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 .
Information Disclosure Statement
The information disclosure statement (IDS) filed on 3/10/2026 has been considered.
Response to Amendment
The amendment filed on 3/10/2026 is acknowledged. Claims 1 and 3-17 are pending and currently under consideration. Claims 2 and 18-51 are cancelled. Applicant’s amendments have overcome the objection of claim 16 and 112(b) rejections of claims 1, 4-5, 6-7, and 16-17 as set forth in the Non-Final Office Action mailed on 12/10/2025.
Response to Arguments
Applicant’s arguments, see page 5, "Objections to the Claims", filed 3/10/2026, with respect to claim 16 have been fully considered and are persuasive. The claim objection of claim 16 has been withdrawn.
Applicant’s arguments, see pages 5-7, "Claim Rejection Under 35 U.S.C §”, filed 3/10/2026, with respect to claims 1-12 and 16-17 have been fully considered and are persuasive. The 112b rejections of claims 1--17 have been withdrawn.
Applicant’s arguments with respect to the 35 U.S.C. § 103 rejection for claims 1-17 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The following rejections are necessitated by the amendment filed on 3/10/2026.
Claim Objections
Claim 11 is objected to because of the following informalities:
There is an extra comma between 14 and (TNFSF14, LIGHT), so "tumor necrosis factor superfamily member 14.
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 3-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While being enabled for: a cell comprising a transposon wherein the transposon is a Sleeping Beauty transposon and a Sleeping Beauty or SB100X transposase; or the transposon is a PiggyBac transposon and a PiggyBac, PiggyBac like, or Super PiggyBac transposase; or the transposon is a Tc Buster transposon and a TcBuster transposase or a hyperactive TcBuster transposase.
The specification does not reasonably provide enablement for: a cell comprising a transposon wherein the transposon is a DNA transposon (Sleeping Beauty, PiggyBac, Tc Buster, or a retro-transposon) and a heterologous transposase (PiggyBac, PiggyBac like, Super PiggyBac, Sleeping Beauty, hyperactive Sleeping Beauty (SB100X), Helitron, Tol2, TcBuster, or hyperactive TcBuster transposase).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The breadth of claims 1 and 3-17 encompass all combinations of transposons and transposases in any cell type. Transposon based systems are distinct and have different mechanisms of action utilizing distinct long terminal repeats (LTRs) and have different transpositions efficiencies for varying transgene cargo sizes.
It is well established in the art that the transposon and the corresponding transposase need to match. The art of VectorBuilder (PTO-892; Reference U) teaches only matching transposase and transposons can be used for efficient genomic integration, so a PiggyBac transposase cannot be effectively used with Sleeping Beauty or Tol2 transposons (VectorBuilder; page 1; “Plasmid Picking”). Each transposon system contains its own unique terminal repeats flanking the coding region for the corresponding transposase to recognize and facilitate the mobilization and insertion of the gene of interest into a target cell (VectorBuilder; page 1; Figure 1; “Transposons: jump around (Jump! Jump!)). Additionally, VectorBuilder teaches each transposase has varying transposition efficiencies across cell types with different cargo capacities where PiggyBac has the highest cargo capacity (27 kb) with the highest transposase activity, Sleeping Beauty has a lower cargo capacity between 2-8kb and a lower transposase activity, and Tol2 has a lower cargo capacity (11 kb) with a lower transposase activity (VectorBuilder; page 2).
The specification discloses (page 18, [0082]; page 30, [0103]) that with a specific transposon system it can have the corresponding transposase and that integration of a transposon to the genome in the target cell requires the expression of a corresponding transposase. The specification additionally provides working examples illustrating the efficiency of the matching transposon-transposase systems where the transgene encodes one to four chimeric antigen receptors.
As such the claims are not enabled for mismatched transposons and transposases. Additionally, the claims are not enabled for a retrotransposon without its matching transposase and a Helitron transposase or a Tol2 transposase without its matching transposon. One of ordinary skill in the art cannot use the combination of transposons and transposases with unpredictable transposition efficiencies.
