DETAILED ACTION
This action is in reply to papers filed 5/2/2025. Claims 134 and 164-182 are pending and examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250382334A1, Published 12/18/2025.
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 134 and 164-182 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 recites, inter alia, “….contacting the target cell with a lipid containing particle
that comprises: (1) a fusion protein that comprises: (i) the gene editing agent, (ii) a cleavable linker, and (iii) a nuclear export sequence (NES), and (2) the gene editing agent cleaved from the fusion protein, wherein the gene editing agent comprises a napDNAbp, and wherein the fusion protein..”
At issue is the recitation of (2). Given the broadest reasonable interpretation, the lipid containing particle contacting the cell comprises (1), as set forth above, and (2), as set above. This is confusing. It is unclear how the target cell is contacted with a lipid particle that contains the gene editing agent comprised within a fusion protein AND the same gene editing agent cleaved from the fusion protein. This is because there is no step of cleaving the gene editing agent from the fusion protein such that the gene editing agent is cleaved. Even if a step was recited, it remains unclear how the target cell will be contacted with both the fusion protein comprising, inter alia, the gene editing agent and separately, the gene editing agent contained within the fusion protein. Claim 177 is separately rejected as it refers to a “cleavage product”. Again, no step of cleavage is recite in independent claim 134 and as a consequence, the metes and bounds of a “cleavage product” are unclear.
Dependent claims are included in this rejection as they fail to clarify the issues set forth above.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 134, 164-169, 171 and 175 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Liu et al. (PgPub US20200172931A1, Published 6/4/2020).
Claim interpretation: In view of the 112 (b) rejection above, Examiner is interpreting claim 134 to comprise contacting the target cell with only (1) of claim 134 and that the fusion protein (1) is delivered to the target cell.
Liu et al. disclose evolved base editors (as in claim 169) which overcome deficiencies of those in art (including increased efficiency and/or decreased requirement for specific sequence-context at an editing site) and which are obtained a result of a phage-assisted continuous evolution (PACE) system (Abstract). In particular, Liu discloses the instant specification provides for evolved cytidine base editors which overcome deficiencies of those in art (including increased efficiency and/or decreased requirement for specific sequence-context at an editing site) and which are obtained a result of a phage-assisted continuous evolution (PACE) system. In addition, the instant specification provides for nucleic acid molecules encoding and/or expressing the evolved base editors as described herein, as well as expression vectors or constructs for expressing the evolved base editors described herein, host cells comprising said nucleic acid molecules and expression vectors, and compositions for delivering and/or administering nucleic acid-based embodiments described herein (Pg. 1, para. 7).
Regarding claim 134, Liu discloses methods comprising delivering one or more polynucleotides or one or proteins transcribed therefrom, to a host cell. Liu discloses non-viral vector delivery systems, such as complexion with a liposome (lipid containing particle), can be used to administer nucleic acids encoding components of a base editor to cells in a host organism (Pg. 78-79,para. 615). In particular, Liu discloses evolved base editor fusion protein comprising: (i) a nucleic acid programmable DNA binding protein (napDNAbp) (as in(as in claim 134 1(i)) and claim 134 (2)); (ii) a cytidine deaminase described (as in claim 166); and (iii) a uracil glycosylase inhibitor domain (UGI) (Pg. 26, para. 342). The nucleic acid programmable DNA binding protein (napDNAbp) can be a Cas9 domain (as in claim 164) (Pg. 26, para. 342). The Cas9 domain can be a nuclease inactive Cas9 (dCas9) or a Cas9 nickase (nCas9) (as in claim 165) (Pg. 26, para. 342). Liu discloses that in some embodiments, the deaminase is an adenosine deaminase, which catalyzes the hydrolytic deamination of adenine or adenosine (e.g., an engineered adenosine deaminase that deaminates adenosine in DNA) (as in claim 167) (Pg. 12, para. 236). Alternatively, in some embodiments, the deaminase or deaminase domain is a cytidine deaminase domain (as in claim 168), catalyzing the hydrolytic deamination of cytosine to uracil (Pg. 12 ,para. 236). Liu further discloses the base editor described herein may comprise any additional protein sequence, and optionally a linker sequence between any two domains (as in claim 134 (ii) and claim 171) (Pg. 52, para. 475). Examples of protein domains that may be fused to a base editor or component thereof include localization sequences such as nuclear export sequences (as in claim 134 (iii) (Pg. 52, para. 475-477).
Liu discloses that to increase base editing efficiency, the inventors sought to identify the factors that limit base editing efficiency in cells. It was surprisingly found by the inventors that expression and nuclear localization in human cells imposed key bottlenecks on editing efficiency. The inventors discovered that by optimizing codon usage, using improved nuclear localization sequences (NLSs) (as in claim 175), and performing ancestral reconstruction of deaminases resulted in base editors with greatly increased editing efficiency, often more than doubling target nucleotide conversion yields as compared to the unmodified counterpart editors (Pg. 55,para. 494).
Accordingly, Liu anticipates the claimed invention.
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.
Prior Art Rejection 2
Claim 170 rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (PgPub US20200172931A1, Published 6/4/2020) as applied to claims 134, 164-169, 171 and 175 and further in view of Kleinstiver et al. (PgPub US20210284978A1, Published 9/16/2021).
