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 1-2, 4-7, 9, 11-15, 46, 55-56, 62-71, 75, 77, 80, 85-86, 88, and 91-93 are pending. Claims 20-21, 23-24, 26-29, 31, 33-36, and 45 are newly cancelled. Claims 46, 55-56, 62-71, 75, 77, 80, 85-86, 88, and 91-93 are withdrawn. Claims 1-2, 4-7, 9, and 11-15 are under examination on their merits.
Response to Arguments
Applicant's arguments filed 7/9/2026 have been fully considered but they are not persuasive.
Applicant argues against the written description rejection of claims under 35 U.S.C. 112(a) on the grounds that the amended claims now require at least 90% sequence identity to SEQ ID NO: 1 and the specific amino acid mutations relative to SEQ ID NO: 1 that result in increased transposition efficiency are now recited (Arguments, paragraph 2 on page 11 through paragraph 1 on page 12).
In response, this argument is unpersuasive because although the specification discloses 25 species of mutant SPIN transposase, each of the mutants has a single amino acid point mutation except for the combination of I509R + S511R (specification, Table 1, [0032]). Furthermore, the specification also discloses that only 5 of the mutants have a transposition efficiency greater than the wild-type transposase (specification [00132]). Even if the person of ordinary skill in the art were to combine the amino acid substitutions at each position in Table I, the resulting polypeptide would have approximately 30 amino acid substitutions (95% sequence identity to SEQ ID NO: 1) rather than the 60 amino acid substitutions necessary for 90% sequence identity to SEQ ID NO: 1. However, the person of ordinary skill in the art would have been unable to predict the effect of the combination of all 30 amino acid substitutions on the transposition efficiency of the mutant SPIN transposase relative to SEQ ID NO: 1.
Regarding Applicant’s request for rejoinder of withdrawn claims, per MPEP 821.04, the propriety of a restriction requirement should be reconsidered when all the claims directed to the elected invention are in condition for allowance. Here, none of the claims are in condition for allowance.
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.
(New Rejection Necessitated by Amendment) Claims 1-2, 4-7, 9, and 11-15 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.
Independent claim 1 recites “A mutant SPIN transposase comprising an amino acid sequence at least 90% identical to full-length SEQ ID NO: 1 and comprising one or more amino acid substitutions selected from I509R, I509S, S511N, Ll24K, and E219K when numbered in accordance with SEQ ID NO: 1, wherein the mutant SPIN transposase has increased transposition efficiency in comparison to a wild-type SPIN transposase having amino acid sequence SEQ ID NO: 1.” Claims 2, 4-7, 9, and 11-15 depend from claim 1. Claim 2 recites “The mutant SPIN transposase of claim 1, comprising one or more amino acid substitutions that increase a net charge at a neutral pH in comparison to SEQ ID NO: 1.”
SEQ ID NO: 1 is 602 amino acids long. Therefore, an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 1 has up to 60 amino acid substitutions.
The person of ordinary skill in the art would not have recognized that the inventors, at the time the application was filed, had possession of the claimed genus of mutant SPIN transposases with at least 90% identity to SEQ ID NO: 1 and having increased transposition efficiency in comparison to SEQ ID NO: 1.
The specification discloses 25 species of mutant SPIN transposase. Each of the mutants has a single amino acid point mutation except for the combination of I509R + S511R. The specification also discloses that only 5 of the mutants have a transposition efficiency greater than the wild-type transposase ([00132]). The specification also discloses the hypothesis that substitutions to a positively charged amino acid such as lysine or arginine in proximity to one of the catalytic triad amino acids (D185, D251, and E555) increase transposition efficiency ([00133]). Fig. 5 depicts the wildtype SPIN transposase amino acid sequence with the catalytic triad amino acids and large italicized lettering indicating amino acids that when substituted to a positively charged amino acid increase transposition efficiency ([00134]). Fig. 5 also depicts amino acids that allegedly could be positively charged amino acids based on the protein sequence alignment to the Buster subfamily ([00134]). The Buster subfamily alignment is depicted in Fig. 2. The Buster subfamily is a subfamily of the hAT transposons ([0004]). The specification does not disclose whether the other members of the Buster subfamily have been tested for transposase activity, or whether these are putative transposases.
