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
Applicant's preliminary amendment filed on February 19, 2025 is acknowledged. Claims 1-16 have been canceled. Claims 17-36 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 17-27) and species (claim 21: FKBP and FRB) in the reply filed on January 9, 2026 is acknowledged.
Claims 28-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 9, 2026.
Claims 17-27 are examined on the merits herein.
Priority
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
There is no information disclosure statement provided with the instant application.
Drawings
The drawings were received on February 18, 2022 and May 12, 2025.
The drawings are objected to because 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”. In addition, Figure 1 is not labeled with A), B), or C) as specified on page 4 of the specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). 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. The objection to the drawings will not be held in abeyance.
Specification
The substitute specification filed on July 31, 2025 has been entered.
The disclosure is objected to because of the following informalities:
The last sentence of the last paragraph on page 1 ends with a comma and is missing a period.
The description of Figure 10 on page 8 is not labeled with Figure 10A or Figure 10B as in the drawings.
Appropriate correction is required.
Claim Objections
Claims 18-21 are objected to because of the following informalities:
Claim 18 recites in part “and the second protein or domain” and should recite “and the second protein or protein domain” (emphasis added).
To improve the grammar of the claim, claim 19 should recite “rapalog, gibberellin, abscisic acid, or any known small molecule.”
Claim 20: “wave length” should be one word instead of two words.
Claim 21 recites in part “and the second protein or domain” and should recite “and the second protein or protein domain” (emphasis added).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 17-27 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 17, 22, and 23 are indefinite because the word “preferably” and “particularly” renders the claim indefinite since it is unclear whether the limitations following the word “preferably” and “particularly” are part of the claimed invention. See MPEP § 2173.05(d). The Examiner will interpret these claims as limitations that are optional and are not required.
Claims 18-22 and 24-27 are indefinite because the claims depend from a rejected claim without addressing the issue of the rejected claim.
Regarding claim 19, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Written Description
Claim 19 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 19 is drawn to the provision of a genus of any known small molecule defined solely by function. The specification discloses that selection of heterodimerization domains allow regulated expression in cells upon presence of one or more inductors that can provide external regulator signals [page 3]. The specification defines the term “heterodimerization inductor” as a signal, a chemical or non-chemical ligand, which cause the heterodimerization of protein domains that do not have intrinsic affinity with each other and cannot be connected independently in the absence of a heterodimerization ligand or signal. A heterodimerization inductor can be a small molecule or light with certain wavelength [page 9]. Further, the addition of a chemical inductor of heterodimerization can trigger heterodimerization of the first component and the second component by heterodimerization of two protein partners thereby resulting in a functional modified CRISPR/Cas system tethered with certain exonucleases which can influence the genome modification of any gene of interest [page 13]. Thus, the claim encompasses a large genus of any known small molecule defined solely by function to induce heterodimerization of the first protein or protein domain and the second protein or protein domain of claim 17.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
The specification describes that a heterodimerization inductor is a signal, a chemical or non-chemical ligand, which cause the heterodimerization of protein domains that do not have intrinsic affinity with each other and cannot be connected independently in the absence of a heterodimerization ligand or signal. Specifically, a heterodimerization inductor can be a small molecule such as a rapalog, abscisic acid, or gibberellin [page 9]. The specification also discloses the following:
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[page 13]. Further, the addition of a chemical inductor of heterodimerization can trigger heterodimerization of the first component and the second component by heterodimerization of two protein partners thereby resulting in a functional modified CRISPR/Cas system tethered with certain exonucleases which can influence the genome modification of any gene of interest [page 13]. No description is provided of any other known small molecules.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of a small group of known small molecules. The results are not necessarily predictive of other small molecules falling within the broadly claimed genus of any known small molecule not limited to any particular structure. Thus, it is impossible for one to extrapolate from the limited examples described herein those known small molecules that would necessarily meet the structural/functional characteristics of the rejected claim.
Gurevich et al. (Handb Exp Pharmacol 2014) discloses that virtually all currently used therapeutic agents are small molecules largely because the development and delivery of small molecule drugs is relatively straightforward. Small molecules have serious limitations: drugs of this type can be fairly good enzyme inhibitors, receptor ligands, or allosteric modulators. However, most cellular functions are mediated by protein interactions with other proteins, and targeting protein–protein interactions by small molecules presents challenges that are unlikely to be overcome with these compounds as the only tools [abstract].
Singh et al. (Adv Protein Chem Struct Biol 2018) discloses that proteins form homo-, hetero-, or oligomerization in the cellular environment to regulate the cellular processes. Protein–protein interactions (PPIs) can be inhibited by antibodies, small molecules, or peptides, and inhibition of PPI has therapeutic value [abstract].
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of any known small molecule that is capable of inducing heterodimerization of the first protein or protein domain and the second protein or protein domain of claim 17.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claim 19.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 26 and 27 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claims 26 and 27 recite the following:
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The specification defines the term “cell” on page 10 as the following:
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In addition, the specification discloses that the invention further provides the combination, the nucleic acid molecule(s) or the vector for use in medicine, or for use as a medicament [page 17, last paragraph].
