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 applicant’s communication filed on 2/16/26.
Claims 1, 2, 4, 6-12, 14-16, 18-20 and 23-29 are pending in this application.
The examiner acknowledges applicant’s election of species filed 2/16/26, which is in response to the election of species requirement filed 2/16/26, as follows:
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These species read on claims 1, 2, 4, 8-12, 14, 16, 18-20 and 23-29. Thus claims 1, 2, 4, 8-12, 14, 16, 18-20 and 23-29 are being examined in this Office Action. Claims 6-7 and 15 are withdrawn as being non-readable on applicant’s elected species.
Priority
The applicant claims benefit as follows:
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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 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 of this title, 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 1, 8-12, 14, 16, 18-20, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Kulchat et al. (“Dynamic Covalent Chemistry of Nucleophilic Substitution Component Exchange of Quaternary Ammonium Salts,” Chem. Asian J. 2015, 10, 2484-2496; in applicant’s IDS filed 5/2/24), in view of Lakhdar et al. (“Nucleophilic Reactivities of Indoles,” J. Org. Chem. 2006, 71, 9088-9095), and further in view of Tayama et al. (“An efficient optical resolution of nitrogen-centered chiral beta-hydroxy-tetraalkylammonium salts via complexation with (R)-BINOL,” Tetrahedron Letters 2007, 48, 4183-4185; in applicant’s IDS filed 5/2/24).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Kulchat teaches dynamic covalent libraries of quaternary ammonium cations formed by reversible nucleophilic substitution exchange reactions of ammonium salts and tertiary amines. Kulchat teaches that the reactions are SN2’ and SN2 exchange reactions, are conducted at 60 C, generate thermodynamically and kinetically controlled mixtures of quaternary ammonium compounds and tertiary amines, and are accelerated by iodide as a nucleophilic catalyst. Kulchat further teaches that the work extends dynamic combinatorial chemistry to nucleophilic substitution reactions. (Kulchat, Abstract, p. 2484.)
Kulchat teaches that quaternary allyl ammonium salts are obtained by reaction of an allyl halide with a tertiary amine, and that reversibility requires dissociation into a tertiary amine and allyl halide by anion attack on the allyl group following an SN2’ mechanism. Kulchat evaluates exchange of ammonium salts with aliphatic tertiary amines and N,N-dimethylaniline-type aromatic tertiary amines at a 1:1 ratio in CD3CN at 60 C. (Kulchat, p. 2485, Figs. 1-2.)
Kulchat further teaches that, to achieve reversibility, the exchange reactions were performed between aromatic partners, including N-allyl-N,N-anilinium salts and N,N-dimethylaniline-type aromatic tertiary amines. Kulchat teaches that the exchange was reversible, and that the same distributions were obtained for the forward and reverse reactions, indicating that thermodynamic equilibrium had been reached. (Kulchat, p. 2486.)
Kulchat also teaches quaternary N-benzyl-N,N-dimethylanilinium salts and benzyl exchange with aromatic tertiary amines. Kulchat teaches that exchange of the tertiary amine moiety between N-benzyl-N,N-dimethylanilinium bromide and an aromatic tertiary amine proceeds by SN2 mechanisms, including an indirect pathway in which bromide attacks the benzylic CH2 carbon to liberate N,N-dimethylaniline and benzyl bromide, followed by reaction of benzyl bromide with the introduced tertiary amine. See Scheme 3 below. (Kulchat, pp. 2489-2491, Scheme 3.)
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Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Kulchat does not expressly teach using N-methylindole/1-methylindole as the tertiary amine/nucleophilic reactant.
However, Lakhdar teaches that indoles are pi-excessive heteroarenes that react much faster with electrophiles than most benzene derivatives. Lakhdar specifically studies the coupling of N-methylindole with benzhydryl cations and determines nucleophilicity parameters for N-methylindole. (Lakhdar, p. 9088, Abstract and Introduction.)
Lakhdar further teaches that N-methylindole is included in the comprehensive nucleophilicity scale based on benzhydrylium electrophiles, which is useful for designing the use of indoles as nucleophiles, and teaches that N-methylindole has nucleophilicity parameters N = 5.75 and s = 1.23. (Lakhdar, pp. 9089-9090, Scheme 1 and Table 2.)
Additionally, Kulchat does not expressly teach carrying out the reversible reaction in the presence of BINOL.
However, Tayama teaches optical resolution of nitrogen-centered chiral beta-hydroxy-tetraalkylammonium bromides using chiral BINOL as a complexing agent. Tayama teaches that N-allyl-N-benzyl-N-(2-hydroxyethyl)-N-methylammonium bromide was treated with (R)-BINOL in dichloromethane at room temperature to precipitate a 1:1 ammonium salt/BINOL complex, and that extractive separation gave enantio-enriched ammonium salt. See Scheme 1 below. (Tayama, pp. 4183-4184, Scheme 1.)
