § 112(a) 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. Claims 1, 3-12, and 15-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for the treatment of solid tumors wherein ASS1 is overexpressed, does not reasonably provide enablement for the treatment of all solid tumors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below: The nature of the invention and breadth of the claims : The claims are directed towards a method of treating a solid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent which increases pyrimidine to purine ratio in a cell without decreasing pyrimidine synthesis. The specification demonstrates that cancers which have increased levels of arginonosuccinate synthase (ASS1) are susceptible to treatment by increasing the pyrimidine levels within the tumors, increasing their susceptibility to immunotherapy. Thus, the claims are directed to a method of treating any solid tumor by increasing the ratio of pyrimidine to purine within the tumor. The state of the prior art and the predictability or unpredictability of the art : Zhao ( Frontiers in Pharmacology , 2022 July 15) provides a review of ASS1 in cancer. Numerous studies have shown that tumoral ASS1 functions both as a tumor suppressor and tumor promoter in a wide variety of tumors. Downregulation of ASS1 has been found to play a tumor suppressor role in multiple malignancies. It is also recognized that ASS1 plays different roles depending on the tumor type that it is found in. Renal tumors exhibit downregulated ASS1, and loss of ASS1 redirects aspartate towards pyrimidine synthesis and regulates NO production to support enhanced proliferation. It has also been demonstrated that ASS1 may function as a tumor suppressor via metabolism-independent mechanisms. In hepatic cell carcinoma cells, ASS1 induces cell death by upregulating ER stress response independent of arginine metabolism. Specifically, ASS1 overexpression effectively inhibits tumor growth by activating PERK/eIF2α/ATF4/CHOP axis in Hih7 and SNU475 cells, indicating upregulating tumoral ASS1 expression as a promising strategy in tumors with low ASS1 expression. ASS1 also has a pro-tumor role in tumor proliferation and metastasis, and the mechanisms vary and differ depending on the specific type of tumor. Colorectal cancer tumors have shown that urea cycle enzymes including ASS1 have been identified to be upregulated in KRAS-mutant primary colorectal cancer cells. Metabolic profiling has pointed that ASS1 inhibition reduces the levels of oncogenic metabolite fumarate, resulting in impaired glycolytic phenotype and reduced colorectal cancer progression . In gastric cancer, ASS1 knockdown leads to impaired tumor cell invasion by promoting autophagy-lysosome machinery to degrade Snail and Twist (Different role of ASS1 in Tumor Progression). However, not all cancers can be successfully treated in this manner as not all solid tumors express high levels of ASS1, and there is evidence that ASS1 has divergent roles in the pathogenesis of cancer depending on the specific cancer type. Further, there is currently no known treatment that can be used to treat all forms of cancer. The relative skill of those in the art : The artisan would generally have an advanced degree related to the treatment or study of various cancers; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of cancer, as not all forms of cancer express high levels of ASS1, and not all forms of solid tumors are sensitive to purine synthesis inhibition. The amount of direction or guidance presented and the presence or absence of working examples : Example 3 (Page 40) of the specification demonstrates that high ASS1 cancers are more sensitive to purine inhibition than low ASS1-expressing tumors , and show data demonstrating in ASS1 expression and NDNO-score is are significantly associated with a lack of response to immunotherapy. The specification states that the data demonstrate that in ASS1 expressing tumors , the purine inhibitor mizoribine can both reverse the high purine to pyrimidine ratio, and enhance the response to immunotherapy. Thus, the specification enables the treatment of cancers which have high levels of ASS1 expression, but does not enable the treatment of all forms of cancer as not all forms of cancer express high levels of ASS1. The quantity of experimentation necessary : Considering the state of the art as described above, in particular with regards to the lack of a panacea for the treatment of cancer due to the heterogenous nature of the disease, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims. Claims 1 , 2 -4 , 6 , 7 and 9 are 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. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art. While all of these factors are considered, a sufficient number for a prima facie case are discussed below: The claims are directed to a method of treating a solid tumor comprising administering to a subject in need thereof a therapeutically effective amount of an agent which increases pyrimidine to purine ratio in a cell without decreasing pyrimidine synthesis, thereby treating the solid tumor. The specification does not provide a definition of “an agent that increases pyrimidine to purine ratio without decreasing pyrimidine synthesis”. The specification states that certain compounds such as anti-folates, mizoribine , purine inhibitors such as azathioprine and mercaptopurine, ethyl protocatechuate, prolyl 4-hydroxylase inhibitors, or agents which enhance purine cyclization, such as BRL-50481, sildenafil, and other phosphodiesterase inhibitors are useful for practicing this invention. However, the specification does not provide a structure or general class of compounds which