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 I in the reply filed on November 6, 2025 is acknowledged. The traversal is on the grounds that Group I and Group II have the same technical feature, which is novel and makes a contribution over the prior art in view of Cost. Therefore, Applicants assert that Groups I and II possess unity.
This is not found persuasive because the claims, as amended, do not relate to a single general inventive concept because they lack the same or corresponding technical feature. The technical feature of Group II are guide RNAs having specified sequences, which are shown by Cowan et al. (PCT Patent Application Publication No. WO 2017/077386, published May 11, 2017), Welstead et al. (PCT Patent Application Publication No. WO 2015/161276, published October 22, 2015), and/or Chen et al. (PCT Patent Application Publication No. WO 2017/093969, published June 8, 2017).
Each of Cowan, Welstead, and Chen disclose CRISPR-Cas related compositions and methods for editing/modifying expression of target sequences (‘386, paragraphs [0034]-[0036] and [0038]; ‘276, abstract and page 1, lines 15-19; ‘969, abstract and page 1, line 23 to page 3, line 10). Cowan discloses guide RNAs that have the sequences of SEQ ID NO: 740, 846, 775 and 848, which are the same as instant SEQ ID NOS: 3, 7, 8, and 9, respectively. Welstead discloses a guide RNA having the sequence of SEQ ID NOS: 464 and 462, which are the same as instant SEQ ID NOS: 5 and 6, respectively. Chen discloses a guide RNA having the sequence of SEQ ID NO: 5498, which is the same as instant SEQ ID NO: 6.
Thus, Cowan, Welstead, and Chen disclose the features of the instantly claimed invention. Therefore, the technical feature of the guide RNA molecules does not make a contribution over the prior art and does not constitute a special technical feature.
The requirement is still deemed proper and is therefore made FINAL.
Claims 6-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 November 6, 2025.
In addition, Applicants canceled claim 2. Thus, claims 1 and 3-5 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, no certified translation of the Chinese patent document has been received.
Information Disclosure Statement
The Information Disclosure Statements filed June 15, 2023; May 9, 2024; and November 6, 2025 have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Figures 12 and 23 include sequences that do not have appropriate sequence identifiers.
Required response – Applicant must provide:
Amended 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 (i.e., “SEQ ID NO:X” or the like) 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.
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. The Sequence Listing Incorporation by Reference paragraph lists the size of the file as 123 KiloBytes (KB), which size should be listed in bytes. The size of the file is listed as 126,728 bytes.
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.
Specification
The use of the term TALEN® throughout the specification, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1 and 3-4 are objected to because of the following informalities:
At claim 1, line 4, “and” should be inserted after “integration;”.
At claim 3, line 3, “or” should be changed to “and.”
At claim 4, line2, “or” should be changed to “and.”
Appropriate correction is required.
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.
Claims 1 and 3-5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for gene editing using CRISPR-Cas systems and a guide RNA, is not enabling for gene editing using TALENS enzymes or zinc finger nucleases with a guide RNA. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1 the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are broadly drawn to a method of performing non-viral gene editing on a target site of a cellular genome comprising providing a cell to be gene-edited. . . . and introducing and enzyme for gene editing . . . and gRNA . . . into the cell. . . wherein the gRNA guides the enzyme for gene editing to perform site-directed cleavage on the target site.
The state of the art, the unpredictability of the art, and the relative skill of the ordinary artisan
It is well established in the art that introduction of a wide variety of gene-editing enzymes can be used to perform editing on a target site in a cell. Generally, these enzymes are different in structure and how they function. For example, Gaj et al. (31(7) Trends in Biotechnology 397-405 (2013)) disclose that CRISPR/Cas systems, which are programmable RNA-guided DNA endonucleases function differently than TALENs and zinc figure nucleases, and employ guide RNA molecules to direct the CRISPR/Cas enzyme to the desired target site for editing (page 402, column 2, first full paragraph). In contrast, Gaj discloses the structure of TALEN enzymes and zinc finger enzymes, which also can be used for gene editing, but do not require or use a guide RNA to direct the enzymes to a target site for editing (Figure 1).
