DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Please note that the Patent Examiner of your application has changed. All communications should be directed to Mary Lyons, Art Unit 1645, whose telephone number is (571)272-2966.
Claim Status
3. The amendment, filed 07/10/25, has been entered.
4. Claims 1-15 are pending. Claims 1 and 3 are amended. Claims 5-15 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/12/24. Claims 1-4 are under examination.
Withdrawal of Objections/Rejections
5. The following are withdrawn from the Office Action, filed 04/11/25:
The rejection of claims 1 and 3 under 35 U.S.C. 112(b) as being indefinite, found on page 6, is withdrawn in light of Applicant’s amendments thereto.
The rejection of claims 1-4 under 35 U.S.C. 103 as being unpatentable over the NCBI Reference Sequence: WP_018340106.1, found on page 8, is withdrawn in light of Applicant’s amendments thereto.
New: Objection to Specification
6. The title of the invention is objected to because of the word “novel” which should not be included in a title; see MPEP 606 and 37 C.F.R. 1.72.
Maintained Rejection: Claim Rejections - 35 USC § 112
7. 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.
8. Claims 1-3 are rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims broadly encompass a large range of aminotransferase variants that are not supported by adequate written description to demonstrate that the inventor had possession of the claimed genus. For example, instant claims are drawn to a branched-chain amino acid aminotransferase variant, in which a valine (V) amino acid at position 156 from an N-terminus of an amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid, wherein the variant has at least 95% (see claim 1) to 99% (see claim 3) or more of identity with the amino acid sequence of SEQ ID NO: 1. However, it is the Office’s position that the sequence variants with 95-99% identity have not been described with sufficient particularity, such that one skilled in the art would recognize that Applicant had possession of the claimed invention, at the time of filing, because of (A) a lack of a correlation, known or disclosed, between the claimed functional requirements and the structures that meet those requirements; and/or (B) a lack of a representative number and variety of species to constitute possession of the full scope of the claimed genus.
The specification does not provide adequate written description to identify the broad genus of the claims because, inter alia, the specification does not disclose a correlation between the necessary structure of the claimed polypeptide (e.g. which 95% to 99% of the amino acids must be maintained and which 1-5% may be substituted within a variant) and the claimed function to be maintained (e.g. aminotransferase activity). It is noted that while the description of the ability of a claimed protein sequence may generically describe that protein molecule's function, it does not describe the protein molecule itself. For example, the specification fails to identify critical amino acids or subsequences within SEQ ID NO: 1 (i.e. other than residue 156) that must be retained in order to maintain the claimed functional activity. Consequently, the specification fails to describe the common attributes or structural characteristics that identify the members of this genus and because the genus of sequences is highly variable (i.e. each sequence has a unique structure; see MPEP 2434), the characteristics of the ability to function as an aminotransferase, is insufficient to describe the genus. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a massive number of partial structures claimed only by a functional characteristic because, without an art-recognized structure-function correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. Thus, disclosure of function alone is little more than a wish for possession and it does not satisfy the written description requirement; See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate").
Further, MPEP §2163 states that if a biomolecule is described only by a functional characteristic (as in the instant case), without any disclosed correlation between function and structure of the sequence (as in the instant case), it is not sufficient for written description purposes, even when accompanied by a method of obtaining the claimed sequences. MPEP §2163 does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. For example, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g. see In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618). Furthermore, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In the instant case, the specification provides complete structural information for SEQ ID NO: 1 having a substitution at residue 156, which is a sequence consisting of SEQ ID NO: 3. However, the claims, as written also encompass partial structures of SEQ ID NO: 1. The instant specification only provides working examples related to one species of branched-chain amino acid aminotransferase variant, the Corynebacterium glutamicum ilvE variant (V156A) in the strains listed in tables 2 and 3 of the specification, which correspond to specification, pages 17-19. There are only 4 strains listed in tables 2 and 3 that contain the V156A mutation – the ‘ATCC13032_ilvE_V156A: CA13-8106’ and ‘CA13-8100_ilvE_V156A: CA13-8107’ strains in table 2, and the ‘KCCM11661P_ilvE_V156A’ and ‘KCCM11662P_ilvE_V156A’ strains listed in table 3. MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In this case, the claims encompass an essentially infinite number of branched-chain amino acid aminotransferase variants, but only one reduced to practice. In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. The specification only discloses working examples from the single V156A aminotransferase variant, but the claims cover a broad genus of branched-chain amino acid aminotransferase variants that can differ from SEQ ID NO: 1 by 1-5% identity. Therefore, there is no disclosure of any other additional variants demonstrating that Applicant was in possession of the full scope of the invention. Furthermore, the specification lacks specific guidelines related to the critical motifs and functional enzymatic residues of Corynebacterium glutamicum ilvE and other suitable branched-chain amino acid aminotransferases.
