DETAILED ACTION
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 .
Election/Restrictions
Applicant's election with traverse of Group II, claims 20-23, 33-36, 43, and 46, alongside the species of (a) present in claims 8-9, 18, 21-23, 40, 43, and 46, in the reply filed on 10 March 2026 is acknowledged. The traversal is on the ground(s) that the Written Opinion of the International Searching Authority issued for PCT/EP2021/077682, to which the instant application claims benefit, did not deem the claims to lack unity of invention in view of WO 2016/166310 (Remarks; pg. 2).
This is not found persuasive because Applicant has not provided any specific arguments pertaining to the art cited in the Restriction/Election requirement filed 11 December 2025. Applicant has not provided any arguments pertaining to how the technical feature makes a contribution over the art cited in the Restriction/Election requirement filed 11 December 2025. Although the Written Opinion of the International Searching Authority did cite the previously cited WO 2016/166310 document utilized in the previously pending restriction requirement, Applicant has not provided any arguments pertaining to how the shared technical feature makes a contribution over the art cited.
Accordingly, the requirement is still deemed proper and is therefore made FINAL.
Claims 1, 3-4, 6-9, 18, and 37-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10 March 2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for Figures 1-26 are preceded by the word "Figure" instead of the abbreviation "FIG.".
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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in Figure 1 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Regarding claims 20-23, 35, 43, and 46, MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.” Examiner suggests utilizing parentheses instead of periods to delineate the different options present in the claims.
Regarding claim 22, the claim recites the following phrase in part (a) of the claim: “wherein the self-splicing intron is 3’ of and in-frame with the start codon and a POI when expressed from the polynucleotide comprises […]”. Examiner suggests amending the phrase to the following to improve clarity: “wherein the self-splicing intron is 3’ of and in-frame with the start codon and a POI, when expressed from the polynucleotide, comprises […]”. The additional commas in the suggested phrase are required in order to correctly incorporate the clause “when expressed from the polynucleotide” within the middle of the phrase.
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.
Claim(s) 20-21 and 33-36 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thompson ( "Group I aptazymes as genetic regulatory switches." BMC biotechnology 2.1 (2002): 21).
Regarding claim 20, the claim requires that the at least one self-splicing intron includes 5’ and 3’ exon nucleotide sequences. Because the exon sequences as claimed do not require that the exons encode different exon sequences, or that the exon sequences comprise a specific claimed structure, the claim is interpreted as encompassing a self-splicing intron that is inserted within a single gene comprising exons such that the intron has exon sequences 5’ and 3’ relative to the self-splicing intron.
Thompson is drawn towards a study concerned with the control of gene expression through the use of self-splicing introns (Abstract). Regarding the isolated polynucleotide, Thompson teaches the use of a plasmid construct (i.e., a polynucleotide) that was transformed into cells (i.e., the plasmid is isolated polynucleotides prior to the transformation (page 10, column 2, paragraph 5), the construct comprising a polynucleotide sequence encoding (ii) a thymidylate synthase gene (i.e. a polynucleotide sequence encoding an ROI), wherein (b) the polynucleotide sequence is interrupted by an intron that is self-splicing (i.e., the self-splicing intron is located within the polynucleotide portion encoding the ROI) (page 5, column 1, last paragraph), and whose splicing activity is under the control of an aptamer, wherein the aptamer has binding affinity for theophylline (i.e. an inducer) (see Figure 2). Regarding part (i), Thompson teaches that upon induction with theophylline, the cells were able to express the thymidylate synthase gene following the self-splicing of the inserted intron (i.e., the gene thymidylate synthase must inherently comprise a promoter functional in a cell) and grow in media (pg. 5, column 1, last paragraph to column 2, first paragraph). Regarding part (iii), Thompson teaches that the intron interrupts the thymidylate synthase gene (i.e., as discussed above, a person of ordinary skill in the art would recognize that the intron is inserted within the interrupted thymidylate synthase gene such that intron comprises 5’ and 3’ thymidylate synthase exon nucleotide sequences) (page 5, column 1, last paragraph).
Regarding claim 21, Thompson teaches that (a) when cells transformed with the isolated plasmid were placed in media containing thymidine, colony growth was observed mediated by the expression of the previously interrupted thymidylate synthase gene (i.e., the ROI was translatable into a POI) (pg. 5, column 1, last paragraph to column 2, first paragraph).
Regarding claim 33, Thompson teaches the use of an expression plasmid (i.e., an expression vector) comprising the construct described above as applied to claim 20.
Regarding claim 35, the instant specification does not define the claimed “kit” as comprising any specific structural components. Accordingly, the compositions of parts (i) and (ii) are discussed above as applied to claim 20 because Thompson teaches both the use of an expression plasmid (i.e., a composition) comprising the claimed polynucleotide and a theophylline inducer (i.e., a composition comprising an inducer) that can activate the self-splicing activity of the claimed intron.
Regarding claims 34 and 36, Thompson teaches that the plasmid may be transformed into host cells and expressed within the cells such that an ROI may be expressed and translated into a functional protein (i.e., a POI) (pg. 5, column 1, last paragraph to column 2, first paragraph).
