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 23, 26, and 29 have been cancelled. Claims 18, 21, 22, 24, 25, 27, and 28 have undergone amendments. Thus, Claims 18, 19, 21, 22, 24, and 25, submitted on 19 December 2025, 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.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 9 October 2025, is acknowledged and has been considered.
Response to Amendment
The objection to the specification is withdrawn. Applicant has amended the specification to properly recite the tradename.
The objection to claims 22 and 25 is withdrawn. Applicant has amended the claims to delete the second recitation of “an anti-PD-1/CTLA-4 bispecific antibody”.
The 35 U.S.C § 112(a) rejection of Claims 18, 19, and 21-26 is maintained. While removing the limitation of “prevention”, the claim is still not fully enabled by the specification as those cancers are not each explicitly dependent upon elevated mPGES-1 levels, and thus, the artisan would not be capable of treating each of these cancers without a burden of undue experimentation.
The 35 U.S.C. § 112(a) rejection of Claims 21, 22, 24, and 25 is withdrawn. Applicant has amended the claims to remove “prevention”.
The 35 U.S.C. § 112(b) rejection of Claims 21, 22, 24, and 25 is withdrawn. Applicant has amended the claims to remove the parenthesis.
The 35 U.S.C. § 112(b) rejection of Claims 22 and 25 is withdrawn. Applicant has amended the claims to remove the trade name.
Response to Arguments
The 35 U.S.C. § 103 rejection of Claims 18, 19, and 21-26 over Otsu in view of Prima, Sasaki, and Nakanishi is maintained. Applicant argues that this rejection should be withdrawn in view of the teachings of Kim, which was not cited in this specific rejection. The Examiner respectfully disagrees. In view of these specific teachings which were cited, it would have been obvious to one of ordinary skill in the art to apply these compounds in combination with immune checkpoint inhibitors for the treatment of the claimed cancers. Prima teaches the role of PD-L1 in immunosuppression within tumors, and demonstrates that inhibition of mPGES1 results in reduced PD-L1 expression. Thus, it flows from the art that the claimed inhibitor, which Otsu demonstrates is a potent mPGES-1 inhibitor, would be useful for the treatment of these cancers which overexpress mPGES-1. While none of the references explicitly teach the use of the specific immune checkpoint inhibitors, it would be obvious to one of ordinary skill in the art to combine the claimed mPGES-1 inhibitor with immune checkpoint inhibitors as the prior art shows a link between prostaglandin signaling and these immune checkpoint markers. It flows from the art that combining these two treatments would result in an improved treatment method of cancer as Prima demonstrates an explicit link between mPGES-1 and induction of PD-L1 in tumor associated macrophages.
The 35 U.S.C. § 103 rejection of Claims 18, 19, and 21-26 over Otsu in view of Ohtani is maintained. Applicant argues that the method of Ohtani requires the use of an EP4-selective antagonist in their method, while the compounds of the examined application have much broader activity than only inhibiting the EP4 receptor. Thus, there would be no motivation to modify the method of Ohtani by substituting a highly selective antagonist for a compound with less specific activity towards EP4. The Examiner disagrees. PGE2 is the primary ligand of EP4, and the antagonism of this receptor ablates the activity of PGE2. By targeting upstream of the EP4 receptor (inhibition of the production of PGE2), a similar result will be obtained, as this will result in less activity at the EP4 receptor due to reduced activity of PGE2. Ohtani explicitly teaches the antagonism of EP4, which is activated by PGE2, in combination with an immune checkpoint inhibitor, for the treatment of liver cancer. The compound of Otsu is an mPGES-1 inhibitor, which would thus prevent production of PGE2 and activation of EP4. The artisan would recognize this, and have a reasonable expectation of success in applying this method as the activity of PGE2 on this receptor drives immunosuppression in certain cancers.
