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
Claims 6, 9-11, 14, 15, 17, 18, 21, 23, 27, 28, 30, 31, 33-36, 38, 39, 42-50, and 52-54 are cancelled. Claims 1-5, 7, 8, 12, 13, 16, 19, 20, 24-26, 29, 32, 37, 40, 41, and 51 are pending.
Election/Restrictions
Applicant's species election with traverse of a TEV protease comprising S3I, P8Q, S31T, T173A, S219R, and A231V substitution mutations, and SEQ ID NO:18, in the reply filed on 01/05/2026 is acknowledged.
The traversal is on the grounds that additional species could be searched without an undue burden. This is not found persuasive because the search of one species does not guarantee all others to be found.
The requirement is still deemed proper and is therefore made FINAL.
Drawings
The Examiner notes that some figures found in the drawings filed 04/26/2023 are pixelated and illegible. Accordingly, replacement drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to this Office action. The replacement sheets should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Claim Objections
Claims 1, 20, 32, and 41 are objected to because of the following informalities: the claims contain grammatical errors and convoluted language.
In claim 1, TEV should be in parentheses after Tobacco Etch Virus, which should not be in parentheses.
Claim 20 may be amended to recite: wherein the polypeptide can cleave…at a turnover rate (kcat) greater than 0.17 s-1.
In claim 32, “claims 29” should be amended to “claim 29”.
In claim 41, “an amino acid bond” should be amended to recite “a peptide bond”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 3-5, and 7 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 3-5 and 7 recite amino acid residues without a reference sequence identified by a SEQ ID NO. Therefore, it is unclear what amino acid sequence should be mutated.
Claim Rejections - 35 USC § 112(d)
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 3 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 3 does not further limit claim 1. Claim 3 should be amended to depend from claim 2, or should be amended to recite: wherein the active mutant TEV protease further comprises a substitution T173A.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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 1-5, 7, 8, 12, 13, 16, 19, 20, 24-26, 29, 32, 37, 40, 41, and 51 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 claims contain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1-5, 7, 8, 12, 13, 16, 19, 20, 24-26, 29, 32, 37, 40, 41, and 51 encompass the limitation of a polypeptide comprising an active TEV mutant protease comprising a substitution mutation at amino acid residues corresponding to S3, P8, S31, and A231 of SEQ ID NO:17.
Claim 40 limits claim 1 to a polypeptide wherein the TEV protease comprises SEQ ID NO:3, 4, or 18. However, claim 40 still encompasses the broad genus of all polypeptides that may comprise the TEV protease mutant, and encompasses all amino acids that the TEV protease mutant may comprise in addition to SEQ ID NOs: 3, 4, or 18.
MPEP 2163.05 II states “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’). The disclosure of only one 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].’”
The instant specification reduces to practice six protease variants shown in Table 2 that exhibit higher activity on the peptide sequence of SEQ ID NO:33 (p. 25), and reduces to practice a variant combining the mutations of variant E2 and S7 that exhibited a 2-fold improvement in catalytic efficiency (para. [0082]). The specification does not disclose the entire genus of all polypeptides comprising the claimed TEV protease variants. The specification does not disclose every possible mutation that may be made at the claimed residues that results in a TEV protease with improved catalytic efficiency, and does not disclose all sequences with up to 5% divergence from instant SEQ ID NOs: 3, 4, and 17 that results in a TEV protease with improved catalytic efficiency. The specification does not disclose what structural properties of the protease are required for increased catalytic efficiency, or disclose which regions of SEQ ID NO:17, the wild type TEV protease, are the active site residue(s) for conserving enzyme activity. Therefore, the disclosed species are not representative of the entire genus of claimed TEV protease variants.