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Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute N-methylindole/1-methylindole for Kulchat’s aromatic tertiary amine component in the reversible nucleophilic substitution exchange process. One would have been motivated to use N-methylindole/1-methylindole because Lakhdar teaches that N-methylindole is an electron-rich indole nucleophile reactive with electrophilic carbon centers, and Kulchat teaches reversible nucleophilic substitution exchange involving aromatic amine components and allylic or benzylic ammonium salt systems.
One would have had a reasonable expectation of success because Kulchat teaches reversible SN2/SN2’ exchange in ammonium salt systems, and Lakhdar teaches N-methylindole as a known nucleophile for electrophilic carbon-center reactions. (Kulchat, pp. 2484-2486 and 2489-2491; Lakhdar, pp. 9088-9090.)
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to conduct Kulchat’s reversible ammonium salt-forming/exchange reaction in the presence of BINOL. One would have been motivated to combine Kulchat’s reversible ammonium salt exchange with Tayama’s BINOL complexation/resolution of N-chiral quaternary ammonium salts, so that the chiral BINOL complexing agent could interact with the ammonium salt product as it forms and thereby favor formation or isolation of an enantiomerically enriched ammonium salt.
One would have had a reasonable expectation of success because Kulchat teaches a reversible, thermodynamically controlled ammonium salt exchange, and Tayama teaches formation, isolation, and dissociation of BINOL/ammonium salt complexes to provide enantiomerically enriched ammonium salts. (Kulchat, pp. 2484-2486; Tayama, pp. 4183-4184.)
Regarding claims 8-12, 14, and 16, Kulchat teaches tertiary amines and ammonium salts including N,N-dimethylaniline-type aromatic tertiary amines, N-allyl ammonium salts, N-benzyl ammonium salts, and halide counterions/leaving groups. Kulchat expressly teaches benzyl bromide and allyl bromide systems, including N-benzyl-N,N-dimethylbenzenaminium bromide and N-allyl-N,N-dialkylbenzenaminium bromide/iodide salts. Furthermore, Lakhdar teaches N-methylindole/1-methylindole as a nucleophilic indole suitable for substitution into the Kulchat process as discussed above. (Kulchat, pp. 2485, 2489-2490, and 2494-2495; Lakhdar, pp. 9088-9090.)
Regarding claims 18-20 and 23-25, Tayama teaches BINOL, i.e., 2,2’-dihydroxy-1,1’-binaphthol, as a chiral complexing agent for N-centered chiral tetraalkylammonium salts. BINOL is a non-racemic atropisomeric biaryl compound having two hydroxy coordinating substituents, and Tayama teaches formation of a 1:1 complex of BINOL with an N-chiral ammonium salt. (Tayama, pp. 4183-4184, Scheme 1 and Fig. 1.)
Therefore, the combination of Kulchat, Lakhdar, and Tayama renders obvious the method of claim 1 and the elected species reading on claims 1, 8-12, 14, 16, 18-20, and 23-25, including 1-methylindole/N-methylindole, benzyl bromide, and BINOL.
Claims 2, 4, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kulchat et al. (“Dynamic Covalent Chemistry of Nucleophilic Substitution Component Exchange of Quaternary Ammonium Salts,” Chem. Asian J. 2015, 10, 2484-2496; in applicant’s IDS filed 5/2/24), in view of Lakhdar et al. (“Nucleophilic Reactivities of Indoles,” J. Org. Chem. 2006, 71, 9088-9095) and Tayama et al. (“An efficient optical resolution of nitrogen-centered chiral beta-hydroxy-tetraalkylammonium salts via complexation with (R)-BINOL,” Tetrahedron Letters 2007, 48, 4183-4185; in applicant’s IDS filed 5/2/24), as applied above, and further in view of Wu et al. (“N-Stereogenic Quaternary Ammonium Salts from L-Amino Acids: Synthesis, Separation, and Absolute Configuration,” Helvetica Chimica Acta 2009, 92, 677-688; in applicant’s IDS filed 5/2/24).
Regarding claim 2, Wu teaches preparing N-chiral quaternary ammonium salts by reacting tertiary amines with RX. Wu’s scheme teaches RX in 2.0 equivalents, MeCN, reflux for 5-48 hours, to provide N-chiral QASs in 84-95% yield. Thus, Wu teaches R-X in greater than one equivalent relative to the tertiary amine. See Scheme below. (Wu, p. 678, Scheme.)
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use R-X in greater than one equivalent in the method of Kulchat, Lakhdar, and Tayama.
One would have been motivated to use excess R-X to drive formation of the ammonium salt product, as taught by Wu for preparing N-chiral QASs from tertiary amines.