Although the level of skill in the art is high, the predictability in the art is low due to the lack of detail regarding critical enzymatic residues of branched-chain amino acid aminotransferases that would apply to variants within the broad scope of the claims. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures, exactly what aminotransferase variants with up to a 5% (or 1% for claim 3) sequence difference to SEQ ID NO: 1 would be suitable for the invention and retain enzymatic activity. Accordingly, in the absence of sufficient written description to demonstrate that the inventor was in possession of the claimed genus, including details about enzymatic residues critical to the function of branched-chain amino acid aminotransferases suitable to the invention, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous sequence variants with both the claimed structural attributes and functional properties have not yet been identified. MPEP 2163 which states an adequate written description of a chemical invention requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed; see, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004).
With regards to the state of the art, manipulating aminotransferases to construct branched chain variants, was still under development and thus, necessarily unpredictable, as evidenced by the art already of record. For example, an NCBI protein BLAST (BLASTp) with SEQ ID NO: 1, using standard databases and scoring parameters with 1000 max target sequences revealed that the valine at position 156 is highly conserved. Out of 1000 search results, only one result (WP_018340106.1) had a mutation at position 156. As described below, the literature teaches that amino acid residues in other species corresponding to the instantly claimed V156 position are highly conserved, and lie within the aminotransferase active site. Further, Tremblay discloses in, “The 1.9 Å structure of the branched-chain amino-acid transaminase (IlvE) from Mycobacterium tuberculosis”, 2009, Acta Crystallogr Sect F Struct Biol Cryst Commun., pgs., 1071-1077., that all type IV PLP-dependent transaminases consist of two domains with an interdomain loop. Tremblay states, “A structural alignment between MtIlvE [branched-chain amino-acid transaminase (IlvE) from M. tuberculosis] and hBCATm [human mitochondrial branched-chain amino-acid transaminase (IlvE)]…highlights several key features…and reveals significant structural conservation. The MtIlvE and hBCATm dimers share a similar interface between the monomer subunits and have comparable buried surface areas. In both instances, each monomer introduces a loop (MtIlvE154–160) into the active site of the other monomer. Within this loop, Val158 of MtIlvE is positioned nearly identically to an equivalent valine in hBCATm... Not surprisingly, this is a strictly conserved residue in BCAT enzymes…these loops positioned at the dimer interface form an adjacent portion of the partner’s active site and house the strictly conserved valine residue for interaction with the hydrophobic branched chain of the substrate. Thus, the loop functions as a substrate-specificity determinant with selectivity towards the branched-chain side chain of the substrate amino acid” (Discussion, Page 1074-1076).