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.
Claim(s) 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Thompson ( "Group I aptazymes as genetic regulatory switches." BMC biotechnology 2.1 (2002): 21) as applied to claims 20-21 and 33-36 above, and further in view of Costa ("Fusion tags for protein solubility, purification and immunogenicity in Escherichia coli: the novel Fh8 system." Frontiers in microbiology 5 (2014): 63).
Regarding claims 22-23, Thompson anticipates claims 20-21 and 33-36 as described above.
It is noted that the intron of Thompson is 3’ of, an in-frame with, the start codon of the polynucleotide encoding the ROI, as discussed above, and that the polynucleotide is rendered contiguous by the self-splicing of the intron.
Thompson does not teach or suggest that the POI, when expressed from the polynucleotide, comprises an amino acid tag that is encoded by the polynucleotide of claim 20 (Claim 22). Thompson does not teach or suggest that the polynucleotide further comprises a polynucleotide encoding an additional amino acid sequence (Claim 23).
Costa is drawn towards a review study concerned with fusion tags for protein solubility, purification, and immunogenicity in E. coli (Abstract). Costa teaches that there are many different fusion tags that are fused to recombinant proteins expressed within E. coli cells are known in the art to enhance the solubility of the recombinant protein (pg. 7; see Table 1). Costa teaches that the tags can be fused to either the N-terminus or C-terminus of a recombinant protein and that N-terminal tags are advantageous because they provide a reliable context for efficient translation initiation, in which fusion proteins take advantage of efficient translation initiation sites on the tag and they can be removed leaving none or few additional residues at the native N-terminal sequence of the target protein (pg. 6).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed POI comprising an amino acid tag through the use of a polynucleotide sequence encoding the amino acid tag because it would have merely amounted to a simple combination of known prior art elements according to known methods to yield predictable results. Because Costa teaches that fusion tags can be used in a similar manner as Thompson, namely the expression of a recombinant protein in an E. Coli cell, then one would have had a reasonable expectation of success in using a fusion tag linked to the POI, translated from the ROI of Thompson, through the use of a polynucleotide sequence encoding the fusion tag. And because Costa teaches that using the fusion tags increases the solubility of the recombinant proteins, one would have been motivated to do so in order to increase the solubility of the self-spliced thymidylate synthase gene.
Claim(s) 43 and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Thompson ( "Group I aptazymes as genetic regulatory switches." BMC biotechnology 2.1 (2002): 21) as applied to claims 20-21 and 33-36 above, and further in view of Vigouroux ("CRISPR tools to control gene expression in bacteria." Microbiology and Molecular Biology Reviews 84.2 (1 April 2020): 10-1128).
Regarding claims 43 and 46, Thompson anticipates claims 20-21 and 33-36 as described above.
Thompson further teaches that the self-splicing intron construct can be used to develop new gene therapies in which patients rely upon drugs that can differentially activate gene expression, rather than having to rely upon a set level of endogenous expression of an introduced gene (pg. 8-9). Thompson teaches that the self-splicing intron could be utilized in a future study that monitors the presence of a drug in a particular organ via the introduction of the self-splicing intron into a luciferase reporter gene (i.e., Thompson is interpreted as teaching that the inducible construct may be applied to other genes than the thymidylate synthase gene) (pg. 8-9). Thompson teaches that such applications could also be melded with other innovations dependent upon the Group I self-splicing intron, such as the introduction of a trans-splicing intron that can potentially repair or modulate the expression of a given mRNA (pg. 8-9). Thompson teaches that the self-splicing introns may have a number of important biotechnology applications, including use as in vivo, real-time reporters and as regulatable gene therapeutics (pg. 8). Thompson teaches that the expression of the ROI is under the control of the self-splicing intron (pg. 5, column 1, last paragraph to column 2, first paragraph).
Thompson does not teach or suggest that the POI is selected from a CRISPR-Cas nuclease (Claims 43 and 46).
Vigouroux is drawn towards a review study concerned with CRISPSR tools to control gene expression in bacteria (Abstract). Vigouroux teaches that inducible gene editing can be achieved in E. coli through the use of an chemically inducible promoter linked to a CRISPR system that encodes a CRISPR effector nuclease and a guide RNA (pg. 9). Vigouroux teaches that utilizing an inducible CRISPR system allows for tunable gene repression and activation in an E. coli host cell (pg. 9).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed CRISPR-Cas ROI because it would have merely amounted to a simple substitution of one known method of inducible control over the expression of a sequence encoding an ROI that is translated into a POI for another. Since Vigouroux similarly teaches expressing an ROI from a chemically inducible construct in the same host cell as Thompson, then it would have been predicable to have substituted the inducible method by which the CRISPR-Cas POI is expressed such that the self-splicing intron described by Thompson is inserted within a gene encoding a CRISPR-Cas ROI in order to utilize an alternative method of inducing the CRISPR-Cas expression. And because Vigouroux teaches that utilizing an inducible CRISPR system allows for tunable gene repression and activation, then one would have been motivated to do so.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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