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 amendment of claims 1, 5 and the addition of new claims 14-17, in the paper of 1/5/2026, is acknowledged. Claims 1-17 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the invention of Group 1, claims 1-6 and newly added claims 14-17, to an aroG aldolase variant, in the paper of 1/5/2026, is acknowledged. Applicant's election with traverse of the following species: Species Group 1: position 462 and Species Group 2: SEQ ID NO:9 (E462A), in the paper of 12/5/2025, is acknowledged. It is noted that applicants did not elect a species from Species Group 3 as defined in the requirement of 11/4/2026.
Claims 7-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.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 7/25/2023, 8/13/2024 and 2/26/2025 are acknowledged and have been considered.
Claim Objections
Claims 1, 4, 5 and 14-17 are objected to because of the following informalities:
Claim 1 recites “SEQ ID NO: 1” and “SEQ ID No:1”. Claims 14-17 recite “SEQ ID No:1”. It is suggested that applicants maintain consistency throughout the claims (i.e. SEQ ID NO:1).
Claim 4 recites “wherein another amino acid is alanine (ala)” which should be “wherein the another amino acid is alanine (ala)”.
Claim 5 and 15-17 depend from rejected claim 1.
Appropriate correction and/or comment is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 is drawn to the variant of claim 1, wherein the variant comprises one or more substitutions from: a substitution of an amino acid corresponding to position 217 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 with an amino acid except arginine; a substitution of an amino acid corresponding to position 310 with an amino acid except lysine; a substitution of an amino acid corresponding to position 403 with an amino acid except arginine; and a substitution of an amino acid corresponding to position 462 with an amino acid except glutamic acid. Claim 1 is drawn to a aroG aldolase (variant, in which at least one amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the aroG aldolase variant has an identity of 80% or more with SEQ ID No: 1. Since amino acid positions 217, 310, 403, and 462 of SEQ ID NO:1 are arginine, lysine, arginine; and glutamic acid respectively, claim 2 does not further limit claim 1 from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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) 1-4, 6 and 14 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) 1-4, 6 and 14 are directed to all possible aroG aldolase (phospho-2-dehydro-3-deoxyheptonate aldolase) variants, in which at least one amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the aroG aldolase variant has a mere identity of 80% or more with SEQ ID No: 1. The specification, however, only provides the representative species of that aroG aldolase variant comprising the amino acid sequence of SEQ ID NO: 1 in which an amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these aroG aldolase (phospho-2-dehydro-3-deoxyheptonate aldolase) variants, 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(s) 1-4, 6 and 14 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that aroG aldolase variant comprising the amino acid sequence of SEQ ID NO: 1 in which an amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, does not reasonably provide enablement for all possible aroG aldolase (phospho-2-dehydro-3-deoxyheptonate aldolase) variants, in which at least one amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the aroG aldolase variant has a mere identity of 80% or more with SEQ ID No: 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claim(s) 1-4, 6 and 14 are so broad as to encompass all possible aroG aldolase (phospho-2-dehydro-3-deoxyheptonate aldolase) variants, in which at least one amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the aroG aldolase variant has a mere identity of 80% or more with SEQ ID No: 1 The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of aroG aldolase variants, broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the aroG aldolase variants encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to that aroG aldolase variant comprising the amino acid sequence of SEQ ID NO: 1 in which an amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass any possible aroG aldolase (phospho-2-dehydro-3-deoxyheptonate aldolase) variants, in which at least one amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the aroG aldolase variant has a mere identity of 80% or more with SEQ ID No: 1, because the specification does not establish: (A) regions of the enzyme which may be modified effecting the aldolase activity; (B) the general tolerance of aroG aldolase enzymes to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of an aroG aldolase enzyme with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required aldolase activities and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495 and Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those aroG aldolase enzyme variants of the claimed genus.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any aroG aldolase (phospho-2-dehydro-3-deoxyheptonate aldolase) variants, in which at least one amino acid selected from the group consisting of amino acids corresponding to positions 217, 310, 403, and 462 from the N-terminus in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the aroG aldolase variant has a mere identity of 80% or more with SEQ ID No: 1. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those aroG aldolase enzyme variants having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Closest Prior Art:
US 7,355,029 discloses a phospho-2-dehydro-3-deoxyheptonate aldolase having 100% sequence identity to instant SEQ ID NO:1 (see SEQ ID NO: 38, RXA01175, Table 1 of US 7,355,029).
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
2/20/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652