The 35 U.S.C. § 103 rejection of Claims 18, 19, and 21-26 over Otsu in view of Yoshida is maintained. Applicant argues that the method of Yoshida requires the use of an EP4-selective antagonist in their method, while the compounds of the examined application have much broader activity than only inhibiting the EP4 receptor. Thus, there would be no motivation to modify the method of Yoshida by substituting a highly selective antagonist for a compound with less specific activity towards EP4. The Examiner disagrees. PGE2 is the primary ligand of EP4, and the antagonism of this receptor ablates the activity of PGE2. By targeting upstream of the EP4 receptor (inhibition of the production of PGE2), a similar result will be obtained, as this will result in less activity at the EP4 receptor due to reduced activity of PGE2. Yoshida explicitly teaches the antagonism of EP4, which is activated by PGE2, in combination with an immune checkpoint inhibitor, for the treatment of several cancers. The compound of Otsu is an mPGES-1 inhibitor, which would thus prevent production of PGE2 and activation of EP4. The artisan would recognize this, and have a reasonable expectation of success in applying this method as the activity of PGE2 on this receptor drives immunosuppression in certain cancers.
The 35 U.S.C. § 103 rejection of Claims 18, 19, and 21-26 over Otsu in view of Kim is withdrawn. Applicant argues that Kim does not demonstrate that inhibition of mPGES-1 results in a decrease in the expression or activity of PD-L1, thus there would be no motivation to combine the mPGES-1 inhibitor with an immune checkpoint inhibitor. The Examiner agrees, and finds this argument persuasive.
Claim Rejections - 35 USC § 112(a)- REJECTIONS MAINTAINED
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 18, 19, 21, 22, 24, and 25 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 cancers associated with elevated expression or activity of mPGES-1 or levels of PGE2, does not reasonably provide enablement for treatment of all instances of the claimed cancers. 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 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 for the treatment of cancer, comprising administering an mPGES-1 inhibitor and immune checkpoint inhibitor in combination to a subject in need thereof, wherein the mPGES-1 inhibitor is selected from one of two compounds, wherein the cancer is selected from a large group of non-specific forms of cancer. Thus, the claims are directed to a method of treating cancer by administering an mPGES-1 inhibitor with an immune checkpoint inhibitor.
The state of the prior art and the predictability or unpredictability of the art:
Wang (Trends Mol. Med., 2015 Dec 17; 22(1): 1-3) provides a review of the involvement of PGE2 in cancers, with PGE2 being the prostaglandin produced by mPGES-1. Tumor-associated inflammation can create an immunosuppressive environment, allowing tumor cells to escape immunosurveillance. Clinical and epidemiologic evidence indicates that chronic inflammation is a risk factor for several malignancies, including esophageal, gastric, hepatic, pancreatic, and colorectal cancer. Clinical and epidemiological evidence has documented evidence that the use of NSAIDS has beneficial effects on reducing the metastasis and mortality of various solid tumors, and this is thought to be primarily due to the reduction of prostaglandins by inhibition of the activity of cyclooxygenase enzymes. COX enzymes are responsible for the production of five prostaglandin, including PGE2. PGE2 is the only prostaglandin that has been shown to play a role in promoting tumor formation, progression, and metastasis by acting directly on tumor cells and tumor stromal cells. The mechanisms underlying the effects of PGE2 on cancer development remain elusive. Currently, it is believed that PGE2 promotes tumor growth by evading immune attack, promoting a shift from Th1 to Th2 immune responses, defective antigen-presenting cell infiltration and function, impaired cytotoxic activity of CD8+ T-cells and natural killer cells, and enhancement of immunosuppressive cells. PGE2 secretion from colorectal carcinoma cells, for example, has been reported to induce macrophage production of pro-inflammatory cytokines and chemokines. Macrophages are highly plastic and can be activated via a classical pathway to M1 macrophages with elevated expression of IL-12, TNFα and MHCII (Th1 response), or alternatively, to M2 macrophages, expressing high levels of IL-10, IL-4, and IL-13 (Th2 responses). In most cancers, tumor-associated macrophages resemble an M2-like phenotype, and are a major component of the leukocytic tumor infiltrate. Genetic deletion of PGE2 in mouse melanoma, breast, or colorectal cancer facilitated a shift toward the classic M1 pathway, indicating that PGE2 can promote tumor growth by inhibiting the accumulation of conventional dendritic cells into tumors, and suppressing tumor-infiltrating dendritic cell activation. PGE2 has also