In view of the quantity of experimentation necessary, the lack of working examples, the unpredictability in the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the encompassed transposons and transposases recited in the claims with unpredictable transposition efficiencies.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Priority
This application claims domestic priority to provisional US application 63/492,110 filed on 03/24/2023 and US application 63/346,547 filed on 05/27/2022.
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 1, 3-4, and 8-17 are rejected under 35 U.S.C. 103 as being unpatentable over AU 2017225733 A1 (PTO-892; Reference N; "Dranoff") in view of Hudecek et al (PTO-892; Reference V; " Hudecek ").
Dranoff teaches that there is a need for CAR cell therapies with enhanced efficacy (enhanced proliferation or prolonged persistence in a patient) since studies have shown limited persistence and proliferation of CAR expressing cells in vivo (Dranoff; page 1, lines 17-28). To overcome these limitations, Dranoff teaches a composition for treating cancer comprising an immune effector cell (i.e. T cell) engineered to express a first chimeric antigen receptor (CAR) and a second CAR each with their own scFv domain; transmembrane domain selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CDS, CDS, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD 134, CD137 and CD 154; an ITAM including but not limited to TCR zeta, FcR gamma, FcR beta, CD3 gamma, CDS delta , CD3 epsilon, CDS, CD22, CD79a, CD79b, CD278 (also known as “ICOS”), FceRI, DAP 10, DAP 12,and CD66d; and an intracellular costimulatory domain selected from the group consisting of CD27, CD28, 4-1BB (CD137), 0X40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CDS, CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD160, B7-H3, and a ligand that specifically binds with CD83 (Dranoff; page 2, lines 3-19; page 8, lines 1-27; page 14, lines 8-10). Dranoff additionally teaches a transposon based non-viral method of delivery of the dual CAR transgene into a target cell where the transposon includes Sleeping Beauty transposon system and a piggyBac transposon system where the use of these systems permits efficiency integration and expression of a transgene (Dranoff; page 217, lines 13-31; page 218, lines 3-32; page 219, lines 1-3). Dranoff teaches advantages of using non-viral vectors to include the ease and relatively low cost of producing sufficient amounts required to meet a patient population, stability during storage, and lack of immunogenicity (Dranoff; page 218, lines 31-32; page 219, lines 1-3).
However, Dranoff does not teach a motivation to use a transposon-based system for a dual CAR transgene of claims 1, 3-4 and 8-17.
Hudecek teaches the sleeping beauty transposon as a tool for gene therapy for stem cell gene therapy and cancer immunotherapy (Hudecek; Abstract). The sleeping beauty transposon system has seen many advances in the clinical and preclinical space for various hematological malignancies with some advantages of this system being ease and reduced cost of manufacturing of clinical-grade, plasmid-based vectors compared to recombinant viral vectors, scalability of vector production, and ease of ensuring quality control for clinical use, and indefinite storage with absolute fidelity (Hudecek; page 105, Concluding Remarks). Additionally, Hudecek teaches SB vectors have been shown to mobilize BAC transgenes of over ~100kb in size at reasonable efficiencies providing evidence that the Sleeping Beauty system is well suited for combinatorial targeting of two tumor antigens by bi-specific CAR constructs accommodating increased size in genetic cargo (Hudecek; page 105, Concluding Remarks).
Therefore, it would have been prima facia obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dual CAR transgene of Dranoff with Sleeping Beauty transposon-based system of Hudecek with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the dual CAR transgene of Dranoff with the sleeping beauty transposon-based system of Hudecek as Hudecek teaches SB vector’s key advantage over viral vectors is their increased capacity to deliver larger gene cargo sizes that is typically seen with dual CAR transgenes with reasonable efficiencies.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claims 1 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Dranoff and Hudecek as applied to claims 1, 3-4, and 8-17 above, and further in view of WO 2020223571 A1 (PTO-892; Reference O; “Burleigh”).
