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
Claim Status
Claims 1-9 are pending. Claims 1-9 are under examination. Claims 1-9 are rejected. No claims allowed.
Filing Receipt
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Note: a new filing receipt confirming the approved power of attorney filed 09/19/2025 is not of record.
Response to Amendments/Arguments
Applicant's amendments and arguments filed 09/19/2025 are acknowledged and
have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below in original or modified form is herein withdrawn.
The obvious non-statutory double patenting rejection of claims 1-9 over US patent 11,999,757 is withdrawn. The terminal disclaimer filed 09/19/2025 has overcome the rejection.
The following maintained 103 rejection constitutes the complete set of rejections and/or objections presently being applied to the instant application.
Response to Arguments
Applicant's arguments filed 09/19/2025 have been fully considered but they are not persuasive.
Applicant argues
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Examiner’s response:
The above interpretation of Karame “at best teaches a compound 2 where n is 3, 4, 6, 7” artificially limits the teachings of Karame. If applicant’s interpretation of the teachings of Karame are true, the making of a compound 2 wherein n is 5, 8, 9, and so on, would have been precluded. As argued in the non-final mailed 05/21/2025 page 4, Karame et al. broadly teach the β-hydroxy esters are available by reaction of the dianion of ethyl acetoacetate with alkyl iodides (p. 1068). Herein, Karame et al. does not restrict the making of other beta hydroxy esters but insists beta hydroxy esters are available and broadly opens the door by teaching one of the reactants being alkyl iodides. As to why one would preclude n being 5, 8, 9, and so on is not understood. At best, it appears Karame et al. teaches examples where n is 3, 4, 6, 7 in Scheme 3, p. 1070.
As is known in the MPEP preferences/examples are not a teaching away.
See MPEP 2123 II. “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” Thus Scheme 3 of Karame et al. are examples of Scheme 1.
With this logical argument n would necessarily include 5, 8, and 9. Additionally, Karame et al. intended, contrary to applicant’s limiting assertion, to have included integers of n outside of the examples in Scheme 3 wherein compound 2 has n values greater than 7. Moreover, as argued in the non-final mailed 05/21/2025 page 4, Karame et al. “broadly teach the B-hydroxy esters are available by reaction of the dianion of ethyl acetoacetate with alkyl iodides (P. 1068).
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The ethyl ester of current compounds (A) and (B) are represented in the above Scheme 1 when n is 2 and x is Cl”.
Additionally, it was argued in the original rejection, “the ordinary artisan would have generated the ethyl ester of the current compound (B) from (A) because Karame et al. teach a Markush group that encompasses the ethyl ester of the current compound (p. 1068). See immediately below. Note: when variable n is two and variable x is Cl, the ethyl ester of the current compound (B) is present, or at least a racemic mixture thereof”.
Applicants arguments do not persuasively conclude that the variable n in Scheme 1 cannot include 2 or for that matter other integers. With the broad teaching of Scheme 1 not being limited by Scheme 3, the variable n in Scheme 1 includes the number 2 as argued in the rejection of record. To limit the variables of n in Scheme 1 with those of Scheme 3 is an interpretation that severely limits the genus of alkyl iodides taught by Karame et al. and nowhere in Karame et al. is there instruction that Scheme 3 limits the variables in Scheme 1.
Concerning the unpredictability in the chemical arts and therefore the change in the functional group may result in significant change of the resulting compound’s property, applicant utilizes the phrase “may result”. This phrase does not denote an absolute, and is not substantiated with evidence.
Concerning Noyori not remedying the deficiencies of Karame, the deficiencies of Karame were argued to be unsubstantiated. Thus, the compounds in Noyori were not needed to be modified to arrive at the instant compounds.
Concerning Sotoguchi not remedying the deficiencies of Karame and Noyori, the deficiencies of Karame and Noyori were argued to be unsubstantiated. Thus, the compounds in Sotoguchi were not needed to be modified to arrive at the instant compounds.
For the reasons stated above the obviousness rejection is being maintained as
set forth below.
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.
Claim(s) 1-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Karame et al (Highly Enantioselective Hydrogenation of β-Alky and β-(ω-Chloroalkyl) Substituted β-Keto Esters, Synthetic Communications, 37, pp. 1067-1076, Published 2007), Noyori et al. (Asymmetric Hydrogenation of β-Keto Carboxylic Esters. A Practical, Purely Chemical Access to β-Hydroxy Esters in High enantiomeric Purity, J. Am. Chem. Soc., 109, p. 5856-5858, published 1987) and Sotoguchi et al. (USPGPub 2003/0105341, Published 06-2003). The above NPL’s can be found in the IDS filed 06/25/2024.
The instant claims are generally drawn to…
Scope of the Prior Art
Karame et al. teach preparation of ethyl ester homologs of current compound (B) via the reduction of the respective β-keto ethyl esters. The reductions can be catalyzed with ruthenium BINAP catalysts. See Karame et al. pages 1068-1070, Table 1, Schemes 1-3.
Karame et al. broadly teach the β-hydroxy esters are available by reaction of the dianion of ethyl acetoacetate with alkyl iodides (p. 1068).
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The ethyl ester of current compounds (A) and (B) are represented in the above Scheme 1 when n is 2 and x is Cl.
Karame et al. teach the β-hydroxy esters are important building blocks for the synthesis of biologically active compounds and natural products (p. 1068, top of page.).
Karame et al. teach Ru[(R)-BINAP]Cl2 catalyst being active in the above hydrogenation (p. 1070). This catalyst reads on variable current variable X1 being Cl.