been reported to promote tumor progression by inducing the differentiation of myeloid-derived suppressor cells from bone marrow myeloid progenitor cells and enhancing immune suppression, indicating that PGE2 can shift from anti-tumor to immunosuppressive responses within the tumor microenvironment. While there is evidence of elevated PGE2 in several types of cancer, not all forms of cancer display these characteristics. Expression of PTGES (the gene regulating mPGES-1) is found to be elevated in several types of cancer, including lung adenocarcinomas. However, other forms of cancer such as glioblastoma do not display significantly elevated expression of this protein. In view of this, inhibition of mPGES-1 would not be expected to provide a predictable treatment for this cancer, or others which do not overexpress mPGES-1 (Human Protein Atlas, PTGES Expression, https://web.archive.org/web/20170308032659/https://www.proteinatlas.org/ENSG00000148344-PTGES/cancer). Moreover, the concept of a universal treatment for all forms of cancer is not supported in the current field of oncology. Beat Cancer Now (Why No Universal Cure For Cancer Exists Yet: A Comprehensive Exploration, https://web.archive.org/web/20250710124955/https://beatcancernow.co.uk/why-no-universal-cure-for-cancer-exists-yet-a-comprehensive-exploration/) describes why a panacea does not exist for cancer. Cancer emerges from within, making it far more difficult to detect and eliminate without harming healthy tissue. Further, there is no single disease called “cancer”. Instead, the term encompasses over 200 distinct types of malignancies, each with its own biological characteristics, rate of progression, and patterns of metastasis. Even within a single type (such as breast cancer), multiple molecular subtypes respond differently to therapy. This biological diversity is a major hurdle to developing a one-size-fits-all cure. The effectiveness of anti-cancer drugs vary widely, with outcomes depending on the tumor type, stage, genetic mutations, and overall health of the patient. The individual variation of each tumor demands personalized approaches rather than a single universal drug; two patients with what appear to be the same type of lung cancer may have vastly different genetic mutations and responses to treatments. Further, the underlying cause of each type of cancer cannot be linked to aberrant activity of mPGES-1, or increased levels of PGE2.
The relative skill of the artisan:
The artisan would likely have an advanced degree in medicine or oncology, and the treatment of various cancer; 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 elevated levels of mPGES-1 or increased PGE2. Further, there is yet to be evidence within the field of oncology of a therapeutic which can be used as a panacea for cancer.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification provides data demonstrating that these compounds inhibit mPGES-1 (Test Example 1, Paragraph 0074). Test example 2 (Paragraph 0075) demonstrates inhibition of PGE2 and PGF2α production in A549 lung cancer cells. Test Example 3 (Paragraph 0078) demonstrates the effect of an mPGES-1 inhibitor and immune checkpoint inhibitory drug in combination in an allograft model of mouse colorectal cancer cell line CT26. Thus, the specification enables the treatment of cancers wherein mPGES-1 is implicated. However, the specification does not provide any working examples demonstrating the treatment of cancers which do not display elevated expression of mPGES-1.
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.
Claim Rejections - 35 USC § 103- REJECTIONS MAINTAINED
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 18, 19, 21, 22, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Otsu (US 2014/0221339; Publication Date: 7 August 2014) in view of Prima (Proceedings of the National Academy of Sciences, 2017, 114, 5, 1117-1122), Sasaki (Oncogene, 2012, 31, 2943-2952), and Nakanishi (Cancer Research, 2008, 68, 9, 3251-3259).
Ostu (See IDS, 12 September 2022) teaches novel heterocyclic derivatives or salts thereof. The compounds of the invention have potent mPGES-1 inhibiting activity and is useful as an agent for the treatment or prevention of a disease, such as malignant tumors (Abstract). One compound of the invention is Compound 11
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(Page 62). This compound is identical to the claimed compound (N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide)). Compound 11 has an IC50 against mPGES-1 of 6.6 nM, and in A549 cells, has a PGE2 production inhibition IC50 of 12.9 nM (Table 15, Page 105). These data provide a rationale for selecting this compound as a mPGES-1 inhibitor, and provide a reasonable expectation of success for utilizing this compound in methods to inhibit mPGES-1 for the treatment of cancer. Claim 18 further claims a method of treating colon cancer, breast cancer, lung cancer, or prostate cancer, comprising administering a compound of the invention.
