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 filed 07/27/2026 is acknowledged. Claims 1-20 are pending.
The instant claims are entitled to an effective filing date of 05/19/2021.
Election/Restrictions
Applicant's election without traverse of Group I, claims 1-3 and 7-8, in the reply filed on 07/27/2026 is acknowledged. Applicant’s election without traverse of Y37V, L71V, V72I, and D182G (claim 2), and L71V and L186A (claim 3) for Genus A; and the following for Genus B: p-acetyl-L-phenylalanine (AcF), p-azido-L-phenylalanine (AzF), O-methyl-L-tyrosine (OmeY), p-propargyloxy-L-phenylalanine (OPG), 4-azidomethyl-L-phenylalanine (AzMF), and 4-ido-L-phenylalanine (IPhe) in the reply filed on 07/27/2026 is also acknowledged. The prior art search has been extended to non-elected species: Y37G, Y37L, Y37T, D182S, F183A, L186V (claim 2), and Bpa (claim 8).
Claims 4-6, and 9-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Accordingly, claims 1-3 and 7-8 are under consideration in this action.
Specification
The disclosure is objected to because of the following informalities:
Tables 6 and 11 recite I37, G182, M183, and A186. However, SEQ ID NO: 1 contains Y37, D182, F183 and L186 residues.
Appropriate correction is required.
Claim Objections
Claims 1-3 are objected to because of the following informalities:
Claims 1-3 recite “Tyrosyl-tRNA Synthase (TyrRS)” in line 1, which should be lowercased to “tyrosyl-tRNA synthase (TyrRS)” because the recitations are in the middle of a sentence. As an alternative, claim 1 in line 1 can be amended to recite “tyrosyl-tRNA synthase (TyrRS)”, and claims 2-3 can be amended to recite “TyrRS”.
Claim 2 recites “L71V” twice in line 4, one of which can be deleted.
Appropriate correction is required.
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 1-3 and 7-8 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 inventor, at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a genus of polypeptides that have tRNA synthetase activity. Claim 1 requires a TyrRS polypeptide, or functional fragment thereof, that has at least about 85% amino acid sequence identity to SEQ ID NO: 1 and comprises alteration of an amino acid selected from Y37, L71, V72, Q179, D182, or Q195 and has tRNA synthetase activity. SEQ ID NO: 1 is 424 residues in length, so the claims encompass polypeptides that have about 64 amino acid residues that vary compared to SEQ ID NO: 1, as long as the polypeptide has the required aminoacyl-tRNA synthetase activity. Claims 2-3 do not substantially limit the structure of the required polypeptide, because claim 2 limits at most 8 residues of the polypeptide, and claim 3 limits at most 7 residues of the polypeptide. Claims 7-8 do not limit the structure of the polypeptide in any way. Rather, claims 7-8 further require the polypeptide to have aminoacylation activity specific for one or more noncanonical amino acid. Thus, claims 7-8 require the polypeptide to have an additional function, but the claims do not limit the structure of the polypeptide associated with the recited function. The specification does not disclose a representative number of species of the claimed genus by reduction to practice and does not provide adequate guidance with regard to the structural features of the polypeptide that is required to provide the recited tRNA synthetase activity. Therefore, one of skill cannot immediately envision which polypeptides will have the required functional characteristics, and one could not conclude that Applicant was in possession of the claimed genus of polypeptides at the time the filing, as discussed more fully below.
