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 .
Status of the Claims
The amendment filed on 04/09/2026 has been entered. Claims 1, 6-7 and 17 have been amended and claim 8 has been canceled. Claims 1-7 and 9-18 are currently pending, claim 17 has been withdrawn from further consideration and claims 1-7, 9-16 and 18 are under examination.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7, 9-16 and 18 in the reply filed on 04/19/2026 is acknowledged.
Claim Objections
Claims 4-7 are objected to because of the following informalities: the claims recite an improper Markush group, “selected from the organic phase” (claim 4) and “selected from phosphazene” (claims 5-7). A Markush group should recite a list of alternatives to define a limitation, for example "a material selected from the group consisting of A, B, and C" or "wherein the material is A, B, or C" (MPEP 2173.05(h)). However, the claims recite only one element and appropriate correction is required.
Claims 3-7, 10, 12, and 14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 102
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 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 1-2, 9 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Patent number US4,453,017A (US’017; cited in IDS 10/20/2023) as evidenced by OrgChemData (Organic Chemistry Data, pages 1-10; Sep. 7, 2001).
Regarding claims 1, 9, and 11, US’017 teaches processes for alkylating compounds with hydroxy group/s with trimethyl phosphate as the alkylating agent in the presence of sodium, potassium, magnesium or calcium carbonate as an inorganic base to produce the alkylated products.
The conjugate acid of the carbonates is bicarbonate (HCO-3) and as evidenced by OrgChemData the pKa of the bicarbonate is 10.3 in water (page 1).
Regarding claim 2, the reference teaches in the examples using purification processes to obtain pure methylated products.
Claims 1, 9, 11, 13 and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jordis (Jordis, U. et al. “Synthesen neuer Chinolon-Chemotherapeutika, 1. Mitt.: Pyridochinoline und Pyridophenanthroline als,,lin-benzo-Nalidixinsäure"-Derivate” Monatshefte fűr Chemie 119, 761-780 (1988)) as evidenced by OrgChemData (Organic Chemistry Data, pages 1-10; Sep. 7, 2001).
Regarding claims 1, 9, 11, Jordis teaches a process for alkylating a carboxyl group of compound 5 with (EtO)3PO as the alkylating agent in the presence of K2CO3 as an inorganic base to produce the alkylated product 9 (Table 1 and page 773).
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Machine translation:
Alternatively, 9 was obtained by alkylation of 5, analogous to the procedure for the synthesis of 14, in 34% theoretical yield.
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The conjugate acid of K2CO3 is bicarbonate (HCO-3) and as evidenced by OrgChemData the pKa of the bicarbonate is 10.3 in water (page 1).
Regarding claims 13-14, compound 5 contains both carboxyl group and nitrogen atom (amine group), and alkylation produces 9 at 34%, wherein both carboxyl group and nitrogen atom are alkylated. The reference is silent that the production ratio of product by alkylation of carboxyl group and alkylation of the nitrogen atom is 1.5 or more. However, since the reference teaches every limitation of the claim steps and the alkylation of both carboxyl group and nitrogen atom produces compound 9 only at 34% yield, the remaining part of the product mixture would necessarily contain products wherein the production ratio of product by alkylation of carboxyl group and alkylation of the nitrogen atom is necessarily 1.5 or more.
Claims 1-2, 9 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Badaway (Badaway, E. et al. “Benzimidazole condensed ring system. IX. Potential antineoplastics. New synthesis of some pyrido[l,2-albenzimidazoles and related derivatives” Eur J Med Chem (1995) 30,327-332) as evidenced by OrgChemData (Organic Chemistry Data, pages 1-10; Sep. 7, 2001).
Regarding claims 1, 9, 11, Badaway teaches a process for alkylating a hydroxy group of compounds 3a,3b with trimethyl phosphate as the alkylating agent in the presence of sodium carbonate as an inorganic base to produce the alkylated product 7 (Scheme 1 and page 330, 2nd col.).
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The conjugate acid of sodium carbonate is bicarbonate (HCO-3) and as evidenced by OrgChemData the pKa of the bicarbonate is 10.3 in water (page 1).
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Regarding claim 2, the reference teaches that after cooling and addition of water, the product was filtered and dried (page 330, 2nd col.).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Patent number US4,453,017A (US’017; cited in IDS 10/20/2023) as evidenced by OrgChemData (Organic Chemistry Data, pages 1-10; Sep. 7, 2001).
The teachings of US’017 as evidenced by OrgChemData have been set forth above.