Dranoff and Hudecek have been discussed above. Dranoff and Hudecek differ from the claimed invention in regards to instant claims 4-5 wherein the transgene is at least 5000 or 6000 nucleotides in length.
Burleigh teaches engineered immune cells expressing a chimeric antigen receptor (CAR) with an scFv specific to BCMA, an immunoglobulin-derived spacer, a transmembrane domain derived from CD28, and a 4-1BB costimulatory domain that is integrated at the endogenous CD247 locus via homologous dependent repair (HDR) (Burleigh; Abstract; [0939]-[0942]). A proposed method for introducing the genetically engineered cell encoding the CAR is a Sleeping Beauty transposon-based system (Burleigh; [0821]). Burleigh additionally teaches the length of the transgene sequence, including coding and noncoding regions, to be between 100 – 10,000 base pairs where the length of the transgene sequence is limited by the maximum length of polynucleotide that can be prepared, synthesized, or assembled and/or introduced into the cell or the capacity of the vector delivery system (Burleigh; [0495; [0592]).
It would have been prima facie obvious, before the effective filing date of the claimed invention, to have modified to dual CAR transgene of Dranoff and Hudecek with the transgene length of Burleigh with reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the transgene length of Dranoff and Huducek to be between 100 – 10,000 base pairs of Burleigh as Huducek teaches the sleeping beauty transposon system can mobilize transgenes of up to 100 kb with reasonable efficiency and Burleigh teaches the transgene size to be limited by the capacity of the vector.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claims 1 and 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dranoff and Hudecek as applied to claims 1, 3-4, and 8-17 above, and further in view of Majzner et al (PTO-892; Reference W; "Majzner") and Mauro (PTO-892; Reference X; “Mauro”).
Dranoff and Hudecek have been discussed above. Dranoff and Hudecek differ from the claimed invention in regards to instant claims 6-7 wherein the coding sequence for each ITAM in the transgene is codon-optimized to not have sequence identity to one another of 12 or 9 consecutive nucleotides or longer.
Majzner teaches that precise design of CAR constructs can tune the threshold for antigen recognition required for optimal CAR T cell activity (Majzner; Abstract; page 3, paragraph 1). To illustrate this, Majzner teaches the generation of CD19-4-1BB CAR with multiple CD3ζ domains (“double zeta”) where DNA fragments were codon optimized to differ in DNA sequence from the domains already contained in the CAR constructs (Majzner; Figure 3c; page 5, paragraph 3; page 13, paragraph 1). When compared to a single zeta CAR, the double zeta expressed similarly on the surface of T cells, upon stimulation with idiotype antibody and pERK and CD3ζ CAR were higher, and increased killing and proliferation in response to target cells (Majzner; page 5, paragraph 4).
Mauro teaches potential considerations for using codon optimization and that codon optimization is routinely used for applications in bioproduction and in vivo nucleic acid therapeutic applications (Mauro; Abstract; page 72, left column, paragraph 4). Codon optimization can increase protein expression by up to > 1000 fold, and increase protein yields, and increase the efficiency of translation rates of codon-optimized mRNAs (Mauro; Abstract; page 77, right column, paragraph 3).
It would have been prima facie obvious, before the effective filing date of the claimed invention, to have modified to dual CAR transgene of Dranoff and Hudecek with the codon optimization of the ITAM of Majzner with the motivation to codon optimize a DNA sequence of Mauro with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Majzner teaches codon optimization of the double zeta CAR construct where it increased killing and proliferation in response to target cells and Mauro teaches codon optimization being a routine method in bioproduction applications and in vivo nucleic acid therapeutic applications where it can increase protein expression and yields and increase translation efficiency. Additionally, since Mauro teaches codon optimization being routine in the field, so codon optimization is a results-effective variable that one of ordinary skill in the art would be motivated to optimize to enhance protein expression in the designated host cell.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH ELIZABETH STEIN whose telephone number is (571)272-0093. The examiner can normally be reached M-F 8-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641