Yi et al., (Engineering of TEV protease variants by yeast ER sequestration screening (YESS) of combinatorial libraries; PNAS. April 30, 2013. Vol 110. No 18. 7229-7234; cited in the IDS filed 01/27/2025) teaches engineered TEV proteases with increased selectivity and high catalytic turnover (Abstract). Yi teaches 6 protease variants comprising up to 4 substitution mutations (Table 1). However, Yi does not disclose all polypeptides comprising TEV protease active site residues or homologs with up to 5% divergence from instant SEQ ID NOs: 3, 4, or 17 that exhibit improved catalytic efficiency.
In summary, neither the instant specification, nor the prior art, discloses a structure-function relationship between conserved amino acid residues in the claimed protease structure and improved catalytic efficiency. One of ordinary skill in the art cannot reasonably predict which residues of SEQ ID NO:17 may be modified to generate a functional protease with improved catalytic efficiency. Based on the instant disclosure, those skilled in the art would not conclude that the applicant was in possession of all claimed polypeptides comprising TEV protease variants.
Pertinent Prior Art
The closest prior art references:
Yi et al., (Engineering of TEV protease variants by yeast ER sequestration screening (YESS) of combinatorial libraries; PNAS. April 30, 2013. Vol 110. No 18. 7229-7234);
Phan et al., (Structural basis for the substrate specificity of tobacco etch virus protease. J Biol Chem. 2002 Dec 27;277(52):50564-7);
Kapust et al., (Tobacco etch virus protease: mechanism of autolysis and rational design of stable mutants with wild-type catalytic proficiency. Protein Eng. 2001 Dec;14(12):993-1000; cited in the IDS filed 01/27/2025);
Cesaratto et al., (A shortcut across biotechnologies. J Biotechnol. 2016 Aug 10; 231:239-249); and
Blommel et al., (A combined approach to improving large-scale production of tobacco etch virus protease. Protein Expr Purif. 2007 Sep;55(1):53-68).
Yi teaches TEV protease variants comprising combinations of the following substitution mutations: S219P, S120R, D148R, T173A, N177K, M218I, S219P, T17A, T146A, D148P, S153C, S168T, S170A, and G79E (Table 1). Yi teaches that the variants can cleave the TENLYFQSGTRRW substrate at rates of 0.13-6.09 kcat s-1 (Table 1).
Phan teaches the crystal structures of two TEV protease mutants: C151A, and S219D (Abstract). Phan teaches that the structures were solved as complexes with a substrate and a product peptide, respectively (Abstract).
Kapust teaches TEV protease variant comprising the following substitution mutations: S219V (Abstract), S219D, S219E, and S219P (p. 994, col. 1, para 1). Kapust teaches that the TEV protease cleaves the amino acid sequence ENLYFQG/S between QG or QS with high specificity, and that systematic studies have implicated E, Y, Q and, to a lesser extent, G/S, as important specificity determinants (p. 993, Introduction, col. 2, para. 2). Kapust teaches that the wild-type and mutant His–TEV–Arg protease catalytic domains used in their study consisted of amino acid residues 189–424 of the mature (49 kDa) nuclear inclusion a (NIa) protease bracketed by polyhistidine (GHHHHHHH) and polyarginine (RRRRR) sequences on the N- and C-termini, respectively (p. 993, Materials and methods, para. 1).
Cesaratto teaches a number of TEVp mutants, with different rate of cleavage, stability and specificity, and a panel of different target cleavage sites, derived from the canonical ENLYFQ-G/S site (Abstract). Cesaratto teaches a fourfold-more efficient TEVp mutant, called TEV-Fast, that contains two other substitutions in addition to Ser219Val: Gly79Glu and Thr173Ala, the latter abolishing glycosylation of Asn171 (4.3.1. ER targeting, para. 2).
Blommel teaches a self-cleaving MBP-His7-TEV-pR5 protease fusion protein comprising the S219V mutation that can undergo proteolysis in vivo at a TEV protease site in the linker region after MBP to liberate MBP and His7-TEV-pR5 (p. 54, Methods, TEV protease expression vectors).
None of the prior art references teach a TEV protease variant with 100% sequence identity to instant SEQ ID NOs: 3, 4, or 18.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657