Nature of the invention, the presence or absence of working examples, and the breadth of the claims
While the specification does provide use of TALENS, zinc finger nucleases and CRISPR-Cas nucleases, it fails to disclose how to provide for gene editing using TALENS and zinc finger nucleases in combination with a guide RNA., the specification does not provide any disclosure to enable the claims over their full scope.
In view of the lack of the predictability of the art to which the invention pertains, undue experimentation would be required to make and use the claimed invention to prevent cancer in a subjection, or recurrence thereof, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on using TALENS and zinc finger nucleases in combination with a guide RNA used to guide the enzymes to a target site, where the gene editing is performed, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of TALENS and zinc finger nucleases to function as required in combination with a guide RNA, the claims are not enabled commensurate in scope with the claimed invention.
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.
Claim 3 is 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.
At claim 3, line 2, the use of the trademarked term TALEN in the claim is improper to identify a particular material or product. See MPEP 2173.05(u).
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.
Claims 1 and 3-5 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cowan et al. (U.S. Patent Application Publication No. 2019/0382798, published December 19, 2019 and claiming priority to PCT Patent Application No. PCT/IB2016/001709, published May 11, 2017 as WO 2017/077386, and cited in the Information Disclosure Statement filed November 6, 2025).
Regarding claim 1, Cowan discloses treatment of Glycogen Storage Disease type 1a (GSD1a) by modulating expression, function and or activity of glucose-6-phosphatase in a cell via editing (abstract). Cowan discloses that a donor template can be introduced into the cell to correct the G6PC gene, which is interpreted as a knock-out/knock-in gene targeted integration (paragraph [0041]). Cowan discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9 and Cpf1, which are able to provide for either single- or double-strand breaks (cleavage) (paragraphs [0041]-[0042]). Cowan discloses that the insertion of the new sequence can take place within or near a safe harbor locus, which includes AAVS1 (paragraphs [0030] and [0042]). Cowan discloses that polynucleotides encoding the DNA endonuclease and guide RNA can be introduced into the cell (paragraphs [0038]-[0040]). Cowan discloses that the polynucleotides can be introduced via a plasmid, transfection, conjugation, lipofection, electroporation, nucleofection, particle guns, micro-injection liposome-mediated transfection, which are non-viral methods of gene editing (paragraphs [00511], [00521], and [00523]). Cowan discloses guide RNAs that have the sequences of SEQ ID NOS: 740, 846, 775 and 848, which are the same as instant SEQ ID NOS: 3, 7, 8, and 9, respectively (Appendices I, V, VI, and VII, respectively).
Regarding claim 3, Cowan discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9 and Cpf1, which are able to provide for either single- or double-strand breaks (cleavage) (paragraph [0042]).
Regarding claim 4, Cowan discloses that the insertion of the new sequence can take place within or near a safe harbor locus, which includes AAVS1 (paragraphs [0030] and [0042]).
Regarding claim 5, Cowan discloses that a donor template can be introduced into the cell to correct the G6PC gene, which is interpreted as a knock-out/knock-in gene targeted integration (paragraph [0041]).
Cowan discloses each and every limitation of claims 1 and 3-5, and therefore, Cowan anticipates claims 1 and 3-5.
Claims 1 and 3-5 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Welstead et al. (PCT Patent Application Publication No. WO 2015/161276, published October 22, 2025).
