EP4 INHIBITORS AND SYNTHESIS THEREOF

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 . Continued Examination Under 37 CFR 1.114 A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 25, 2026 has been entered. DETAILED ACTION 3. Claims 1 – 2, 14 – 15, 17 – 23, and 29 – 35 are pending in this application. Applicant’s Amendment and Remarks, filed March 25, 2026, is entered, wherein claim 1 is amended, claims 3 – 13, 16, and 24 – 28 are canceled, and claims 23 and 29 – 35 are withdrawn. Claims 1 – 2, 14 – 15, and 17 – 22 are examined on the merits herein. Priority 4. This application is a continuation of 17/258,527, filed January 7, 2021, which is a national stage application of PCT/US2019/041351, filed July 11, 2019, that claims benefit of provisional application 62/696,440, 62/737,250, and 62/834,525, filed July 11, 2018, September 27, 2018, and April 16, 2019, respectively. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: i. Determining the scope and contents of the prior art. ii. Ascertaining the differences between the prior art and the claims at issue. iii. Resolving the level of ordinary skill in the pertinent art. iv. Considering objective evidence present in the application indicating obviousness or nonobviousness. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 1 – 2, 14 – 15, and 17 – 22 are rejected under 35 U.S.C. 103 as being unpatentable over Nakao et al. (US6710054B2, cited in the previous Office Action mailed November 10, 2025). a. Regarding claims 1 – 2, 14 – 15, and 17 – 22, Nakao et al. teach an invention relates to aryl or heteroaryl fused imidazole compounds, pharmaceutical compositions, and the medical uses (Col. 1, lines 10 – 13). Nakao et al. teach the core structure of formula (I): PNG media_image1.png 184 188 media_image1.png Greyscale . Nakao et al. teach a species encompassed by formula (I): PNG media_image2.png 168 254 media_image2.png Greyscale with a name of 2-ethy-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine (Col.19, lines 40 – 42), which corresponds to claimed compound II. Nakao et al. also teach the general formula of formula (II): PNG media_image3.png 122 149 media_image3.png Greyscale with a specific example of: PNG media_image4.png 189 162 media_image4.png Greyscale . The exemplified compound differs from impurity compounds I-9 and I-10 in the position of Y2, Y4, and R1. However, Nakao et al. teach in formula (II) that the positions can be N, CH, and C1-8 alkyl, respectively (Col. 5, lines 8 – 35). The aryl or heteroaryl fused imidazole compounds of this invention have an antagonistic action towards prostaglandin and are thus useful in therapeutics, particularly for the treatment of a disorder or condition such as pain, fever, or inflammation associated disorder, wherein the disorder is a cancer (Col. 3, lines 20 – 24; line 35). Nakao et al. teach that the pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients (Col. 4, lines 66 – 67; Col. 5, lines 1 – 2). In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 95% by weight (Col. 87, lines 26 – 28). To yield the compound of formula (I), PNG media_image5.png 200 400 media_image5.png Greyscale is used as a reactant. Nakao et al. teach an example of synthesizing PNG media_image6.png 217 295 media_image6.png Greyscale , wherein 2-chloro-4,6-dimethyl-3-nitropyridine PNG media_image7.png 200 203 media_image7.png Greyscale is used (Col. 88, line 65). Nakao et al. also teach that modifications of the reactant can be made at the positions Y2 and Y4, wherein Y2 is N and Y4 is CH (Col. 5, lines 8 – 62; Col. 41, lines 55 – 65), which corresponds to the claimed impurity compound VII. The preparation of the compound of formula (I) also involves suitable solvents, such as water, acetonitrile (Col. 73, line 24), and inert solvent, such as ethyl acetate (Col. 70, lines 1 – 2). Moreover, Nakao et al. teach Scheme 20: PNG media_image8.png 490 353 media_image8.png Greyscale , wherein compound of formula 20-1 reacts with an appropriate acylating reagent to give a compound of formula 20-2, which corresponds to compounds C and D in S-4. Suitable acylating reagent includes an acid anhydride, such as acetic anhydride (Col. 79, lines 10 – 50). R1 in 20-2 and 20-3 may be C1-8 alkyl (Col. 1, line 62) and R20 may be NP, wherein P is a protecting group, such as Boc (Col. 80, line 63). The resulting amide compound of formula 20-2 may be cyclized to form compound of formula 20-3 or Ie-4 with a benzimidazole or imidazopyridine ring, which corresponds to compound B, in the presence of a base, such as sodium hydroxide with inert solvent, such as water (Col. 80, lines 25 – 33). The compound of formula Ie-4 may further react via deprotection: PNG media_image9.png 191 274 media_image9.png Greyscale as shown for obtaining the compound of formula 1e-5, which corresponds to compound A (Col. 38, lines 45 – 60). Nakao et al. further teach that that the compound of formula (1a) may be obtained via (Col. 26, lines 35 – 65): PNG media_image10.png 384 283 media_image10.png Greyscale , wherein R1a is hydrogen (Col. 68, line 34), which is the compound of formula 1e-5. Z may be 5 – 12 membered monocyclic aromatic ring substituted with C1-4 alkyl (Col. 2, lines 41 – 46). The claimed composition comprises compound II and the impurities in an unspecified amount. Under the broadest reasonable interpretation, the claims encompass any amount of one or more of the recited impurity compounds. There is no limitation on how much is present. The synthetic process for the impurity is also not limiting. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the exemplified compound of formula (I): PNG media_image2.png 168 254 media_image2.png Greyscale and the exemplified compound of formula (II): PNG media_image4.png 189 162 media_image4.png Greyscale with the modification of Y2 is N; Y4 is CH; and R1 is C1-8 alkyl as taught by Nakao et al. to treat the same disease because Nakao et al. teach that the aryl or heteroaryl fused imidazole compounds of this invention may be used to treat cancer. It would have been obvious for one of ordinary skill in the art to do this because both species of formulae (I) and (II) are fused imidazole compound that are known in the prior art for the purpose of treating disorder, such as cancer, and it would have been obvious to combine them to treat the same disease. It would also have been obvious to modify formula (II) because the substituents are known in the art and the modification will still yield a compound for the same purpose. Nakao et al. teach the claimed synthesis of compound II, which includes acylation, cyclization, deprotection, and coupling. For the limitation “propionyl protecting reagent”, which later being specified as “propionic acid anhydride”, it would have been obvious to substitute the acetic anhydride as taught by Nakao et al. with propionic acid anhydride because it has long been established that this type of difference, which is varying the size of a chain, constitutes a form of homology, and is a fact of a very close structural similarity, rendering the homolog obvious. Nakao et al. teach that the compounds of this invention may present at a concentration of 5% by weight. Based on the suggestion, one would have performed routine experimentation to discover the best therapeutically-effective concentration of these compounds of the invention for optimal treatment characteristics. Nakao et al. teach to use 2-chloro-4,6-dimethyl-3-nitropyridine as the reactant when synthesizing PNG media_image6.png 217 295 media_image6.png Greyscale . It is expected that the reactant would be modified to PNG media_image11.png 86 100 media_image11.png Greyscale with Y2 is N and Y4 is CH for the synthesis of PNG media_image2.png 168 254 media_image2.png Greyscale . For the limitations of claims 18 – 21, Nakao et al. teach that the reactant used to yield the compound of formula (I), water, ethyl acetate, and acetonitrile are used in the preparation of the compounds. It would have been obvious to include a residual amount of reactant and solvent remaining from the synthesis, since such reactant and solvents are used in preparing the claimed compound, and one of ordinary skill in the art would recognize that trace or small amounts may remain in the final product without affecting its pharmaceutical properties. One would also have performed routine experimentation to control the residual solvent and reactant content to meet purity standards. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine the compound of formula (I) and formula (II) as taught by Nakao et al. to treat the same disease because it is well known to combine drugs to treat the same disease, and further Nakao et al. teach that the compound of formula (I) can be used in combination with other drugs. Responses to Applicant’s Remarks: Applicant’s Remarks, filed March 25, 2026, have been fully considered and are found to be not persuasive. In the last response, Applicant argues that the synthetic route to obtain compound II in the present application is via the BOC protection route, but Nakao et al. teach the sodium azide route. Applicant further explains that the BOC protection route is adopted for the preparation of compound A and utilizes compound B as a key synthetic intermediate. Applicant argues that the sodium azide route does not suggest or predict to produce impurity compounds I-1, I-2, I-9, or I-10 because these four impurities come from the ring closure reaction of compound D to compound B. The argument is not persuasive. The modified rejection based on Nakao et al. clearly demonstrates that the claimed compound II may be produced via the BOC protection route. As discussed above, there is no limitation on how much the impurity is present and they synthetic process for the impurity is not limiting. Therefore, the rejection over Nakao et al. render the claimed invention obvious. Conclusion No claim is found to be allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached Monday - Thursday 7:30 - 17:30. 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, SCARLETT GOON can be reached at 571-270-5241. 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