can be used to practice this invention, as there is no known specific class of compounds which can function as claimed. There are no complete structures provided which would allow the artisan to recognize that the inventor was in possession of every compound which can function as claimed, and as such, the artisan would only know which compounds can function as claimed in the invention through a posteriori testing and analysis , and would not know prior to utilizing a compound if it will increase the pyrimidine to purine ratio without inhibiting pyrimidine synthesis. The artisan would understand what these compounds functionally do, but without specific guidance from the specification as to what classes of compounds can perform this function, there would no expectation of predictability for practicing this invention. Thus, there is no support in the specification that applicant was in possession of the claimed invention as a whole at the time of filing. Claim 5 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. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art. While all of these factors are considered, a sufficient number for a prima facie case are discussed below: Claim 5 claims the method of Claim 4 wherein the agent comprises mizoribine or a derivative thereof. The specification describes sugar-modified analogs of mizoribine , carbocyclic analogs of mizoribine , as well as other analogs of mizoribine (Page 15, Lines 10-15). However, it is unclear if these are the only derivatives/analogs which are covered by the invention, or what specifically a derivative comprises. There is no data demonstrating that each derivative will function as claimed in the invention, nor is there any full definition of what can be added to the mizroibine structure and still be considered a derivative. The artisan would have no expectation of predictability in practicing this invention as there is no clear definition of what comprises a derivative, which can almost be an infinite amount of compounds. The artisan would not know which derivatives are capable of successfully practicing this invention, as all derivatives may not have the same inhibitory activity as mizoribine . Therefore, there is no support in the specification that indicates that applicant was in possession of the whole invention as claimed at the time of filing. Claim Rejections - 35 USC § 112(b) The following is a quotation of 35 U.S.C. 112(b): (b ) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the appl icant regards as his invention. Claim 5 is 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. Claim 5 claims the method of Claim 4 wherein the agent comprises mizoribine or a derivative thereof. The specification describes sugar-modified analogs of mizoribine , carbocyclic analogs of mizoribine , as well as other analogs of mizoribine (Page 15, Lines 10-15). However, these do not describe the entirety of what a derivative can encompass, leading the artisan to question what constitutes a derivative. The definition of derivative is not provided within the specification, and is not a term of the art. The use of “derivative thereof” leads to the metes and bounds of the claim being undefined, and therefore, indefinite. Claim 10 is 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. Regarding claim 10, the phrase "e.g., Viagra" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 10 is 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. Claim 10 contains the trademark/trade name VIAGRA. 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 sildenafil and, accordingly, the identification/description is indefinite. Claim Rejections - 35 USC § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale , or otherwise available to the public before the effective filing date of the claimed invention. Claims 1, 3, and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sjogren (US Patent No. 5,380,879; Patent Date: 10 January 1995). Sjogren discloses derivatives of mycophenolic acid that are therapeutic agents advantageous for the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents (Abstract). The compounds of the invention are inhibitors of inosine monophosphate dehydrogenase (IMPDH) and thus inhibit de novo purine synthesis; they have anti-proliferative effects (Column17, Lines 30-32). As anti-tumor agents, the compounds are useful in treating solid tumors and malignancies of lymphoreticular origin (Column 17, Lines 63-65). Claims 1, 3, and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Carrera (US Patent No. 5,840,505; Patent Date: 24 November 1998). Carrera discloses an in vivo method for depleting mammalian cells of adenosine 5’-monophosphate (AMP) useful in the treatment of certain cancers. Hosts having methylthioadenosine phosphorylase ( MTAse ) deficient tumors are treated with a therapeutically effective amount of an agent which inhibits the activity of adenylsuccinate synthetase, which converts inosine 5’-monophosphate to AMP, thus depleting the tumor cells of substrates for de novo AMP production. L- alanosine is the preferred ASS inhibitory agent for use in the method of this invention (Abstract). Claims 1, 3, 4, and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Carson (US 2004/0127435; Publication Date: 1 July 2004) . Carson discloses methods of treating cancer using inhibitors of inosine monophosphate dehydrogenase (IMPDH). The IMPDH inhibitors are combined with compounds that inhibit cellular processes regulated by GTP or ATP. Also provided are prodrugs of the IMPDH inhibitor and its aglycone. The prodrugs are useful in practicing the methods of the invention, including immunosuppressive therapy and treatment of cancer by prolonged administration