The teachings of Liu et al. are relied upon as detailed above. And although Liu teaches an adenine base-editor, Liu et al. fails to teach the base editor is an ABE8e editor (as in claim 170).
Before the effective filing date of the claimed invention, Kleinstiver disclosed a fusion protein comprising a linker between the dCas9 variant and a heterologous functional domain, such as an ABE8e editor (as in claim 170) (Abstract; Pg. 1,para. 115). Kleinstiver discloses the fusion protein can be used for altering the genome of a cell (Pg. 17, para. 120; Pg. 27, para. 208).
When taken with the teachings of Liu et al., one of ordinary skill in the art would have found it prima facie obvious to use the ABE8e editor in the method of Liu et al. because Kleinstiver teaches ABE8e improved the base editing efficiencies of SpG and SpRY.
Thus, the modification would have been prima facie obvious.
Prior Art Rejection 3
Claim 172-174 and 176-179 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (PgPub US20200172931A1, Published 6/4/2020) as applied to claims 134, 164-169, 171 and 175 and further in view of Doudna et al. (PgPub US20230193255A1, Filed 11/15/2019) and Robert et al. (Mol Biotechnol. 2017 Jan;59(1):9-23.).
The teachings of Liu et al. are relied upon as detailed above. However, Liu et al. fails to teach the fusion protein further comprises a gag protein (as in claim 172).
Before the effective filing date of the claimed invention, Doudna et al. teach a nucleic acid comprising a nucleotide sequence encoding a pseudo typed VLP(Pg. 21, para. 195), such as a vesicular stomatitis virus (VSV) glycoprotein (VSV-G protein) (as in claim 179) (Pg. 22, para. 196), comprising a fusion polypeptide that comprises: a) a retroviral gag polyprotein (as in claim 172) comprising a matrix (MA) polypeptide, a capsid (CA) polypeptide, and a nucleocapsid (NC) polypeptide; b) one or more therapeutic polypeptides; and c) one or more heterologous protease cleavage sites (Pg. 5, para. 81), wherein the one or more heterologous protease cleavage sites is between the gag polyprotein (as in claim 178) and the therapeutic polypeptide, wherein a suitable therapeutic polypeptide includes a base editor (Pg. 45+, para. 298).
Continuing, Doudna teaches a therapeutic polypeptide is a fusion therapeutic polypeptide comprising: i) a therapeutic polypeptide; and ii) one or more heterologous fusion partners (one or more heterologous fusion polypeptides). In some cases, a fusion therapeutic polypeptide comprises one or more localization signal peptides. In some cases, a fusion CRISPR/Cas effector polypeptide comprises one or more localization signal peptides (Pg. 66,para. 439). Suitable localization signals (“subcellular localization signals”) include, e.g., a nuclear localization signal (NLS) for targeting to the nucleus; a sequence to keep the fusion protein out of the nucleus, e.g., a nuclear export sequence (NES) (as in claim 174); a sequence to keep the fusion protein retained in the cytoplasm. In one embodiment, Doudna teaches the heterologous polypeptide is a pseudotyping viral envelope protein that provides for binding to a target cell, wherein said protein is derived from the Moloney murine leukemia virus (Mo-MLV) (as in claim 176) (Pg. 45,para. 290).
And although Doudna and Liu et al. teach a nuclear export signal, neither Doudna nor Liu teach the NES is inserted between a gag protein and the editing agent (as in claim 173).
Before the effective filing date of the claimed invention, Robert et al. taught that it has been shown that insertion of a nuclear export signal (NES) could improve the packaging effectiveness of transcription factors within VLPs . Therefore, the same strategy was adopted by inserting an optimized NES of protein kinase inhibitor type into VP16KLF4 (Fig. 6a). Robert teaches transduced cells with VLP-Gag-NES-VP16KLF4 (as in claim 173) had a fluorescence index of 1.4- and 2.4-fold superior to cells transfected with pGag-VP16KLF4 (Pg. 17).
When taken with the teachings of Liu et al., one of ordinary skill in the art would have found it prima facie obvious to include a gag protein in the method of Liu et al. because Doudna teaches gag proteins help drive particle formation. Moreover, one of ordinary skill in the art would have found it prima facie obvious to place the NES between the gag protein and editing agent because Robert observed superiority when the NES was inserted between the a gag protein and a heterologous protein.
Thus, the modification would have been prima facie obvious.
Prior Art Rejection 4
Claim 180 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (PgPub US20200172931A1, Published 6/4/2020) as applied to claims 134, 164-169, 171 and 175 .
The teachings of Liu et al. are relied upon as detailed However, Liu fails to teach the NH2-[1X-3X NES]-[the cleavable linker]-[the gene editing agent]-COOH, wherein each instance of]-[ independently comprises an optional linker (as in claim 180).
However, such a structure would have been prima facie obvious in view of Liu’s fusion protein comprising NH2-[NLS]-[cytidine deaminase]-[napDNAbp]-[UGI]-[UGI]-[NLS]-COOH, wherein each instance of “-” comprises an optional linker and wherein Liu teaches an equivalency in the structure of localization sequences (Pg. 51,para. 464 and Pg. 52, para. 477).
Allowable Subject Matter
Claims 181-182 are free of the art.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
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