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
The amendment after non-final office action filed July 15, 2026 is acknowledged. Claims 9-11, 14-17 were cancelled, claims 7-8 were amended and claims 1-8, 12-13 are pending.
Election/Restrictions
The restriction requirement was deemed proper and made FINAL in a previous office action. Claims 1-6, 12-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention/species, there being no allowable generic or linking claim.
Claims 7-8 are examined on the merits of this office action.
Withdrawn Objections/Rejections
The rejection of claims 7-8, 16 \under 35 U.S.C. 103 as being unpatentable over Albert US20160178627 A1 (effective filing date 12/19/2014 (62/094495) and 11/25/2015 (62/260162), cited in Applicant’s IDS) in view of Andres (WO2012150321, cited previously) and Wenfang (WO2000043492 A2, cited previously) is withdrawn in view of Applicant’s arguments filed July 15, 2026. In particular, the rejection is withdrawn in view of Applicant’s submission establishing that Albert is excluded as prior art under 35 U.S.C. 102(b)(2)(C) pursuant to 35 U.S.C 102(c). Applicant has stated that the subject matter disclosed in Albert and the claimed invention were developed or made by or on behalf of parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, that the claimed invention resulted from activities undertaken within the scope of the joint research agreement, and has identified the parties to the joint research agreement in the application. Accordingly, Albert is not available as prior art under 35 U.S>C. 102(a)(2) for purposes of the rejection. Because the rejection relied on Albert for limitations not taught or suggested by Andres and Wenfang, the rejection of claims 7 and 8 under 35 U.S.C. 103 is withdrawn.
The objection to claims 7-8 are withdrawn in view of amendment of the claims filed July 15, 2026.
The rejection of claim 16 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed July 15, 2026..
The rejection of claim 16 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 is withdrawn in view of amendment of the claims filed July 15, 2026..
Maintained/Revised Rejection
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.
Claims 7-8 remain 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
The claims are “An in vitro method for labelling a protein of interest, comprising
a) providing a recombinant transglutaminase (TG) substrate being attached to a protein of interest, wherein the recombinant transglutaminase (TG) substrate is according to the following general formula I (F*-L)y-X Formula (I) wherein F* is an FKBP domain of a Thermus thermophilus SlyD polypeptide, wherein an "insert-in-flap" (IF) domain of the FKBP domain of the Thermus thermophilus SlyD polypeptide is at least partially replaced with a Q-tag, wherein the Q-tag comprises an amino acid sequence of 11 to 20 amino acids, and comprises the peptide sequence G1-YRYRQ (SEQ ID NO: 30) -G2,wherein sections of the FKBP domain of the Thermus thermophilus SlyD polypeptide of F* that are not replaced with the Q-tag comprise an amino acid sequence that is identical to the corresponding sections of an amino acid sequence of an FKBP domain of a thermus thermophilus SlyD polypeptide (SEQ ID NO. 29), L is absent or is a linker amino acid sequence; and X is a protein of interest attached thereto selected from the group consisting of an enzyme, an antigen, an antibody or fragment thereof; y is an integer of between 1 and 100; G1 is Gly Gly Gly; and G2 is Gly Gly Gly b) providing an effective amount of the transglutaminase of Kutzneria albida, according to SEQ ID NO: 23,c) providing a suitable label comprising an alkyl-amine group, wherein said label is a Ruthenium containing chemiluminescent label, and contacting said components according to a) to c), whereby said transglutaminase attaches said label to said substrate, wherein said labelling is achieved in a stoichiometric ratio of label and protein of interest at about 1:1.
Given the language of “at least partially replaces” the insert-in-flap domain can be completely replaced with the “Q-tag” thus the peptide not having an insert-in-flap domain. With the FKBP peptide having an “insert in flap” domain, the Q-tag can partially replace the insert in flap domain meaning that domain can be completely replaced (missing) or the Q-tag can be replaced part of the sequence (an amino acid stretch of the domain as low as one amino acid missing with the Q-tag inserted and wherein the Q tag can be up to 20 amino acids in length). Thus, the requirements of the claim are that the FKBP is identical to Thermus Thermophilus SlyD SEQ ID NO:29 it the sequence that is not replaced or partially replaced by the Q-tag.
Importantly, the phrase “at least partially replaced” encompasses a broad continuum of embodiments including but not limited to replacement of a single amino acid of the IF domain, replacement of multiple contiguous or non contiguous residues, replacement of majority of the domain and complete replacement (with a Qtag that can be up to 20 amino acids).
As stated above, Claim 7 further defines y as an integer from 1-100. Because each F* is defined as containing the recited Q tag, the claim encompasses recombinant TG substrates having from one to 100 Q tag containing F* units associated with a single protein of interest X. Claim 7 nevertheless requires labeling at about a 1:1 stoichiometric ratio of label to protein of interest.
Therefore, to meet the written description requirement of 35 U.S.C. § 112, first paragraph, the specification must disclose a representative number of species that meet both the structural and functional limitations of the genus or the specification and/or the prior art must identify the structural elements that correlate to the claimed function in a manner that demonstrates to one of ordinary skill in the art that Applicant was in possession of the claimed genus at the time the application was filed. In the instant case, the specification must establish which of the vast number of peptide sequences encompassed by the claims that satisfy the structural limitations of the claim are also able to be a substrate specifically for Kutzneria albida TG for attaching a label to said substrate and a scaffold for a protein of interest.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification demonstrates reduction to practice for only a narrow subset of the claimed scope. In particular, Applicants disclose specific FKBP scaffolds derived from Thermus thermophilus SlyD (no variants); Insertion or replacement of a substantial portion of the IF domain with a defined Q-tag sequence (e.g., YRYRQ-based motifs); Q-tag insertions that are flanked by long glycine-rich linker sequences, a limited set of fusion architectures, such as SlyD-Q-tag-gp21 and SlyD-Q-tag-SlpA constructs; and demonstrated TG-mediated labeling (e.g., biotin or ruthenium labels), often achieving approximately 1:1 labeling stoichiometry.