Regarding claims 15-16, US’017 fails to exemplify a method for producing a compound constituting a compound library and wherein a mixture containing 10 or more compounds is produced. However these are obvious for reasons set forth below.
US’017 teaches in a nonexemplified embodiment that the phenols than can be alkylated are monohydric phenols as phenol and o-, m- and p-cresol and guaiacol; phenolic aldehydes such as protocatechualdehyde, vanillin, syringaldehyde, p-hydroxybenzaldehyde and 5-formylvanillin; phenolic ketones such as p-hydroxyacetophenone, acetovanillone, acetosyringone, acetamidophenol; and phenolic acids such as vanillic acid, syringic acid and p-hydroxybenzoic acid.
Regarding claim 15, a skilled artisan would thus have been motivated to conduct alkylation reaction for each of these phenolic compounds as a parallel synthetic approach using a compound library of the phenolic compounds and would have a reasonable expectation of success to rapidly obtain a library of methylated products.
Regarding claim 16, combining the above phenolic compounds and conducting the alkylation process, a skilled artisan would have a reasonable expectation of success in obtaining multiple methylated products. In accordance to MPEP § 2143, the Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham and discussed circumstances in which a patent might be determined to be obvious. In this case, at least prong (A) Combining prior art elements according to known methods to yield predictable results applies.
It would thus have been prima facie obvious to a skilled artisan before the effective filing date the of the instant invention to method for producing a compound having an alkylated acidic functional group, the method comprising reacting, in a mixture containing two or more compounds having an acidic functional group as substrates, the compounds with an alkylating agent selected from compounds represented by formula A in the presence of a base to alkylate the acidic functional group, wherein the base is a base selected from the group consisting of an organic base whose conjugate acid has a pKa of 23 to 34 in acetonitrile and an inorganic base whose conjugate acid has a pKa of 9 to 20 in water, and wherein the method for producing a compound constituting a compound library, and wherein a mixture containing 10 or more compounds is produced in view of the teachings of US’017.
Citation of Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Fevig (Fevig, J. M. ”Trimethyl Phosphate” e-ERPS 2001, pages 1-3) alkylation of a compound with dicarboxylic acid groups with trimethyl phosphate as the alkylating agent and NaOH as the inorganic base.
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The conjugate acid of NaOH is H2O and as evidenced by OrgChemData the pKa of the H2O is 14.0 (page 1).
Allowable Subject Matter
The subject matter of claims 3-7, 10, 12, and 14 is free of prior art reference. The closest references have been set forth above.
Regarding claim 3, the base used in the above references, potassium carbonate, sodium carbonate and sodium hydroxide are barely soluble in DMF. For example, as reported by Forryan (Forryan, C. L. et al. “Heterogeneous Kinetics of the Dissolution of an Inorganic Salt, Potassium Carbonate, in an Organic Solvent, Dimethylformamide” J. Phys. Chem. B 2005, 109, 8263-8269), the solubility of potassium carbonate in DMF is 2-3 ppm at room temperature (page 8267, 1st col.), which is equivalent to 1.89-2.83 mg/mL and much lower than the claimed solubility.
Regarding claims 4-7 and 10, none of the above references teach or even suggest modifying the base to the claimed organic base or phosphazene.
Regarding claims 12 and 14, there is no teaching in any of the references where the substrate contains one or more compounds containing a phenolic hydroxy group as the acidic functional group and a nitrogen atom that can be alkylated, and in the compound having a nitrogen atom in which alkylation proceeds most among the substrate, a production ratio of products by alkylation of the phenolic hydroxy group (alkylation A) and alkylation of the nitrogen atom (alkylation C), (alkylation A/alkylation C), is 1.5 or more. In fact, Badaway teaches alkylation of both amine group and hydroxy group in compounds 3a,b to obtain compound 7 (see below), but the hydroxy groups of compounds 3a,b are not phenolic hydroxy groups. Furthermore, one would not modify these compounds to containing a phenolic hydroxy group as required by the instant claimed
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In view of the foregoing, the claims 3-7, 10, 12, and 14 are deemed novel and unobvious over the closest prior art references.
Conclusion
Claims 1-2, 9, 11, 13, 15-16 and 18 are rejected and no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEDHANIT W BAHTA whose telephone number is (571)270-7658. The examiner can normally be reached Monday-Friday 8am-5pm.
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/MEDHANIT W BAHTA/ Primary Examiner, Art Unit 1692
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