One would have had a reasonable expectation of success because Wu demonstrates that tertiary amines react with RX in excess to give N-chiral QASs in high yields. (Wu, p. 678.)
Regarding claim 4, Wu teaches using more than 0.5 equivalents of BINOL in a BINOL complexation/separation procedure. In particular, Wu teaches that, with 0.55 equivalents of (S)-BINOL, N-chiral QASs [N(R)]-2g and [N(R)]-2h were separated according to the Tayama method. Thus, Wu teaches a ratio where the non-racemic chiral compound is present in more than 0.5 equivalents relative to the ammonium salt/amine component. (Wu, p. 687, section 5.4.)
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use more than 0.5 equivalents of BINOL in the method of Kulchat, Lakhdar, and Tayama. One would have been motivated to use a sufficient amount of BINOL to form and isolate the BINOL/ammonium salt complex, and Wu teaches that 0.55 equivalents of BINOL is suitable for separating N-chiral QASs by the Tayama BINOL complexation method.
One would have had a reasonable expectation of success because Wu demonstrates successful separation using 0.55 equivalents of BINOL. (Wu, p. 687, section 5.4.)
Regarding claims 26-28, Tayama teaches that a 1:1 complex of ammonium salt 1a with (R)-BINOL precipitated from dichloromethane, the complex was isolated by filtration, and the complex was dissociated by extractive separation in diethyl ether/water to provide enantio-enriched ammonium salt. (Tayama, pp. 4183-4184, Scheme 1 and Scheme 2.)
Wu similarly teaches Tayama and Tanaka’s method for chiral BINOL complexes with N-chiral QASs. Wu teaches adding BINOL to QAS 2a in CH2Cl2, stirring for 24 hours, isolating the precipitate by filtration, crystallizing the precipitate from ethanol to give a corresponding 1:1 complex, and extracting with H2O and Et2O to dissociate the complex and obtain a single diastereoisomer. (Wu, p. 687, section 5.4.)
As a result, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to isolate the ternary complex, recrystallize the complex, and recover the ammonium salt in the method of Kulchat, Lakhdar, and Tayama.
One would have been motivated to use the known BINOL complex isolation, crystallization, and dissociation steps taught by Tayama and Wu to purify and enrich the ammonium salt product. One would have had a reasonable expectation of success because Tayama and Wu demonstrate that BINOL complexes of N-chiral ammonium salts can be isolated, crystallized, and dissociated to recover enriched ammonium salts. (Tayama, pp. 4183-4184; Wu, pp. 679 and 687.)
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Kulchat et al. (“Dynamic Covalent Chemistry of Nucleophilic Substitution Component Exchange of Quaternary Ammonium Salts,” Chem. Asian J. 2015, 10, 2484-2496; in applicant’s IDS filed 5/2/24), in view of Lakhdar et al. (“Nucleophilic Reactivities of Indoles,” J. Org. Chem. 2006, 71, 9088-9095) and Tayama et al. (“An efficient optical resolution of nitrogen-centered chiral beta-hydroxy-tetraalkylammonium salts via complexation with (R)-BINOL,” Tetrahedron Letters 2007, 48, 4183-4185; in applicant’s IDS filed 5/2/24), as applied above.
Regarding claim 29, Kulchat teaches ammonium salts having different anions, including bromide, iodide, hexafluorophosphate, and triflate. Kulchat teaches that counterion identity affects the exchange reaction, and that PF6 salts react much more slowly than bromide salts. Kulchat further teaches preparing N-allyl-N,N-dimethylbenzenaminium hexafluorophosphate by dissolving the corresponding bromide salt in water and adding saturated potassium hexafluorophosphate, thereby exchanging bromide for PF6. (Kulchat, pp. 2487-2488 and 2494.)
Also, Kulchat further teaches benzyl and allyl ammonium/pyridinium systems where the distributions include benzyl bromide and allyl bromide, and teaches exchange systems involving bromide salts and other counterions. (Kulchat, pp. 2490-2492, Tables 4-5 and Fig. 4.)
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to exchange or select the anion of the ammonium salt for another known ammonium salt counterion, including PF6, OTf, Br, or I, in the method of Kulchat, Lakhdar, and Tayama. One would have been motivated to vary the anion because Kulchat teaches that counterion identity affects the reversible ammonium salt exchange process.
One would have had a reasonable expectation of success because Kulchat expressly teaches ammonium salts having different anions and gives an example of exchanging bromide for PF6. (Kulchat, pp. 2487-2488, 2490-2492, and 2494.)
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer Cho Sawyer whose telephone number is (571) 270 1690. The examiner can normally be reached on Monday-Friday 9 AM - 6 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-274-1690.
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Jennifer Cho Sawyer
Patent Examiner
Art Unit: 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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