An NCBI protein BLAST (blastp) global alignment of SEQ ID NO: 1 and the aforementioned MtIlvE, referenced by Tremblay, (accessed via UniProt Accession No. P9WQ75, https://www.uniprot.org/uniprotkb/P9WQ75/entry#sequences) results in a 59% sequence identity. Further, the V156 of SEQ ID NO: 1 aligns with the aforementioned V158 of MtIlvE. Additionally, the well conserved adjacent residues corresponding to positions 155 (L), and 156 (G) of SEQ ID NO: 1 align with positions 156 and 157 of MtIlvE. Figure 4 of Tremblay shows the conservation of valine at position 158 across species of BCAT enzymes (the diamond in the bottom sits below the column corresponding to position 158):
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Thus, it is highly likely that the conserved V156 of SEQ ID NO; 1 is part of the conserved loop region that protrudes into the aminotransferase active site, and plays an important role in aminotransferase substrate specificity. Due to the highly conserved nature of V156 and its likely position in the aminotransferase active site, a skilled artisan would not know which residues of SEQ ID NO: 1 could be mutated without abrogating aminotransferase activity. It is unknown which residues could replace valine at position 156 independently, and in combination with other mutations at conserved regions, and elsewhere. Accordingly, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the polypeptide per se (e.g. its sequence and/or critical domains within its sequence) and therefore does not provide adequate written description support for which structural features of the polypeptide would predictably retain their functional activity (i.e. the state of the art is not sufficient to identify which amino acids must be conserved in order to maintain the claimed functions).
Therefore, neither the specification nor the state of the art provides sufficient written description to support the genus encompassed by the claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.).
Therefore, it is the Office’s position that Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112(a).
Applicant’s Arguments and Response to Arguments
9. All of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record. For example:
With regards to the argument that amending the claims from 80% to 95% results in only 14 options which is small enough to be fully supported by the instant specification (see Remarks, pages 4-5); the Office disagrees and notes that SEQ ID NO: 1 comprises 367 amino acids. Sequence variants that are at least 95% similar over the entire length, require 349 of the 367 to be maintained, leaving as little as 1, but up to 18, amino acids to be substituted (i.e. 349/367*100 = 95%; 367-349 = 18). However, as written, the claims require 1 substitution at a particular position (i.e. residue 156) leaving up to 17 additional amino acids (i.e. 18-1 = 17) of the remaining 366 choices, to still be modifiable while still meeting the structural limitation of at least 95% similar over the entire length of SEQ ID NO: 1. However, there are an almost unfathomable number of ways in which 1 to 17 amino acids (i.e. the sum of results for 1 change, 2 changes, 3 changes … 17 changes) can be selected from the 366 remaining residues (i.e. 367 total length – 1 required = 366 still available to modify) because, without any other limitations in the independent claim, each particular residue can be substituted with any one of the other 19 naturally occurring amino acids and still meet the limitation. For example, for just 1 change (i.e. only one additional amino acid substitution), there would be 366 unique sequences, but because the change at each residue can be substituted with any one of the other 19 naturally occurring amino acids, then the actual number of unique sequences encompassed is 6,954 (i.e. a sequence having an additional substitution at, for example, residue 33 with a cysteine, would be structurally distinct from a sequence having a substitution at residue 33 with a tryptophan; and 366 * 19 = 6,954). Yet, the claims allow for up to 17 unrestricted changes, anywhere along the length of SEQ ID NO:1, so with order of selection not important and repetition not allowed, the equation is X = 19 * [n!/(r!(n-r)!)], which for 17 changes, results in a number having more than 40 zeros (i.e. a trillion only has 12 zeros).
Consequently, it remains the Office’s position that the specification fails to describe the common attributes or structural characteristics that identify the members of this genus and because the genus of sequences is highly variable (i.e. each sequence has a unique structure; see MPEP 2434), the characteristics of the ability to function as a branched aminotransferase variant, is insufficient to describe the genus. Thus, this argument is not persuasive because, as set forth above, it is the Office’s position that the sequence variants with 95-99% identity have not been described with sufficient particularity, such that one skilled in the art would recognize that Applicant had possession of the claimed invention, at the time of filing, because of (A) a lack of a correlation, known or disclosed, between the claimed functional requirements and the structures that meet those requirements; and/or (B) a lack of a representative number and variety of species to constitute possession of the full scope of the claimed genus.
Therefore, all of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Potentially Allowable Subject Matter
10. Claim 4 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
11. No claims are allowed at this time.
12. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
13. 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY MAILLE LYONS whose telephone number is (571)272-2966. The examiner can normally be reached on Monday-Friday 8 am to 5 pm 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, Dan Kolker can be reached on (571)-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY MAILLE LYONS/Examiner, Art Unit 1645
March 26, 2026
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