For claims drawn to a genus, MPEP § 2163(3)(a)(ii) indicates 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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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 instant specification reduces to practice TyrRS mutants that vary compared to SEQ ID NO: 1 by up to 8 amino acid residues (i.e. ≥98% identity match). In example 1, the specification teaches constructing a mutagenesis library of the E. coli Tyrosyl-tRNA synthase. See p. 57 line 9. Degenerate codons at positions Y37, L71, Q179, D182, F183, L186, and Q195 are designed to reduce the size of residues in the active site that are expected to interact with the noncanonical amino acid (ncAA) as it is charged to the cognate tRNACUA. See p. 57 lines 15-18. In example 2, yeast display systems report on ncAA incorporation during screens with fluorescence-activated cell sorting. See p. 57 lines 30-31. In example 3, EcTyrRS libraries are screened against several aromatic and aliphatic ncAA targets to isolate aminoacyl-tRNA synthases capable of charging diverse and unique ncAAs. See p. 64 lines 2-5. A-BPheRS-2 is able to charge BPhe (4-borono-L-phenylalanine) at detectable levels. The specification suggests that incorporation of BPhe into proteins in yeast has not been achieved before. See p. 64 lines 21-22. The A-BPheRS-2 clone has the following mutations: Y37G, L71T, Q179N, G182S, F183V, L186E, and Q196I mutations. See table 8. In example 6, B-PolyT1RS-7 clone is found to be one of the most active clones as it encodes 4 out of 6 ncAAAs. See p. 75 line 26. Tables 24-25 show all of the TyRS clones reduced to practice. Although table 25 includes 62 clones, these clones represent a small fraction of potential SEQ ID NO: 1 mutants because the clones disclosed in table 25 only vary by at most 8 positions relative to SEQ ID NO: 1, Y37, L71, V72, Q179, D182, F183, L186, and Q195.
MPEP 2163(3)(a)(ii) states that “the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation. Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date”. Considering the lack of guidance provided in the specification, one would appraise support from the state of the art to extrapolate the correlation between the claimed polypeptide structure and the required tRNA synthetase function.
With respect to the state of the art on TyrRS polypeptides, Hartman (ChemBioChem 2022), a past filing date reference, discloses that the plasticity of the ecTyrRS active site has been exploited extensively, and a wide variety of amino acids, many of which do not significantly resemble tyrosine, can be incorporated. See p. 9 last passage. Hartman teaches ecTyrRS mutants including one with Y37G, D165G and D182G mutations, and one with Y37G, L56E, L71H, T76G, S120Y, A121H, D182G, F183I, and L186G mutations. Hartman suggests that the mutations are associated with different noncanonical amino acid substrates. See the caption of figure 15. Kiga (Proc Natl Acad Sci U S A 2002) teaches a TyrRS from E. coli that is engineered to preferentially recognize 3-iodo-L-tyrosine (i.e. noncanonical amino acid) rather than L-tyrosine. See the abstract. Thus, Hartman and Kiga illustrate the unpredictability of the relationship between the TyrRS polypeptide structure and aminoacyl-tRNA synthetase function.
In view of the prior art, the instant disclosure does not satisfy the written description requirement because the species disclosed do not adequately represent the substantial variation within the claimed genus. As discussed above, the breadth of potential structures encompassed by the claims is substantial. The instant specification teaches TyrRS clones that vary compared to SEQ ID NO: 1 by up to 8 residues (Y37, L71, V72, Q179, D182, F183, L186, and Q195) and show activity towards noncanonical amino acids (ncAAs). However, this represents a small fraction of the possible number of species within the breadth of the claims. As evidenced by Hartman, TyrRS mutations at positions D165, L56, T76, S120, and A121 may also be associated with activity towards ncAAs. Kiga further suggests that altering the structure of a TyrRS polypeptide for specificity towards a ncAA may consequently hinder its wild-type function for tyrosine. Thus, Hartman and Kiga illustrate the unpredictability of TyrRS polypeptides that accept tyrosine and ncAAs as substrates. Consequently, one of skill could not conclude that Applicant was in possession of the claimed genus at the time the application was filed.
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.
Claim 1-3 and 7-8 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.
Claim 1 is indefinite because it is unclear whether the polypeptide or functional fragment thereof is required to have any tRNA synthetase activity, or specifically Tyrosyl-tRNA Synthetase activity. A broad limitation together with a narrow limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “tRNA synthetase activity” in lines 12-13 and the claim also recites “Tyrosyl-tRNA Synthetase” in line 1 which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 1 recites the term “about” in line 2, which is a term of approximation. The specification discloses that the term “about” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. See p. 30 lines 20-22. However, this description is insufficient because it is unclear whether the disclosed percents of variation are permissible for the claimed “at least about 85% amino acid sequence identity” limitation recited in claim 1 in line 2. As such, the “about 85%” limitation could reasonably be interpreted as 60%, 70%, 80%, etc. Consequently, one of ordinary skill in the art cannot ascertain the metes and bounds of the required percent identity match to SEQ ID NO: 1.