Otsu does not teach the use of the mPGES-1 inhibitor in conjunction with an immune checkpoint inhibitor for the treatment of cancer.
Nakanishi (See IDS, 12 September 2022) evaluated the chemopreventive efficacy of targeting mPGES-1 which is responsible for generating PGE2 in two murine models of intestinal cancer. Genetic deletion of mPGES-1 resulted in marked and persistent suppression of intestinal cancer growth by 66%, while suppression of large adenomas was almost 95%. MPGES-1 deletion reduced the size and number of preneoplastic aberrant crypt foci in a model of colon cancer. The data show the feasibility of targeting mPGES-1 for cancer chemoprevention with the potential for improved tolerability over traditional NSAIDs and COX-2 inhibitors.
Sasaki (See IDS, 12 September 2022) showed the pro-tumorigenic role of mPGES-1 in colorectal cancer carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks. The growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout mice. These findings suggest that inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.
Otsu, Nakanishi, and Sasaki fail to teach the use of immune checkpoint inhibitors in combination with mPGES-1 inhibition.
Prima (See IDS, 12 September 2022) that co-culture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow derived myeloid cells. Tumor induced expression of PD-L1 was limited to F4/80+ macrophages and Ly-6C+ myeloid-derived suppressor cells. These PD-L1 expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor infiltrating PD-L1+ cells isolated from tumor-bearing mice exerted morphology of tumor-associated macrophages and expressed high levels of the PGE2 forming enzyme mPGES1. Inhibition of mPGES1 or genetic overexpression of the PGE2-degrading enzyme 15-PGDH resulted in reduced PD-L1 expression. The results demonstrates that the COX2/mPGES1/PGE2 pathway is involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells, and therefore, reprogramming of PGE2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in the host.
Otsu, Prima, Sasaki, and Nakanishi are considered analogous to the claimed invention as all are involved in the treatment of cancer through targeting of mPGES-1. 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 utilize the mPGES-1 inhibitor of Otsu in combination with an immune checkpoint inhibitor for the treatment of cancer as Prima demonstrated that mPGES-1 is directly linked to the induction of PD-L1 in tumor-associated macrophages, which are immunosuppressive, and by inhibiting mPGES1 or increasing degradation of PGE2, there is a reduction in PD-L1 expression. The artisan would have a reasonable expectation of success in performing this combination as the compound of Otsu is a potent mPGES-1 inhibitor, and the data provided by Sasaki and Nakanishi indicate that inhibition of mPGES-1 is a viable treatment for certain cancers. The use of the compound of Otsu in combination with an immune checkpoint inhibitor for the treatment of cancer is prima facie obvious as the prior art teaches that mPGES-1 is linked with immunosuppression through elevated expression of PD-1 and PD-L1. The art demonstrates that inhibition or knockdown of this enzyme results in reduced expression of these immune checkpoint markers. It then flows from the art that, with a reduction in immunosuppression, that immune checkpoint inhibitors would be more effective at treatment of cancer, and the artisan would recognize this, arriving at the claimed invention.
Regarding Claims 21, 22, 24 and 25, none of the cited references explicitly teach the use the specific immune checkpoint inhibitors which are claimed. However, the artisan would recognize that using these inhibitors, such as an anti-PD-1 or anti-PD-L1 antibody, would be effective as serving as an immune checkpoint inhibitor in view of the teachings cited above. The selection of the specific inhibitor is prima facie obvious art recognized suitability for an intended purpose (See MPEP § 2144.07). The materials which are claimed are known in the art to be immune checkpoint inhibitors, and the artisan would recognize this. In view of the cited teachings, the artisan would have a reasonable expectation of success in the use of each inhibitor as the compound of Otsu is a potent inhibitor of mPGES-1, while Prima demonstrates the direct link between mPGES-1 expression/activity and immune checkpoint molecules. It thus flows from the art that the use of these inhibitors in combination with the compound of Ostu would result in an improved method for the treatment of cancer. Further, the combination of the known mPGES-1 inhibitor, with an immune checkpoint inhibitor is prima facie obvious combining equivalents known for the same purpose (See MPEP § 2144.06 I). The mPGES-1 inhibitor of Otsu is known to be useful for the treatment of cancer, with Prima showing that mPGES-1 is linked to induction of PD-L1 in TAMs. As immune checkpoint inhibitors are known to be useful for the treatment of cancer, a combination therapy of immune checkpoint inhibitors with an mPGES-1 inhibitor would be prima facie obvious.
