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 .
Application Status
The Response to the Restriction Requirement mailed on January 13, 2026 is acknowledged. Applicant's election without traverse of the invention of Group I (claims 42-50), drawn to a method for generating an engineered immune cell with enhanced effector function, in the reply filed on March 10, 2026 is entered.
The amended claims filed on March 10, 2026 are acknowledged. Claims 42-61 are pending. Claim 44 has been amended. Claims 51-61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 42-50 are under examination herein.
Claim Objections
Claim 49 is objected to because of the following informalities: It is suggested that the wherein clause reciting “wherein further comprising introducing…” be amended for clarity, e.g., by removing “wherein”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 46 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.
Claim 46 recites the limitation that the nucleic acid comprised in the engineered immune cell of claim 42 comprises a polynucleotide sequence having “sufficient sequence complementarity to a target sequence within an endogenous genomic locus encoding the mediator complex subunit”. As noted by Applicant's disclosure (e.g., ¶ 0066), the mediator complex is composed of at least 31 subunits in eukaryotes. The metes and bounds of what is considered “sufficient” is not defined in the claim, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention based on Applicant's disclosure. The specification does recite, “In some embodiments, the polynucleotide sequence has at least 70%, at least 80%, at least 90%, at least 95%, … or at least 99% sequence identity to its target sequence within an endogenous genomic locus encoding the mediator complex subunit. In some embodiments, the polynucleotide sequence has 100% sequence identity to the target sequence within an endogenous genomic locus encoding the mediator complex subunit except for one, two, three, four, or five mismatches” (¶ 0073). However, the specification does not provide a showing that polynucleotide sequences having less than 100% identity to a known target sequence are sufficiently complementary to all possible desired target sequences. Morgens (Nature Communications (2017) 8: 15178; cited in IDS) teaches that for CRISPR/Cas9-mediated gene editing, off-target activity or binding to large numbers of target sites by the guide sequence can result in toxicity (e.g., Introduction). Morgens used the number of 0-, 1- and 2-bp mismatch off-target sites to predict “off-target activity” (Results, page 2). Morgens also notes that the effect of a single mismatch on off-target toxicity differs depending on whether the mismatch is more distal from or more proximal to the PAM site (e.g., Results, page 4). Applicant's disclosure does not provide a standard for ascertaining that any polynucleotide sequence having, e.g., “at least 70%” sequence identity, or one, two, or three mismatches relative to a target sequence, is sufficient to target the desired mediator complex subunit gene and is thus capable of reducing expression level of said gene. Which bp mismatches are acceptable and which are not? Accordingly, the claim is indefinite because one of ordinary skill in the art cannot readily determine what would be considered “sufficient” as it relates to the instantly claimed invention.
Claim Rejections - 35 USC § 102
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.
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.
Claims 42-48 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Pritchard (WO 2021/076744 A1; earliest priority date: October 15, 2019; cited in IDS).
Pritchard discloses methods for modifying T cells in which the expression of a selected nuclear factor(s) is inhibited or overexpressed to influence expression of IL2RA, IL-2, and other genes involved in immune regulation, thus manipulating immune cell activity (e.g., Abstract; ¶ 0005-0006). In embodiments of the invention, Pritchard teaches a method of making a modified T cell, comprising the step of inhibiting expression of the nuclear factor MED12 by contacting a polynucleotide encoding said nuclear factor with a targeted nuclease (e.g., Cas9), a guide RNA, an antisense RNA, or short hairpin (sh)RNA (e.g., ¶ 0027-0028; claims 13-23), anticipating claims 42-45 and 47. Regarding claim 46, Pritchard teaches that in some embodiments, “inhibiting comprises contacting the polynucleotide encoding the nuclear factor with at least one gRNA and optionally a targeted nuclease, wherein the at least one gRNA comprises a sequence selected from one or more of Tables 1- 8” (¶ 0028). Table 2 (at page 42), Table 5 (at page 76), Table 7 (at pages 108-109), and Table 8 (at page 124) illustrate exemplary sgRNA target sequences for MED12. Regarding claim 48, Pritchard teaches that the modified T cells of the invention include those which are CD4+ and/or CD8+, and include naïve T cells, cytotoxic T cells, or memory T cells (e.g., ¶ 0078). Pritchard teaches that genetically modified T cells having reduced expression of MED12 have higher expression of IL-2RA and IL-2, and possess utility in treating cancer (e.g., ¶ 0036-0042, 0094-0095).
