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 .
DETAILED ACTION
This office action is in response to the Response to Election/Restriction filed 29 July 2026 for application 18/634,246 filed 12 April 2024. Claims 24-51 are new. Currently, claims 24-51 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 29 July 2026 was filed after the mailing date of the application on 12 April 2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because three of the structures, possibly the same structure, are not well-resolved (i.e. too blurry). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 29 July 2026 is acknowledged. The traversal is on the ground(s) that Group II is materially related to the subject matter of Group I as Group II recites a process that utilizes Compound 4b, while Group I recites a process for preparing Compound 4b and its precursor Compound 4a. Thus, the process of Group I produces an intermediate that is directly used in the process of Group II The moiety prepared according to the Group I process forms part of Compound 8, which is the product prepared by the Group II process…as Compound 4b contributes a defined structural portion of Compound 8, the subject matter of Groups I and II do overlap in scope and are capable of being utilized together. Thus, the related groups are indistinct.
This is not found persuasive because while the products are understood to be precursors of other Groups, the methods of preparation are still distinct. As the claims are method claims (except for claims 50 and 51) and not composition claims, the relationship between Groups in terms of the compounds produced/used has less standing in determining distinction. Furthermore, as an example, the product of Group I, Compound 4b, has several commercial sources (52 according to SciFinder©) including Aaron Chemicals ((S)-3bromo-2-(1-methoxyethyl)pyridine, aaronchem.com/prod/2641451-44-5) which lists the compound to be available in a range of 250 mg ($4.00) to 500 g ($1,030). This belies the notion that the method of Group II is intrinsically dependent on the product of Group I as very economically viable sources are readily available.
The requirement is still deemed proper and is therefore made FINAL.
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 non-obviousness.
Claims 24-26 and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Aggen et al. (RAS inhibitors, US 2021/0130326 A1, 2021) in view of Yang et al. (Efficient reduction of aromatic ketones with NADPH regeneration by using crude enzyme from Rhodotorula cells and mannitol as cosubstrate, Biochemical Engineering Journal 2008, 42, 1-5).
Aggen discloses conversion of 3-bromo-2-acetylpyridine to 3-bromo-(2-hydroxy)-(S)-2-ethylpyridine alcohol (pg. 204, left col.).
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They do not, however, teach this conversion through the use of a ketoreductase enzyme.
This deficiency is rectified by Yang who teaches an enzyme-coupled system containing a ketoreductase for prochiral ketones reduction and mannitol dehydrogenase for NADPH regeneration. This was used to reduce several aryl and pyridyl ketones including 2-acetylpyridine, compound 1a illustrated below, in a reaction system that utilized a 100 mM NaHCO3-Na2CO3 buffer system to maintain the system at pH 9.0.
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Optimal reaction conditions, shown in table 2 on pg. 4 and illustrated below, gave yields of compound 1a of 96.8% with <99% ee of the S-isomer:
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There are two apparent motivations to choose enzyme reduction over metal-catalyzed reduction as disclosed by Aggen. First is the removal of the metal catalyst, which may be cost prohibitive to use and will have to be removed within safety margins before issuance of the final product. Second, as Yang teaches, the use of isolated enzymes is advantageous because the undesired enantiomer formed by contaminating ketoreductases is minimized, with enantioselectivities achieved potentially better than chemical reduction means (pg. 1 – introduction). Since enzyme-catalyzed reactions are, by their nature, highly chemo- and enantio-selective, a person of ordinary skill in the art, as a creative entity, could consider applying the enzymatic ketoreduction method to the bromo substrate of Aggen with a reasonable expectation of success.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of ketoreductases in the production of compound 4a in the interest of toxicity safety, ease of production, and scale of compound needed.
Regarding the limitations of claim 25 are met as Aggen discloses methylation of compound 4a using methyl iodide as the methyl source to form compound 4b, illustrated below (pg. 204, left col.):
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Concerning the limitations of claim 26 are met as Aggen uses methyl iodide as the methyl source and sodium hydride as a base (pg. 204, left col.).
Pertaining to the limitations of claim 28 are met as Yang teaches the use of NADPH in the presence of mannitol dehydrogenase and crude ketoreductase from Rhodotorula sp. AS2.2241 in a NaHCO3-Na2CO3 buffer system.
With regards to the limitations of claim 29 are met as Aggen uses methyl iodide as the methyl source (pg. 204, left col.).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Aggen and Yang as applied to claims 24-26 and 28-29 above, and further in view of Mealy et al. (Effect of ligand structure on the asymmetric cyclization of achiral olefinic organolithiums, J. Org. Chem. 2004, 69, 18, 6042-6049).
Aggen discloses the methylation of secondary alcohol compound 4a with methyl iodide to give ether compound 4b.
They do not, however, utilize potassium tert-butoxide as the base.
Mealy addresses this paucity by teaching the use of potassium tert-butoxide as the base in the methylation of a secondary alcohol using methyl iodide as the methylating agent (pg. 6047 – procedure B):
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As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of other non-nucleophilic bases such as sterically bulky potassium tert-butoxide for deprotonation of the secondary alcohol if bases such as sodium hydride were not available.
Summary
Claims 24-29 are rejected under 35 U.S.C 103. Claims 30-51 are withdrawn.
Conclusion
Claims 24-29 are rejected. Claims 30-51 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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