Regarding claim 1, Welstead discloses treatment of cancer using CRISPR-Cas-related compositions by editing a target nucleic acid sequence (abstract and page 1, lines 16-19). Welstead discloses that a donor template can be introduced into the cell to alter expression of T cell-expressed genes, and that T cell-expressed genes can be knocked out and an insertion being the alteration of the target site (page 3, line 32 to page 4, line 16 and , which is interpreted as a knock-out/knock-in gene targeted integration (page 4, line 31 to page 5, line 9 and page 56, line 19 to page 57, line 28). Welstead discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9, which are able to provide for either single- or double-strand breaks (cleavage) (page 11, lines 5-20). Welstead discloses that the insertion of the new sequence can take place within or near the TRAC gene (page 3, lines 23-31). Welstead discloses that the DNA endonuclease and guide RNA can be introduced into the cell (page 11, lines 21-34, page 41, line 28 to page 42, line 16, and page 44, lines 21-33). Welstead discloses that the Cas9 and guide RNAs, and polynucleotides encoding them, can be introduced via non-viral methods of gene editing (page 339, lines 1-20). Welstead discloses guide RNAs that have the sequence of SEQ ID NOS: 464 and 462, which are the same as instant SEQ ID NOS: 4 and 5, respectively (Appendices III and IV respectively).
Regarding claim 3, Welstead discloses that a donor template can be introduced into the cell to alter expression of T cell-expressed genes, and that T cell-expressed genes can be knocked out and an insertion being the alteration of the target site (page 3, line 32 to page 4, line 16 and , which is interpreted as a knock-out/knock-in gene targeted integration (page 4, line 31 to page 5, line 9 and page 56, line 19 to page 57, line 28). Welstead discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9, which are able to provide for either single- or double-strand breaks (cleavage) (page 11, lines 5-20).
Regarding claim 4, Welstead discloses that the insertion of the new sequence can take place within or near the TRAC gene (page 3, lines 23-31).
Regarding claim 5, Welstead discloses that a donor template can be introduced into the cell to alter expression of T cell-expressed genes, and that T cell-expressed genes can be knocked out and an insertion being the alteration of the target site (page 3, line 32 to page 4, line 16 and , which is interpreted as a knock-out/knock-in gene targeted integration (page 4, line 31 to page 5, line 9 and page 56, line 19 to page 57, line 28).
Welstead discloses each and every limitation of claims 1 and 3-5, and therefore, Cowan anticipates claims 1 and 3-5.
Claims 1 and 3-5 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chen et al. (PCT Patent Application Publication No. WO 2017/093969, published June 8, 2017).
Regarding claim 1, Chen discloses treatment of genome editing systems for immunological use (abstract). Chen discloses that simultaneous and sequential knockout of TRAC and B2M, and insertions can be indicated, which is interpreted as a knock-out/knock-in gene targeted integration (Example 8). Chen discloses a donor template can be inserted at or near a target sequence that has been modified by cleavage by a CRISPR system comprising guide RNAs (page 1, lines 23-28). Chen discloses that the insertion of the new sequence can take place within or near the B2M or TRAC loci (page 1, line 29 to page 2, line 2). Chen discloses that polynucleotides encoding the DNA endonuclease and guide RNA can be introduced into the cell (page 15, line 28 to page 16, line 2). Chen discloses that the polynucleotides can be introduced via non-viral vectors, including plasmids, minicircles, nanoplasmids, and RNA vectors (page 15, line28 to page 16, line 2). Chen discloses a guide RNA that has sequence of SEQ ID NO: 5498, which is the same as instant SEQ ID NO: 6 (Appendix IV).
Regarding claim 3, Chen discloses a donor template can be inserted at or near a target sequence that has been modified by cleavage by a CRISPR system comprising guide RNAs (page 1, lines 23-28).
Regarding claim 4, Chen discloses that the insertion of the new sequence can take place within or near the B2M or TRAC loci (page 1, line 29 to page 2, line 2).
Regarding claim 5, Chen discloses that simultaneous and sequential knockout of TRAC and B2M, and insertions can be indicated, which is interpreted as a knock-out/knock-in gene targeted integration (Example 8). Chen discloses a donor template can be inserted at or near a target sequence that has been modified by cleavage by a CRISPR system comprising guide RNAs (page 1, lines 23-28).
Chen discloses each and every limitation of claims 1 and 3-5, and therefore, Chen anticipates claims 1 and 3-5.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636