In total, three amino acid substitutions support the hypothesis that positively charged amino acids in the vicinity of the catalytic triad increase transposition efficiency. However, claim 9 recites “one or more amino acid substitutions that increase a net charge at a neutral pH in comparison to SEQ ID NO: 1, wherein the one or more amino acids are located in proximity to Dl85, D251, or E555, when numbered in accordance to SEQ ID NO: 1.” Claim 11 recites “wherein the proximity is a distance of about 5 to 80 amino acids.” There are an insufficient number of species of positively charged amino acid substitutions in proximity to Dl85, D251, or E555 that increase transposition efficiency of the SPIN transposase mutant relative to SEQ ID NO: 1 for the person of ordinary skill in the art to reasonably predict and visualize the structures of all the species within the claimed genus.
Therefore, although the specification attempts to establish a structure-function relationship between the property of increased transposition efficiency relative to SEQ ID NO: 1, there is insufficient evidence of record to support the claimed genus because of the small number of mutants that actually have increased transposition efficiency relative to SEQ ID NO: 1 (Fig. 4) as well as the lack of functional information disclosed regarding the sequences of the alignment in Fig. 2. An alignment of many hypothetical proteins with only a few characterized proteins would not be sufficient to support a structure-function relationship of the entire class of SPIN transposase proteins.
Pace et al. (Proceedings of the National Academy of Sciences 105.44 (2008): 17023-17028; cited in the Non-Final Action mailed on 4/10/2026) teaches a class of transposons called Space Invaders or SPIN (Abstract). The consensus sequences are over 96% identical over their entire length (2.9 kb) in the genomes of murine rodents (Abstract). Pace hypothesizes the high sequence identity is due to the horizontal gene transfer across divergent species (Abstract). However, Pace generates no mutants of SPIN, nor does Pace functionally characterize any of the transposases.
Li et al. (Proceedings of the National Academy of Sciences 110.6 (2013): E478-E487; cited in the Non-Final Action mailed on 4/10/2026) teaches an active version of red flour beetle Tribolium castaneum SPIN transposase as well as another transposase of the Buster family called TcBuster (Abstract). Li generates mutants of TcBuster (page E482, right column, TcBusterCO Transposase Mutation Results in Increased Transposition in Yeast and Mammalian Cells). Li also teaches several mutants of SPIN (page E479, left column, Results, Resurrection of a SPIN transposon; Supplementary Table S2)., but each of the mutants has less activity than SPINON (Table S2, Activity column). Li specifically teaches the SPINON mutant M8 containing the amino acid substitution M220T, which is one of the claimed amino acid substitutions, but this mutant has less activity than SEQ ID NO: 1 (SPINON).
Hyperactive variants of the Sleeping Beauty and piggyBac transposases are taught by the prior art: see the Abstract of Baus et al. (Molecular Therapy 12.6 (2005): 1148-1156; cited in the Non-Final Action mailed on 4/10/2026) and the Abstract of Yusa et al. (Proceedings of the National Academy of Sciences 108.4 (2011): 1531-1536; cited in the Non-Final Action mailed on 4/10/2026), respectively. However, SPIN transposases differ from both Sleeping Beauty and piggyBac transposases: Li teaches that both TcBuster and SPIN belong to the Buster family of hAT transposases and have different target site selection patterns with respect to mammalian genome features than piggyBac and Sleeping Beauty (page E479, left column, paragraph 3).
Hyperactive variants of TcBuster have also been identified. For example, Largaespada et al. (WO 2018/112415 A1; cited in IDS filed on 3/7/2023) teaches mutants of TcBuster with increased transposition efficiency (Largaespada claim 1 and Tables 2-3). However, TcBuster and SPIN are still sequence-divergent transposases: see the phylogenetic tree of Fig. 1 of Arensburger et al. (Genetics 188.1 (2011): 45-57; cited in the Non-Final Action mailed on 4/10/2026), which shows SPIN transposases in one branch of the tree, separate from TcBuster1.
Given the above analysis, the person of ordinary skill in the art would not have recognized, as of the effective filing date of the claimed invention, that the inventors had possession of the claimed genus of mutant SPIN transposases with at least 90% identity to SEQ ID NO: 1 and having increased transposition efficiency in comparison to SEQ ID NO: 1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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