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 .
Applicant’s cancellation of claims 6-9, in the paper of 4/8/2025, is acknowledged. Claims 1, 2, 4 , 6, 12-16, 20, 22, 25-29, 31, 33, 35, 38, 40, 41, 43, 45 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the invention of Species Group 1 Species: G is CO2Et and Species Group 2 Species: Vibrio flunialis transaminase, in the paper of 5/18/2026, is acknowledged.
Claims 20, 31, 35 41, and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Applicants filing of information disclosure statements on 9/6/2024, 8/21/2025 and 5/18/2026 are acknowledged and have been considered.
Claim Objections
Claims 1, 25 and 26 are objected to because of the following informalities:
Claim 1 is objected to because applicants have deleted the claim number “1” from claim 1.
Claims 25 and 26 recite “claim 14” while other claims such as claim 22 recite “Claim 14”. It is suggested that applicants maintain consistency throughout the claims.
Appropriate correction and/or comment is required.
Specification
The disclosure is objected to because of the following informalities:
Applicants specification is objected to because applicants specification comprises Nucleotide and/or Amino Acids Disclosures Requiring a "Sequence Listing".
Applicants attention is directed to 37 CFR 1.821(a) which presents a definition for "nucleotide and/or amino acid sequences." This definition sets forth limits, in terms of numbers of amino acids and/or numbers of nucleotides, at or above which compliance with the sequence rules is required. Nucleotide and/or amino acid sequences as used in 37 CFR 1.821 through 37 CFR 1.825 are interpreted to mean an unbranched sequence of four or more amino acids or an unbranched sequence of ten or more nucleotides.
Specifically applicants specification at Figure 3 lists amino acid sequences which require a sequence identifier and are to be included in applicants sequence listing as per 37 CFR 1.821 through 37 CFR 1.825.
Further when an amino acid sequence is listed in a figure there must also be a sequence identifier for the sequence either in the figure or the “Description of the figure”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 22, 33 and 43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 22, 33 and 43 are indefinite in the recitation “SEQ ID NO. 2/” as it is unclear what a “/” is.
Appropriate correction and/or comment is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1, 2, 4, 6, 12-16, 22, 25-29, 33, 38, 40, 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim(s) 1, 2, 4, 6, 12-16, 22, 25-29, 33, 38, 40, 43 are directed to all possible processes of producing (1r,4r)-4-substituted cyclohexane-1-amine of formula (T) or a salt thereof
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, wherein G represents a substituent,selected from
- a hydrogen atom;
- a C1-6 alkyl group;
- an ester moiety (-COOR), wherein R represents an suitable alkyl, aralkyl, or aryl group, preferably a C4-6 alkyl group, more;
- a CH2-OR' group, wherein R' represents a hydrogen atom or a hydroxyl protecting group;
- a protected aldehyde group of formula
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, wherein n is an integer of 1 to 2;
- a substituted or unsubstituted aryl group; or-
an aralkyl group,
the process comprising:
reacting a diastereomeric mixture of 4-substituted cyclohexane-1-amines (formula (C) + formula (T)) or salts thereof
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with a single transaminase biocatalyst in whole-cell, soluble, or immobilized form in the presence of an amine acceptor used in a sub-equimolar or equimolar quantity, encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species of methods of use of any tranaminase. The technical effect, which has been shown for certain embodiments of the process wherein specific transaminases have been used, is that the amount of trans-product produced can be higher than the amount initially present in the cis/trans-mixture. Thus, a dynamic kinetic resolution can be achieved with such transaminases, pushing the yield beyond the theoretical maximum of a simple (non-dynamic) kinetic resolution of isomers. Such an effect has been demonstrated for resolutions using the specified transaminases Chromobacterium violaceum and Vibrio fluvialis T As ( CvSw60cTA and VfS-TA, respectively; see instant pages 21-24 and tables 1 and 2) (Fiorati et al., ADVANCED SYNTHESIS AND CATALYSIS, Vol. 362, No. 5, 4 March 2020 (2020-03-04), pages 1156-1166). However, it cannot be reasonably expected that the same effect would be present using any transaminase in combination with any amino acceptor substrates. Rather, it appears that this effect is a particularity associated to the use of the specific transaminases CvSw60c-T A and VfS-T A. Thus the specification fails to describe additional representative species of these required transaminases and methods of their use by any identifying structural characteristics or properties, for which no predictability of structure is apparent.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
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.
Claim(s) 1, 2, 4, 12-16, 25-29, 38, 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mathe et al. (WO 2010/070368 A1), Maguire et al. (WO 2020/025646 A1) and Fiorati et al., ADVANCED SYNTHESIS AND CATALYSIS, Vol. 362, No. 5, 4 March 2020 (2020-03-04), pages 1156-1166.