Thus, in view of the specification, the broadest reasonable interpretation of the claimed cell in claim 26 and claim 27 part iv) includes a human being. Therefore, the claims are directed to nonstatutory subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 17-27 are rejected under 35 U.S.C. 103 as being unpatentable over Komor et al. (Nature 2016) in view of Inobe et al. (Journal of Bioscience and Bioengineering 2016).
Claim 20 depends from claim 18, which recites “wherein heterodimerization of the first protein or protein domain and the second protein or domain is inducible via a chemical or non-chemical signal.” Claim 20 recites “wherein the non-chemical signal inducing heterodimerization is light with a predetermined wave length.” Thus, claim 20 reads on heterodimerization inducible via a chemical signal or light with a predetermined wave length. Claim 20 reads on the elected species of FKBP and FRB based on chemical heterodimerization.
Regarding claims 17-21, Komor et al. teaches a new approach to genome editing that enables the direct, irreversible conversion of one target DNA base into another in a programmable manner, without requiring dsDNA backbone cleavage or a donor template. Specifically, Komor et al. engineered fusions of CRISPR/Cas9 and a cytidine deaminase enzyme that retain the ability to be programmed with a guide RNA, do not induce dsDNA breaks, and mediate the direct conversion of cytidine to uridine, thereby effecting a C→T (or G→A) substitution [abstract].
Regarding claims 22 and 23, Komor et al. teaches that conjugation of dCas9 with an enzymatic or chemical catalyst that mediates the direct conversion of one base to another could enable RNA-programmed DNA base editing [page 420, right column, first paragraph]. Komor et al. also teaches that the deamination of cytosine (C) is catalysed by cytidine deaminases and results in uracil (U), which has the base-pairing properties
of thymine (T). Most known cytidine deaminases operate on RNA, and the few examples that are known to accept DNA require single-stranded DNA. Recent studies on the dCas9–target DNA complex reveal that at least nine nucleotides (nt) of the displaced DNA strand are unpaired upon formation of the Cas9–guide RNA–DNA ‘R-loop’ complex. Indeed, in the structure of the Cas9 R-loop complex, the first 11 nt of the protospacer on the displaced DNA strand are disordered, suggesting that their movement is not highly restricted. It has also been speculated that Cas9 nickase-induced mutations at cytosines in the non-template strand might arise from
their accessibility by cellular cytosine deaminase enzymes. We reasoned
that a subset of this stretch of ssDNA in the R-loop might serve as an efficient substrate for a dCas9-tethered cytidine deaminase to effect direct, programmable conversion of C to U in DNA [page 420, right column, first full paragraph].
Regarding claims 24-27, Komor et al. teaches HEK293T cells were seeded on 48-well collagen-coated BioCoat plates (Corning) and transfected at approximately 85% confluency. Briefly, 750 ng of BE and 250 ng of sgRNA expression plasmids were transfected using 1.5 μl of Lipofectamine 2000 (ThermoFisher Scientific) per well according to the manufacturer’s protocol [page 425, right column, Transfections]. Komor et al. also teaches that deaminase and fusion genes were cloned into pCMV
(mammalian codon-optimized) or pET28b (E. coli codon-optimized) backbones [page 425, left column, Cloning].
However, Komor et al. does not teach the following:
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Komor et al. also does not teach inducing heterodimerization via a chemical signal (claims 18 and 20) wherein the chemical inducing heterodimerization is a small molecule (claim 19). Komor et al. also does not teach that the first protein or protein domain and the second protein or protein domain is FKBP and FRB (claim 21).
Inobe et al. demonstrated that fusion proteins comprising the induced heterodimer formation proteins FRB and FKBP formed various oligomers upon addition of rapamycin [abstract]. Inobe et al. teaches that one of the most useful dimerization systems is the FRB-FKBP-rapamycin heterodimer formation system. Rapamycin, an antifungal antibiotic macrolide, simultaneously binds to the 12-kDa FK506 binding protein (FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) and mediates their tight heterodimer formation. By the conditional dimerization of proteins of interest fused to FKBP or FRB on the addition of rapamycin, various cellular functions, such as gene expression and protein translocation, were controlled artificially [page 40, left column, second paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the fusion protein of Komor et al. with the proteins of Inobe et al. because Komor et al. taught that fusion of CRISPR/
Cas9 and a cytidine deaminase enzyme retains the ability to be programmed with a guide RNA, does not induce dsDNA breaks, and mediates the direct conversion of cytidine to uridine, thereby effecting a C→T (or G→A) substitution and Inobe et al. taught that fusion proteins comprising the induced heterodimer formation proteins FRB and FKBP formed various oligomers upon addition of rapamycin and generation of an inducible tetramer formation system was achieved by adjusting the configuration of fusion proteins. One would have made such a substitution in order to predictably form a complex that retains the function of CRISPR/Cas9 and a cytidine deaminase enzyme as taught by Komor et al.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637