Ascertain the Differences
Karame et al. does not teach the t-butyl protecting group nor the specific catalysts of claims 1 and 7.
Secondary References
Noyori et al. teach a methyl, ethyl and t-butyl β-keto esters being reduced to the equivalent β-hydroxy esters utilizing ruthenium Br2/Cl2[(S/R)-BINAP] catalysts (Table I., p. 5857). Although the catalysts taught by Noyori et al. are not the current catalyst, this teaching establishes t-butyl as a protecting group utilized in the current chemistries.
Noyori et al. goes on to teach broad success with the use of asymmetric catalytic hydrogenation for production of optically active β-hydroxy esters:
“Thus, synthetic organic chemists no longer must envy bakers' yeast to effect stereoselective reduction of β-keto esters. The hydrogenation method is clean, operationally simple, economical, and hence is capable of conducting large-scale production of optically active β-hydroxy esters. A wide range of hydroxy esters of either chirality sense is available in high enantiomeric purity” (p. 5857).
Additionally, the teachings of Noyori et al. overlap with Karame et al. in that BINAP Ru catalysts are utilized to reduce β-keto esters to the corresponding alcohols. These teachings render Noyori et al. analogous art to the invention.
Sotoguchi et al. was brought in to teach the use of the current catalysts in reductions of β-keto esters to the respective β-hydroxy esters (par. 31 and pages 3 and 4 and Example 3 and page 5). For example, Sotoguchi et al. teach BINAP and H8-BINAP (partially hydrogenated BINAP) and SegPhos (claim 1) can be used in a reaction to reduce a β-keto ethyl ester to a β-hydroxy ester.
Alternatively, Sotoguchi et al. teaches [RuCl{(S)-segphos}]2(µ-Cl3[Me2NH2] catalyst utilized in a reaction to reduce a β-keto ethyl ester to a β-hydroxy ester with a chemical purity, optical purity and yield being 95.5, 99.1 and 87.6% respectively (Example 3) (current claims 7-9).
Concerning the S or R configuration of the catalyst, choosing the R or S
configuration of the catalyst is dependent on the desired product chirality. For example, Sotoguchi et al. teach the configuration (R or S) is chosen to obtain the absolute configuration of the reduced product (par. 79).
The teachings of Sotoguchi et al. overlap the teachings of Noyori et al. and Karame et al. in that Ru BINAP catalysts are utilized to reduce β-keto esters. The above teachings render Karame et al., Noyori et al. and Sotoguchi et al. analogous art.
Obviousness
It would have been prima facie obvious for an ordinary artisan before the effective filing date of the claimed invention to have prepared the compound of formula 2 taught by Karame et al. with a reasonable expectation of success. The ordinary artisan would have done so because Karame et al. teach the β-hydroxy esters are important building blocks for the synthesis of biologically active compounds and natural products (p. 1068, top of page). There would have been a reasonable expectation of success because Karame et al. teach the β-hydroxy esters are available by reaction of the dianion of ethyl acetoacetate with alkyl iodides (p. 1068).
The ordinary artisan would have generated the ethyl ester of the current compound (B) from (A) because Karame et al. teach a Markush group that encompasses the ethyl ester of the current compound (p. 1068). See immediately below. Note: when variable n is two and variable x is Cl, the ethyl ester of the current compound (B) is present, or at least a racemic mixture thereof.
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Next, the ordinary artisan would have known that other protecting groups for esters existed and would have tried the t-butyl protecting group with a reasonable expectation of success because Noyori et al. teach a t-butyl β-keto ester being reduced to the equivalent β-hydroxy ester utilizing a ruthenium catalyst. The ordinary artisan would have looked to Noyori et al. due to the overlapping subject matter as argued above.
Next, the ordinary artisan, needing a catalyst would have utilized the
[RuCl{(S)-segphos}]2(µ-Cl3[Me2NH2] catalyst taught by Sotoguchi et al. with a reasonable expectation of success. The ordinary artisan would have done so because of the chemical purity, optical purity and yield of the product being 95.5, 99.1 and 87.6% respectively when reducing a β-keto ethyl ester to a β-hydroxy ester. The ordinary artisan would have looked to Sotoguchi et al. due to the overlapping subject matter as argued above.
Alternatively, due to Sotoguchi et al. teaching overlapping phosphine ligands as taught by Karame et al., Noyori et al., mainly BINAP ligands, and further teaching ligands SegPhos and H8-BINAP, it would have been obvious to place the ligands in the Ru catalysts to make Cl2/Br2[(R/S)-ligand] versions of the Cl2[(R)-BINAP] catalyst and arrive at the invention.
Regarding the S and R chirality if the current catalysts, this is chosen depending on the desired product.
Concerning claims 5-6 and 8-9, the combined processes of the prior art are substantially identical to those of the prior art. Thus, the products would be substantially identical, especially with Sotoguchi et al. teaching optical purity of 99.1%.
Substantially identical methods yield substantially identical products. See MPEP 2112.01 I. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
After combining the teachings of Karame et al., Noyori et al., and Sotoguchi et al. the ordinary artisan would have arrived at the current invention.
Conclusion
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
Any inquiry concerning this communication or earlier communications from the
examiner should be directed to BLAINE G DOLETSKI whose telephone number is
(571)272-2766. The examiner can normally be reached M-F 7-4 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, Scarlett Goon can be reached at (571)270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/B.G.D/Examiner, Art Unit 1692 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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