Claim 1 recites “having at least about 85% amino acid sequence identity to the following polypeptide sequence:…(SEQ ID NO: 1), and comprising an alteration at an amino acid position selected from the group consisting of Y37, L71, V72, Q179, D182, and Q195”, which renders the claim indefinite because it is unclear whether the polypeptide is required to be at least about 85% identical to SEQ ID NO: 1 before the alterations, or the polypeptide is required to be at least about 85% identical to SEQ ID NO: 1 in addition to the alteration. In other words, it is unclear whether the claim is requiring the TyrRS polypeptide or functional fragment thereof to be at least about 85% identical to SEQ ID NO: 1 before or after the polypeptide is altered.
Claims 2-3 and 7-8 depend upon claim 1 and are rejected for the reasons set forth above.
Claim 2 recites “further comprising an alteration at an amino acid position wherein: i) Y37 is…; ii) L71 is…iii) V72 is… iv) Q179 is…;v) D182 is…; vi) F183 is…;vii) L186 is…; and viii) Q195 is”, which is indefinite because there are multiple reasonable claim interpretations. In the first interpretation, claim 2 requires the polypeptide of claim 1 to further comprise an additional alteration selected from i)-viii), so that the polypeptide is altered at two positions. This first interpretation is reasonable because claim 2 recites “further comprising an alteration”, which indicates that claim 2 is introducing one alteration requirement in addition to the alteration requirement of claim 1. In the second interpretation, claim 2 encompasses polypeptide embodiments with only one alteration, because claim 2 limits positions Y37, L71, V72, Q179, D182 and Q195, which are recited in claim 1.
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.
Claims 7-8 are 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.
Claims 7-8 fail to include all the limitations of the claim upon which they depend. Claim 1 recites “A Tyrosyl-tRNA Synthetase (TyrRS) polypeptide” in line 1. Claim 7 depends from claim 1 and recites “The polypeptide of claim 1” in line 1. Claim 8 depends from claim 7 and recites “The polypeptide” in line 1. The term “polypeptide” recited in claims 7 and 8 is broader in scope compared to the “Tyrosyl-tRNA Synthetase (TyrRS) polypeptide” recited in claim 1, because a TyrRS polypeptide has aminoacyl-tRNA synthetase activity for tyrosine. As such, claims 7-8 do not include the TyrRS limitation of claim 1.
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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chatterjee (WO 2020/219708).
Regarding claim 1, Chatterjee teaches composition comprising a variant E. coli tyrosyl-tRNA synthetase (EcTyr-RS) wherein the variant EcTyr-RS preferentially aminoacacylates an E. coli tyrosyl-tRNA (EctRNAtyr ) with a tyrosine analog over the naturally-occurring tyrosine amino acid, wherein the variant EcTyr-RS comprises the amino acid sequence of SEQ ID NO:1, or an amino acid sequence with at least 90% sequence identity with the full-length SEQ ID NO:1, wherein the EcTyr-RS variant is mutated, relative to SEQ ID NO:1, such that the leucine (L) at position 71 is replaced with valine (V), the aspartic acid (D) at position 182 is replaced with G, the phenylalanine at position 183 is either conserved or mutated to Y, and the L at position 186 is either conserved, or is replaced with M, I, or V. See claim 1 of Chatterjee. Chatterjee’s SEQ ID NO: 1 is identical to instant SEQ ID NO: 1. See the office action appendix for the alignment. Thus, Chatterjee teaches L71, and D182 alterations.
Regarding claim 2, Chatterjee teaches a variant EcTyr-RS comprising SEQ ID NO:1, or an amino acid sequence with at least 90% sequence identity with the full-length SEQ ID NO:1, wherein the EcTyr-RS variant is mutated, relative to SEQ ID NO:1, such that the leucine (L) at position 71 is replaced with valine (V), the aspartic acid (D) at position 182 is replaced with G, and the L at position 186 is either conserved, or is replaced with M, I, or V. See claim 1 of Chatterjee. Thus, Chatterjee teaches L71V, D182G, and L186V alterations.