Claims 18, 19, 21, 22, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Otsu (US 2014/0221339; Publication Date: 7 August 2014) in view of Ohtani (US 2018/0125832; Publication Date: 10 May 2018).
The teachings of Otsu are described above and fully incorporated into this rejection.
Otsu does not teach the use of the mPGES-1 inhibitor in conjunction with an immune checkpoint inhibitor for the treatment of cancer.
Ohtani discloses a prostaglandin E2 receptor 4 (EP4) antagonist useful in the treatment of nonalcoholic steatohepatitis (NASH)-associated liver cancer. This method may include a pharmaceutical composition comprising the EP4 antagonist, and may may include one or more other active agents and/or therapies (Abstract). The role of the EP4 receptor in liver cancer has recently been reported. PGE2/EP4 receptor signaling upregulated c-Myc expression and resulted in promoting cell growth in HCC cells in vitro. PGE2 also promoted a hepatic stellate cell-induced myeloid-derived suppressor cell (MDCS) accumulation in invitro and in vivo experiments, simulating growth of liver cancer. The literature indicates that PGE2/EP4 signaling may have some role in liver cancer growth. Suppression of PGE2/EP4 receptor signaling alone or in combination with a PD-1 antibody restores CD8+ T-cell functional activity (Paragraph 0010). In certain embodiments, the methods provided herein comprise administering the compounds of the invention in combination with one or more second active agents. Examples of second active agents include immune checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, and other immune-oncological drugs targeting, for example, indoleamine 2,3-dioxytenase (IDO). Moreover, molecular-targeted anti-cancer drugs and cancer chemotherapeutics are also included as the second active agent. More particularly, the second active agents include, for example, PD-1 antibodies such as nivolumab, labrolizumab/pembrolizumab, REGE2810, PD-L1 antibodies, such as abelumab, atezolizumab, durvalumab, pembrolizumab, CTLA-4 antibodies such as ipilimumab and tremelimumab, molecular targeted drugs such as anti-HER2 antibody, anti-VEGF antibody, anti-EGFR antibody, tyrosine kinase inhibitors against EGFR receptor, PDGFR receptor, VEGFR receptor kinases, c-kit, and Bcr-Abl, and anti-tumor chemotherapeutics such as alkylating agents, microtubule inhibitors, hormonal therapeutics, platinum drugs, topoisomerase inhibitors, and humor therapeutics (Paragraph 109). Immune checkpoint inhibitor refers to a type of drug that blocks certain proteins made by some types of immune cells, such as T-cells, and some cancer cells. These proteins keep immune responses in check and can keep T cells from killing cancer cells. Examples of immune checkpoint inhibitors include, but are not limited to PD-1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, BTLA inhibitors, PD-L2 inhibitors, PD-L2 inhibitors, B7-1 inhibitors, B7-2 inhibitors, galectin-9 inhibitors, and HVEM inhibitors (Paragraph 0111).