without additional therapeutic compounds (Abstract). Cancers which can be treated include slowly proliferating breast, prostate, and thyroid cancer (Paragraph 0010). Claims 1, 6, and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Erez (WO 2018/167780; Publication Date: 20 September 2018). Erez (See IDS, 6 February 2023) discloses methods of treating cancer. The method comprises determining a shift from the urea cycle to pyrimidine synthesis in a cancerous cell and treating the subject with an immune modulating agent when the shift is indicated (Abstract). According to specific embodiments, the cancer is selected from the group consisting of hepatic cancer, osteosarcoma, breast cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, kidney cancer, prostate cancer, head and neck cancer, bile duct cancer and bladder cancer (Page 16, Lines 20-23). According to specific embodiments, the lung cancer is lung squamous carcinoma (a form of NSCLC) (Page 16, Line 31). According to specific embodiments, the cancer therapy comprises an agent which induces a pyrimidines to purines nucleotide imbalance. According to another specific embodiment, the cancer therapy comprises an immune modulation agent and an agent which induces a pyrimidines to purines nucleotide imbalance (Page 41, Lines 26-29). As used herein the term “induces a pyrimidines to purines nucleotide imbalance” refers to an increase in the ratio of pyrimidines to purines in a cell in the presence of an agent as compared to same in the absence of agent, which may be manifested in e.g., increased levels of pyrimidines, decreased levels of purines, and/or increased level of purine to pyrimidine transversion mutations (Page 42, Lines 3-7). According to specific embodiments, the agent which induces pyrimidines to purines nucleotide imbalance comprises an anti-folate agent. Anti-folate agents include methotrexate, pemetrexed, and proguanil (Page 42, Lines 19-24). Claim 36 claims a method of treating cancer comprising treating said subject with an agent which induces a pyrimidines to purines nucleotide imbalance. Claim 37 claims this method further comprising treating said subject with an immune modulation agent, with Claim 38 specifying that this agent comprises anti-PD1. Claims 1, 3, and 6-8 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Han ( PLoS One , 2014 September 18; 9(9)) . Han performed a study of ethyl-3,4-dihydroxybenzoate (ethyl protocatechuate, EDHB) in the treatment of esophageal cancer. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, they investigate the cytotoxic effect of EDHB on esophageal squamous cell carcinoma cells in vitro and identified key regulators of EDHB induced cell death through transcription expression profiling. They found that EDHB induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Autophagy and apoptosis were activated together in esophageal cancer cells after exposure to EDHB (Abstract). While Han does not disclose that this method of treating cancer is the result of the enhancement of pyrimidine synthesis, they disclose the treatment of a solid tumor using EDHB, and because this compound is identical to the compound claimed in Claim 8, it necessarily meets the limitations as this compound will have the same properties as what is claimed, thus anticipating the claims. Claims 1, 3, 6, 7, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goldhoff ( Clinical Cancer Research , 2008; 14(23), December 1 2008). Goldhoff investigated the role of cyclic AMP phosphodiesterase-4 (PDE4) in brain tumors and examined the utility of the PDE4 as a therapeutic target. IHC was used to evaluate the expression pattern of PDE4A in multiple brain tumor types. The brain specific isoform PDE4A1 was overexpressed in xenografts of Daoy medulloblastoma and U87 glioblastoma cells. T o determine therapeutic potential of PDE4 inhibition, Rolipram, temozolomide, and radiation were tested alone and in combination on mice bearing intracranial U87 xenografts. PDE4A was overexpressed in medulloblastoma, glioblastoma, oligodendro -glioma, ependymoma, and meningioma. Rolipram in combination with first-line therapy for malignant gliomas (temozolomide and conformal radiation therapy) enhanced survival of mice bearing xenografts of U87 glioblastoma cells. The study shows that PDE4 is widely expressed in brain tumors and promotes their growth and that inhibition with Rolipram overcomes tumor resistance and mediates tumor regression (Abstract). Inhibition of PDE4 prevents the degradation of cyclic AMP, which enhances the cyclization of AMP, a purine. Claims 1, 3, 6, 7, and 9-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sponziello ( Endocrine , 2015, 50:434-441). Sponziello analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs). They also tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. Upregulation of PDE5 was detected in tumor tissue proteins. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. The findings demonstrate that there is an overexpression of PDE5 in PTCs, and that inhibition of PDE5 blocks the proliferation of thyroid cancer cells in culture, suggesting that specific inhibition of PDE5 may be proposed for treatment of these tumors (Abstract). Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 1, 3, 6, 9-12, and 15-21 are rejected under 35 U.S.C. 103 as being unpatentable over Peng ( European Journal of Medicinal Chemistry , 150, 2018, 742-756) in view of Erez (WO 2018/167780; Publication Date: 20 September 2018). Peng provided a review of phosphodiesterases , their involvement in cancer, and how inhibition of phosphodiesterases is a treatment strategy for cancer. Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets (Abstract). PDE4 is the largest of the PDE families and specifically hydrolyzes cAMP. PDE4 is expressed in a wide variety of tissues, such as brain, olfactory system, liver, heart, smooth muscle, lung, endothelial cells, and immunocytes. In 41 of 60 tumor cell lines, cAMP-specific PDE4 showed the highest cAMP-hydrolyzing activities. PDE4 is widely expressed and promotes the growth of brain tumors, including glioblastoma, medulloblastoma, ependymoma, oligodendroglioma, and meningioma. PDE4C induces apoptosis and suppressed migration in U87 cells through cAMP-p53 pathway. Appreciably higher PDE4 levels was found to express in lung cancer cells in comparison to normal lung cells via PDE4-cAMP-PKA/EPAC axis regulating HIF signaling. Upregulation of PDE4 by TGF-β1 promotes epithelial-mesenchymal transition in alveolar epithelial cells and PDE4 may be a novel therapeutic target to attenuate EMT-associated lung diseases including lung cancer. High dose roflumilast can reduce lung carcinogenesis in B [a]P-induced murine lung cancer model. Exisulind , a dual inhibitor for PDE4 and PDE5 through block cGMAP hydrolysis, is a novel drug with proapoptotic properties. In colon cancer cells and in rat bladder tumors, this compound reduced multiplicity and incidence of the tumorigenic events. Exisulind was also shown to induce apoptosis by inhibiting PDE1, PDE2, and PDE10 in colon, pancreatic, and bladder cancer cell lines. PDE5 specifically hydrolyzes cGMP. Overexpression of PDE5 occurs in many carcinomas, including urinary bladder, prostate cancer, breast, brain cancers, colonic adenocarcinomas, chronic lymphocytic leukemia cells, oral squamous cells, and non-small lung cells. The specific PDE5 inhibitors sildenafil and tadalafil reduced proliferation and cellular migration in thyroid cancer. PDE/cGMP/PKG signaling has an important role in maintaining stemness of PC3-derived cancer stem cells, and PDE5 inhibitors in combination with chemotherapeutic agents effectively prevented initiation, metastasis, and relapse of prostate cancer. PDE5 inhibitors may enhance sensitivity of certain types of cancer to common chemotherapeutic drugs. Sildenafil and vardenafil were shown to reverse ABCB1- or ABCG2-mediated multidrug resistance in cancer cells by directly blocking their drug efflux function. A combination of PDE5 inhibitors with chemotherapy agents enhanced killing of gastrointestinal/genitourinary cancers and medulloblastoma cells. PDE5 inhibitors may also increase the efficacy of anti-cancer drugs by increasing the endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer. PDE7 is highly selective for cAMP. PDE7 mRNA and protein are expressed in a wide variety of immune cells. Overexpression of PDE7A in EC cells promoted cancer cell migration and invasion via downregulation of the miR-1/133a cluster, and the PDE7 inhibitor BRL-50481 increased cAMP-PKA specific apoptosis in CLL cells. Peng fails to teach a co-treatment with an immune checkpoint modulator that is a PD1 antagonist. The teachings of Erez are described in the prior rejection and are fully incorporated into this rejection. Peng and Erez are considered analogous to the claimed invention as all are involved in the treatment of cancer by modifying the pyrimidine to purine ratio. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the methods of Erez through the use of phosphodiesterase inhibitors such as sildenafil or B RL-50481 as Peng has shown that it is well known in the art of chemotherapy that these compounds possess anti-cancer activity. These compounds inhibit the enzymes which hydrolyze cAMP and cGMP, thus enhancing purine cyclization which does not affect purine synthesis but does increases the pyrimidine to purine ratio within the cell without decreasing pyrimidine synthesis. The methods of Erez are directed to methods of treating cancer by inducing a pyrimidine to purine imbalance, and the artisan would recognize that using these known anticancer agents would accomplish this. The substitution of PDE inhibitors into the method of Erez is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); PDE inhibitors are known to be useful for treating cancer, and Erez discloses methods to treat cancer by inducing a pyrimidine to purine imbalance. It flows from this art that PDE inhibitors would be useful in the methods of Erez. Regarding Claims 11 and 15 , Peng teachers that PDE inhibitor such as sildenafil and vardenafil can reverse multidrug resistance in cancer by blocking their drug efflux function, and may increase the efficacy of anti-cancer drugs by increasing the endocytosis-mediated cellular uptake. It flows from this teaching PDE inhibitors can be useful for the treatment of cancers which are non-responsive to immune-modulating drugs, and would be administered prior to administering the immune-modulating drug. Regarding Claim 19 , PRB is known in the art to result in an increased purine to pyrimidine ratio, and is associated with cancers. The artisan would recognize this, and would know that by modulating this ratio with agents known to alter this ratio would predictably result in an effective treatment for cancers which are characterized by PRB . Conclusion Claims 1, 3-12, and 15-21 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT PHILLIP MATTHEW RZECZYCKI whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (703)756-5326 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday Thru Friday 730AM-5PM EST . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Andrew Kosar can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-0913 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /P.M.R./ Examiner, Art Unit 1625 /Andrew D Kosar/ Supervisory Patent Examiner, Art Unit 1625