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 1-32 and 35-65 are pending. Claims 33-34 are newly cancelled. Claims 1-27, 50-51, and 53-63 are withdrawn. Claims 28-32, 35-49, 52, and 64-65 are under examination on their merits.
Response to Arguments
Applicant's arguments filed 7/17/2026 have been fully considered but they are not persuasive.
Applicant argues against the written description rejection of claims 28-32, 35-49, 52, and 64 under 35 U.S.C. 112(a) on the grounds that the amended claims ensure that the claimed variants preserve both the overall structural scaffold and the specific functional residues that the inventors identified as essential for the invention (Arguments, bottom paragraph on page 13).
In response, this argument is unpersuasive because Applicant discloses exactly nine amino acid substitutions in the iLight variant (as recited in dependent claim 32). Each of these amino acid substitutions is made together in a single variant (see Table 1 starting on page 14 of the specification). SEQ ID NO: 2, 3, and 4 are 532, 872, and 1049 amino acids long, respectively. Thus, an amino acid sequence with at least 90% identity to SEQ ID NO: 2, 3, or 4 differs by up to 53, 87, and 104 amino acids. The person of ordinary skill in the art would not have recognized that the inventors had possession of the claimed genus of variants, as discussed below in the written description rejection under 35 U.S.C. 112(a).
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 the Amendment) Claims 28-32, 35-49, 52, and 64 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.
Claim 28 recites a genus of light-responsive polypeptides comprising at least 90% sequence identity to SEQ ID NO: 2, 3, or 4 or comprising the amino acid sequence of SEQ ID NO: 2, 3, or 4, wherein the light-responsive polypeptide comprises at least the amino acid substitutions I68F, R295H, and L464V relative to SEQ ID NO: 1. SEQ ID NO: 2, 3, and 4 are 532, 872, and 1049 amino acids long, respectively. Table 1 of the specification describes each of the sequences. Each of SEQ ID NO: 2-4 comprise all of the mutations I68F, H80Q, A86T, R90S, S242C, R274K, R295H, I360V, and L464V. SEQ ID NO: 3 additionally comprises LexA408 DNA binding domain at positions 1-87. SEQ ID NO: 4 additionally comprises a Gal4 DNA binding domain at positions 1-65. Table 2 depicts two additional IsPadC variants with subsets of the 9 mutations (specification page 54).
Claims 29-49 depend from claim 28. Claim 29 recites that the light-responsive polypeptide is associated with a chromophore and capable of (i) switching from a first state to a second state when exposed to illumination by a first wavelength and (ii) switching from a second state to the first state when exposed to illumination by a second wavelength, or returning from the second state to the first state in darkness. Claim 38 recites that at least a portion of the light-responsive polypeptide exists in a dimeric form in the first state. Claim 39 recites that at least a portion of the light-responsive polypeptide exists in a tetrameric form in the second state. Claim 42 requires the first wavelength and the second wavelength are in far-red or near-infrared spectrum. Claim 45 limits the second wavelength to between about 740 nm and about 800 nm. Claim 52 is drawn to a polypeptide encoded by the polynucleotide of claim 1. The polypeptide encoded by the polynucleotide of claim 1 is a chimeric polypeptide comprising a light-responsive polypeptide linked to a DNA-binding domain, wherein the light-responsive polypeptide has at least 90% identity to SEQ ID NO: 1 (wild-type IsPadC-PCM, see Table 1 of the specification on page 14).
These dependent claims set forth a variety of functional requirements. Namely, the specific wavelengths for the transition from a first state to a second state and from a second state to a first state, as well as a dimeric form in the first state, and a tetrameric form in the second state.
Applicant discloses nine amino acid substitutions in the iLight variant (as recited in dependent claim 32). Each of these amino acid substitutions is made together in a single variant (see Table 1 starting on page 14 of the specification). The specification hypothesizes that the amino acid substitutions improve protein folding and biliverdin binding, which is needed for the formation of the IsPadC-PCM dimer (lines 7-9 on page 64). The variant with all nine amino acid substitutions is called “iLight.” Only the iLight variant is characterized with regards to the wavelengths of light required for the photoconversion from a first state to a second state. The iLight variant can be photoconverted by 640-720 nm light with a maximum photoconversion efficiency at 700 nm (page 58, lines 23-30, Fig. 3B). iLight returns from the Pfr state back to the ground Pr state under illumination with 780 nm light (lines 3-4 on page 59). However, the required wavelengths for photoconversion between the first and second states are not disclosed for any other variants except iLight.