Otsu and Ohtani are considered analogous to the claimed invention as all are involved in the treatment of cancer using compounds which modulate PGE2 signaling. 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 apply the mPGES-1 inhibitor of Otsu to the method of treating NASH-associated liver cancer as taught by Ohtani. The compounds of Ohtani are EP4 receptor antagonists; PGE2 is the primary ligand of EP4, and by antagonizing this receptor, the action of PGE2 is ablated. Ohtani describes the relationship between the action of PGE2, EP4, and immunosuppression, wherein suppression of PGE2 signaling on EP4 alone or in combination with an anti-PD-1 antibody results in increased CD8+ T-cell function. It flows from this teaching that by targeting upstream of the EP4 receptor by inhibiting the production of PGE2, a similar effect result. The use of the compound of Otsu in the methods of Ohtani is prima facie obvious substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); Ohtani teaches antagonism of EP4, which is activated by PGE2, in combination with an immune checkpoint inhibitor, as a method for treating cancer. The compound of Otsu is an mPGES-1 inhibitor, and would thus prevent production of PGE2 and activation of EP4. The artisan would recognize this, and have a reasonable expectation of success in applying this method as the activity of PGE2 on this receptor drives immunosuppression in certain cancers.
Regarding Claims 21, 22, 24, and 25, the combination of the known mPGES-1 inhibitor with an immune checkpoint inhibitor is prima facie obvious combining equivalents known for the same purpose (See MPEP § 2144.06 I). The mPGES-1 inhibitor of Otsu is known to be useful for the treatment of cancer, and immune checkpoint inhibitors are also known in the art of oncology to be useful for the treatment of cancer. As such, a combination therapy of two known anti-cancer agents for the treatment of cancer is prima facie obvious.
Claims 18, 19, 21, 22, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Otsu (US 2014/0221339; Publication Date: 7 August 2014) in view of Yoshida (US 2019/0255013; Publication Date: 22 August 2019).
The teachings of Otsu are described above and fully incorporated into this rejection.
Otsu does not teach the use of the mPGES-1 inhibitor in conjunction with an immune checkpoint inhibitor for the treatment of cancer.
Yoshida discloses a medicament comprising a compound of Formula (I) and an immune checkpoint inhibitor, which exhibits a strong anti-tumor effect and thus is useful for the treatment of cancer (Abstract). The compounds of the invention are antagonists of the prostaglandin EP4 receptor, whose primary ligand is PGE2 (Paragraph 0004, 0005, 0026). One embodiment of the invention is a compound according to the description, and an immune checkpoint inhibitor. The immune checkpoint inhibitor is an immune checkpoint molecule selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDO1, Arginase 1, TIGIT, and CD115 (Paragraph 0131). The methods of the invention are useful for the treatment of leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, stomach cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder/bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, corpus uteri cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cancer, renal pelvis/ureter cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, osteosarcoma/soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, and cancer of unknown primary (Paragraph 0135).
Otsu and Yoshida are considered analogous to the claimed invention as all are involved in the treatment of cancer using compounds which modulate PGE2 signaling. 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 apply the mPGES-1 inhibitor of Otsu to the method of treating cancer as taught by Yoshida. The compounds of Yoshida are EP4 receptor antagonists; PGE2 is the primary ligand of EP4, and by antagonizing this receptor, the action of PGE2 is ablated. The relationship between the action of PGE2, EP4, and immunosuppression is known in the art, wherein suppression of PGE2 signaling on EP4 alone or in combination with an anti-PD-1 antibody results in increased CD8+ T-cell function. It flows from this that by targeting upstream of the EP4 receptor by inhibiting the production of PGE2, a similar effect result. The use of the compound of Otsu in the methods of Yoshida is prima facie obvious substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); Yoshida teaches antagonism of EP4, which is activated by PGE2, in combination with an immune checkpoint inhibitor, as a method for treating cancer. The compound of Otsu is an mPGES-1 inhibitor, and would thus prevent production of PGE2 and activation of EP4. The artisan would recognize this, and have a reasonable expectation of success in applying this method as the activity of PGE2 on this receptor drives immunosuppression in certain cancers.
Regarding Claims 21, 22, 24, and 25, the combination of the known mPGES-1 inhibitor with an immune checkpoint inhibitor is prima facie obvious combining equivalents known for the same purpose (See MPEP § 2144.06 I). The mPGES-1 inhibitor of Otsu is known to be useful for the treatment of cancer, and immune checkpoint inhibitors are also known in the art of oncology to be useful for the treatment of cancer. As such, a combination therapy of two known anti-cancer agents for the treatment of cancer is prima facie obvious.
Conclusion
Claims 18, 19, 21, 22, 24, and 25 are rejected.
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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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625