The examples consistently involve large, contiguous insertions replacing a substantial portion of the IF domain and do not demonstrate minimal or incremental IF-domain replacements with the Qtag as defined.
Thus, the examples do not demonstrate that Q tags within the claimed scope (up to 20 amino acids) were actually made and used the claimed FKBP IF domain configuration (for the intended use). Further, the disclosed examples do not demonstrate the full scope of y=1-100 in combination with the claimed about 1:1 label to protein ratio.
One of ordinary skill in the art would not consider the examples provided in the instant specification to be representative of the full scope of the claimed genus.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
As stated above, the complete structure of SlyD FKBP domain from specific bacterial species with the Q-tag YRYRQ is disclosed.
The sequence RYRQ was grafted into the SlyD sequence of SEQ ID NO: 29 (see pages 17-18) yielding instant SEQ ID NO: 52. A similar Q-tag construct was tested comprising slyD Q-Tag gp21 fusion (see figure 3B, insertion between 65-122 of SlyD). A further labeling assay was done with a recombinant fusion between the chaperone SlyD and gp21 and SlpA (see page 19). Figures 5-6 shows labeling efficacies with these constructs. Thus, all the examples reduced to practice where using the slyD FKBP domain from Thermus thermophilus with insertion of the Q-tag (RYRQ) which is not representative of the scope of the claims. The specification does not identify structural characteristics defining the claimed genus of Qtags and insertion within the IF domain (partially or fully) and the desired function of labeling.
Physical and/or chemical properties:
The specification describes the FKBP scaffold and particular Qtag containing constructs. However, it does not provide sufficient physical or chemical characteristics establishing that the various degrees and configurations of the IF domain replacement (including the Qtag as defined in the claim) possessed the claimed properties including labeling efficiencies.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The specification does not describe a general correlation between structure and function for the claimed genus. The role of the amino acids in the Thermus Thermophilus SlyD polypeptide, the INF domain and in particular the QTAG, regarding TG substrate activity is not sufficiently described.
The specification asserts that the IF-domain modification “does not substantially interfere” with FKBP structure or function. The specification describes labeling activity for particular disclosed Qtag constructs. However, the specification does not disclose a sufficient correlation between the extent/configuration of the IF domain replacement (including the Qtag as defined in the claims) and retention of the claimed TG substrate and labeling function to establish possession across the full claimed range.
Method of Making
The specification teaches methods for making specific exemplified FKBP-Q tag constructs, including recombinant expression and insertion of Q tag sequences at defined IF domain locations. However, it does not demonstrate itself possession of the full range of IF-domain replacement (including the Qtags as defined) encompassed by the claims.
Conclusion
In conclusion, Applicant’s amendment overcomes the portion of the previous written description rejection concerning FKBP domain variants having less than 100% identity to SEQ ID NO:29, and that basis of the rejection is withdrawn. However, the amendment does not resolve the previously identified breadth associated with the Qtag replacement of the IF domain. Claim 7 continues to encompass a genus of Qtag modified FKBP constructs in which differing portions of the IF domain may be replaced by the Q tag, from partial through complete replacement. The specification does not disclose representative number of species or sufficient identifying characteristics, including a sufficient structure function correlation to convey possession of the full genus.
Response to Applicant’s Arguments
Applicant argues “Amended claim 7 requires that the sections of the FKBP domain of the Thermus thermophilus SlyD polypeptide that are not replaced with the Q-tag be identical to the corresponding sections of an FKBP domain of a Thermus thermophilus SlyD polypeptide (SEQ ID NO: 29). This limitation is expressly supported by the originally filed specification. The specification defines SEQ ID NO: 29 as the amino acid sequence of the FKBP domain of SlyD of Thermus thermophilus, and the working examples employ this specific FKBP domain in the reduced-to-practice constructs. The amended claim therefore recites subject matter that the specification reasonably conveys to a person having ordinary skill in the art that the inventor had possession of as of the filing date. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). By requiring identity to SEQ ID NO: 29 outside the Q-tag, amended claim 7 no longer encompasses the genus of FKBP variants having as little as 95% identity to SEQ ID NO: 29 that the Office identified as unsupported. The written description concern as to the FKBP domain is thereby resolved.
Applicants arguments have been fully considered and are persuasive with respect to the previously identified description issue concerning FKBP variants having less than 100% sequence identity to SEQ ID NO:29. The amendment requiring the sections of the FKBP domain not replaced by the Qtag to be identical to the corresponding sections of SEQ ID NO:29 resolves this deficiency. However, the amendment does not overcome the previously identified deficiency concerning the claimed genus of Qtag/IF domain configurations. Claim 7 continues to encompass partial through complete replacement of the IF domain by the Qtag as defined in the claim as 11-20 amino acids, while the specification does not disclose sufficient representative species or identifying characteristics to demonstrate possession of the full claimed genus. Accordingly, the rejection under 35 U.S.C. 112(a) is maintained.
New Objections
Claim 7 is objected to for the following informality: it is suggested that Applicants insert “(SEQ ID NO:29)” following “Thermus thermophilus SlyD polypeptide” in line 7.
Furthermore, the limitation of “Kutzneria albida” should be italicized in claim 7.
Conclusion
No claims are allowed.
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 ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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