Claims 1-2 and 7-8 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wang (US 2012/0077224, as cited in the IDS filed 11/17/2023).
Regarding claim 1, Wang teaches an isolated orthogonal synthetase protein comprising SEQ ID NO: 36 with an Asp265Arg substitution and one to ten additional amino acid substitutions to generate an orthogonal synthetase for a unnatural amino acid (UAA). See claim 19 of Wang. The one to ten additional amino acid substitutions are selected from the group consisting of: Y37G, D182G, L186A; Y37L, D182S, F183A, L186A; Y37I, D182G, F183M, L186A; Y37T, D182T, L183M [sic. F183M]; and Y37G, D182S, F183M. See claim 20 of Wang.
Residues 5-428 of Wang’s SEQ ID NO: 36 are a 100% identity match to instant SEQ ID NO: 1 (residues 1-424), and the positions taught by Wang are identical to that of SEQ ID NO: 1. See the alignment below, Therefore, Wang teaches the instantly required Y37 and D182 alterations.
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736
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Regarding claim 2, Wang teaches Y37G, Y37I, Y37L, and Y37T alterations. Wang teaches D182G and D182S alterations. Wang teaches a F183A alteration. See claim 20 of Wang
Regarding claims 7-8, Wang teaches a E. coli TyrRS, Ome-TyrRS, specific for o-methyl-L-tyrosine (i.e. a noncanonical amino acid). See [0261]. Wang teaches the synthetase, BpaRS, which is specific for p-benzyoylphenylalanine (bpa) (i.e. 4-benzoyl-l-phenylalanine). See [0262]. The following mutations are included for the p-benzyoylphenylalanine (bpa) Y37G, D182G, and L186A. See [0058].
Claim Rejections - 35 USC § 103
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 3 is rejected under 35 U.S.C. 103 as being unpatentable over Chatterjee (WO 2020/219708) in view of Wang (US 2012/0077224).
The teachings of Chatterjee and Wang with respect to claim 1 are set forth above and incorporated herein.
Regarding claim 3, Chatterjee teaches composition comprising a variant E. coli tyrosyl-tRNA synthetase (EcTyr-RS), wherein the EcTyr-RS variant is mutated, relative to SEQ ID NO:1, such that the leucine (L) at position 71 is replaced with valine (V), the aspartic acid (D) at position 182 is replaced with G, the phenylalanine at position 183 is either conserved or mutated to Y, and the L at position 186 is either conserved, or is replaced with M, I, or V. See claim 1 of Chatterjee. Thus, Chatterjee teaches L71, and L186 alterations.
Chatterjee does not teach a combination of alterations selected from (1) Y37L and L71V, (2) Y37G, L71T, and D182S, (3) L71V and L186A, (4) Y37V and L71V, (5) Y37L, L71V, and L186A, and (6) L71I, V72V, Q179Q, D182G, F183M, L186A, and Q195Q.
Wang teaches an isolated orthogonal synthetase protein comprising SEQ ID NO: 36 with amino acid substitutions to generate an orthogonal synthetase for a unnatural amino acid (UAA). See claim 19 of Wang. The substitutions are selected from a group that includes L186A. See claim 20 of Wang. Wang suggests that the L186A mutation is associated with orthogonal synthetases that are particular for p-benzoylphenylalanine, p-azidophenylalanine, and p-acetyl-phenylalanine. See [0058].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to alter the L186 position in the EcTyr-RS variant taught by Chatterjee based on the suggestion of Wang, and in the process arrive at a TyrRS with a L71V and L186A alteration combination. One of ordinary skill in the art would have been motivated to do so because Wang suggests that the L186A mutation is associated with activity particular for the unnatural amino acids (i.e. noncanonical amino acids) p-benzoylphenylalanine, p-azidophenylalanine, and p-acetyl-phenylalanine. There would have been a reasonable expectation of success because Chatterjee teaches mutating position L186 and Wang teaches an identical L186 position with a L186A substitution.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