Regarding the formation of a tetramer (dependent claims 39-40), the specification hypothesizes that I68F, R295H, and L464V amino acid substitutions are the most important based on the results depicted in Fig. 2E, 3F, and 15 (lines 17-19 on page 63). The I68 residue is located in the PAS domain and adds to the overall iLight rigidity and may facilitate the biliverdin incorporation, whereas the R295 residue is located in the GAF domain and may be involved in the light-induced interaction of the two iLight dimers, resulting in their tetramerization (lines 19-27 on page 63). The specification discloses that the N-terminus of IsPadC in the Pr ground state forms an α-helical structure that is turned by its N-terminus towards the PHY domain because of the interaction with the tongue structure (lines 19-21 on page 59). However, 660 nm light causes the PHY tongue to restructure from β-sheets into an α-helix in only one protomer of the IsPadC-PCM dimer, whereas another IsPadC PCM protomer in the photoactivated dimer still remains in the Pr state (lines 19-25 on page 59). The specification concludes that these structural features of the IsPadC-PCM do not allow fusion of DNA-binding domains to the N-terminus of each protomer in the photoactivated IsPadC-PCM dimer (lines 27-30 on page 59). The specification discloses first assembling two dimers, each dimer containing DNA-binding domains, and then photoactivating them to form an active tetramer at the target DNA sequence (Fig. 4A; lines 1-3 on page 60). Each of the 9 amino acid substitutions is tested individually for the ability to suppress a target gene sequence, which is a function of the variant’s ability to form a tetramer upon photoactivation (Fig. 2E and specification, page 58, lines 14-17). The complexity of the nature of the interactions within the protein structure during photoactivation and the importance of even the N-terminus of the protein clearly indicate that the person of ordinary skill in the art cannot reasonably predict and visualize the structures of all the species within the claimed genus of variants with these functional requirements (formation of a dimer in a first state, formation of a tetramer in a second state, and photoconversion between the first and second state at specific wavelengths of light).
Gourinchas et al. (Sci Adv 3: e1602498." 2017; hereafter Gourinchas 2017) teaches PadC from Idiomarina sp. A28L (IsPadC) with accession WP_007419415 (Materials and Methods, Protein expression and purification, left column, paragraph 1 on page 8). WP_007419415 is 98% identical to the instant SEQ ID NO: 2 (OA Appendix A). Gourinchas discloses light-responsive truncation variants of IsPadC: see Table 1 and Supplementary Figure S8. However, each of these truncations excludes the photosensory module because the photosensory module ends at amino acid residue 510 and each of these truncations start at amino acid residue 514: compare Fig. 1a of Gourinchas et al. (Elife 7 (2018): e34815; hereafter Gourinchas 2018), which shows the amino acid residues of the photosensory module, to Table 1 of Gourinchas et al., (Sci Adv 3: e1602498 (2017); hereafter Gourinchas 2017), which shows the positions of the truncations. Gourinchas 2017 generates variants of IsPadC in the coiled-coil (cc) region, which is not part of the photosensory module (see page 4, left column, paragraph after Fig. 2 of Gourinchas 2017 and compare to Fig. 1a of Gourinchas 2018, which excludes the cc module from the photosensory module).
The light-responsive behavior of IsPadC is based upon the three-dimensional structure of the protein and the association of the biliverdin cofactor within this three-dimensional structure. Gourinchas 2017 teaches that illumination with 700 nm (far-red) light drives the transition from the Pfr to Pr state (Table 1), whereas illumination with red light at 630 nm drives the transition from the Pr to Pfr state (left column, paragraph 1 on page 10).
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 light-responsive variants with these functional requirements (formation of a dimer in a first state, formation of a tetramer in a second state, and photoconversion between the first and second state at specific wavelengths of light). There are an insufficient number of species of the genus disclosed within the specification or taught by the prior art and the structure-function correlation is not established either in the specification or in the prior art.
Allowable Subject Matter
Claim 65 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.
The following is a statement of reasons for the indication of allowable subject matter: the prior art does not teach a light-responsive polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
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.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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