Claim Rejections – 35 USC § 103
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.
Claims 42 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Pritchard (WO 2021/076744 A1; supra) as applied to claims 42-48 above, further in view of Gehrke (WO 2020/150534 A2; published July 23, 2020; cited in IDS) and Lynn (Nature (2019) 576: 293-300; cited in IDS).
The teachings of Pritchard are recited in the 35 U.S.C. § 102 rejection above.
However, Pritchard does not expressly teach introducing a recombinant immune receptor into the modified T cells.
Gehrke describes genetically modified immune cells having enhanced anti-neoplasia activity, resistance to immune suppression, and/or decreased risk of promoting graft-versus-host disease (GVHD), and methods of use and production thereof (e.g., Abstract). The methods of producing a population of modified immune cells according to Gehrke comprise the step of modifying (reducing) at least four gene sequences (including, for example, an immune response regulation gene sequence) by contacting the immune cell with at least four guide nucleic acid sequences, wherein the immune cell is a T cell (e.g., a cytotoxic or regulatory T cell) or an NK cell (e.g., ¶ 0004-0011, 0042-0043, 0067-0070), relevant to claims 42 and 45-48. Pertinent to claims 49-50, Gehrke further recites that said method further comprises contacting the immune cell or population of immune cells with a polynucleotide encoding an exogenous functional chimeric antigen receptor (CAR) (e.g., ¶ 0072). Gehrke also discloses immune cells in which a composition comprising at least four guide nucleic acid sequences (including, among others, the mediator complex subunit gene of CDK8) has been introduced via electroporation (e.g., ¶ 00257-00266, 00532-00536; claims 268-275, 278-279, 283).
Lynn teaches, “CAR-expressing T cells demonstrate impressive response rates in B cell malignancies, but fewer than 50% of patients experience long-term disease control and CAR T cells have not mediated sustained responses in solid tumours” (Introduction). Lynn discloses that one factor limiting the effectiveness of CAR-T cell therapies is intrinsic T cell dysfunction due to T cell exhaustion (e.g., Abstract; Introduction). Using a modeling system with a tonically signaling CAR, Lynn demonstrates that exhausted T cells show significant defects in the production of IL-2 (e.g., Abstract; pages 293-294; Figure 1 and Extended Data Figure 1). Lynn further provides that a separate manipulation (c-Jun overexpression) that enhances transcriptional activation of IL-2 in CAR-T cells prevents CAR-T cell exhaustion (e.g., pages 295-296; Figure 3). Lynn teaches that the enhanced long-term proliferative capacity induced by c-Jun overexpression is IL-2 dependent (e.g., page 296; Figure 3).
Based on the further teachings of Gehrke and Lynn, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to further modify the genetically modified T cells described by Pritchard by introducing an exogenous CAR. The skilled artisan would have been motivated to do so because Lynn teaches that CAR-T cells have shown promise in the treatment of some cancers, and the CAR would direct the modified T cells to tumor-associated antigen-expressing cells in the tumor microenvironment. Furthermore, Pritchard sets forth that inhibiting expression of MED12 in a T cell increases IL-2 production and that MED12-inhibited cells of the invention can be used to treat cancer. Based on the teachings of Lynn, increased production of IL-2 by the engineered immune cell would be expected to reduce T cell exhaustion and thus increase its efficacy for CAR-T cell therapy. There would have been a reasonable expectation of success because Gehrke provides a proof-of-concept that T cells which have been manipulated to inhibit expression of selected genes involved in immune regulation via gene editing can be further modified by introducing an exogenous functional immune receptor.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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