Mathe et al. (WO 2010/070368 A1) disclose a process for the preparation of trans 4-amino-cyclohexyl ethyl acetate HCI from 4-nitrophenyl acetic acid, which comprises two consecutive hydrogenation steps in the presence of Pd/C, followed by esterification of the obtained 4-aminocyclohexyl acetic acid with ethanol. According to Mathe et al. (WO 2010/070368 A1), this compound and its derivatives are excellent starting materials for the synthesis of active pharmaceutical agents. For the synthesis of active pharmaceutical agents only the optical (stereomerically) pure trans isomer form may be applicable (see page 1, line 11-16).
Further, it is disclosed that when the cis/trans mixture of 4- aminocyclohexyl acetic acid ethyl ester HCI salt prepared according to the invention is treated with acetonitrile, the trans product can be isolated in extremely high purity and good yield (page 3, line 17-19). This is done by adding acetonitrile to the ester product obtained as a distillation residue in the process, and the mixture is cooled to a temperature between -5 - 0 °C and the crystals precipitated are washed with acetonitrile (page 3, line 26-29).
The subject-matter of claim 1 therefore differs from this known method in that, the separation of the trans form from the cis/trans mixture of compounds is done by reacting the mixture with a single transaminase biocatalyst in the presence of an amine acceptor used in sub-equimolar up to equimolar quantities. According to the description, such reaction results in the formation of ketone product from the cis-form of the compound, whereas the trans-form of the compound remains unconverted (page 13, scheme 2; page 18, lines 3-9). The technical effect issuing from this difference and the problem to be solved is that an alternative method to separate the trans-form from the mixture of cis/ trans-forms of the compound is provided.
It is noted here that an additional technical effect, which has been shown for certain embodiments of the process wherein specific transaminases have been used, is that the amount of trans-product produced can be higher than the amount initially present in the cis/trans-mixture. Thus, a dynamic kinetic resolution can be achieved with such transaminases, pushing the yield beyond the theoretical maximum of a simple (non-dynamic) kinetic resolution of isomers. This allows to obtain higher yields of trans-isomer in comparison to the prior art method.
Maguire et al. (WO 2020/025646 A1) disclose a method of enantioselectively resolving a racemic amine substrate by transformation to a ketone product by oxidative deamination, in which the amine substrate comprises a reacting site, a first stereocentre at the reacting site and a second stereocentre remote from the reacting site, the method comprising a step of reacting the racemic amine substrate with an isolated w-transaminase enzyme of SEQ. ID NO: 1, or a functional variant thereof, wherein the isolated w-transaminase enzyme or functional variant thereof exhibits (a) stereoselectivity at the second stereocentre remote from the reactive site and (b) reactive selectivity for one enantiomer of the racemic amine.
The w-transaminase enzyme of SEQ. ID NO: 1 is obtained from a Pseudovibrio bacterium (see abstract).
One of skill in the art before the effective filing date in light of Mathe et al. (WO 2010/070368 A1) would look for alternative isomer separation methods and would have become aware of Maguire et al. (WO 2020/025646 A1). Thus one of ordinary skill in the art before the effective filing date in the light of Maguire et al. (WO 2020/025646 A1), would be motivated to modify the method of Mathe et al. (WO 2010/070368 A1), making use of the transaminase of Pseudovibrio to resolve the cis/trans-mixture of compounds, thereby arriving at the claimed subject-matter in an obvious way. It is noted that, while the exemplified substrates converted by the transaminase in Maguire et al. (WO 2020/025646 A1) are not identical to the substrate 4-amino-cyclohexyl ethyl acetate of Mathe et al. (WO 2010/070368 A1), or the other substrates covered by present claim 1, these are sufficiently similar. The core structural element, the 4-substituted cyclohexane-1-amine, is present in the exemplified substrates 8a and 8b.
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Further Claims 2, 4, 12-16, 25-29, 38, 40 seem to relate to obvious options or alternatives, or an obvious range. The expectation of success is high based upon the high level of skill in the art as exemplified by Mathe et al. (WO 2010/070368 A1), Maguire et al. (WO 2020/025646 A1) and Fiorati et al., ADVANCED SYNTHESIS AND CATALYSIS, Vol. 362, No. 5, 4 March 2020 (2020-03-04), pages 1156-1166, who teach all the methodology and techniques required to practice the obvious methods.
Thus claim(s) 1, 2, 4, 12-16, 25-29, 38, 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mathe et al. (WO 2010/070368 A1), Maguire et al. (WO 2020/025646 A1) and Fiorati et al., ADVANCED SYNTHESIS AND CATALYSIS, Vol. 362, No. 5, 4 March 2020 (2020-03-04), pages 1156-1166.
Remarks
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached 6-3 EST Mon-Fri.
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rgh
7/10/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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