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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US2021/036171, filed on 06/07/2021, which claims domestic benefit to US provision application 63/036,021, filed 06/08/2020.
Claim Status
The Amendment, filed on 12/15/2025, is acknowledged in which:
Claims 1-45 and 47-48 are canceled.
Claims 46, 49, 54, and 61-62 are currently amended.
Claims 50-53, 55-60, and 63-65 were previously presented.
Claims 46 and 49-65 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/15/2025 has been considered by the examiner.
The information disclosure statement filed 03/20/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. CARTELLIERI et al. (2014) (NPL 169) has been placed in the application file, but the information referred to therein has not been considered. All other references, where not lined through, have been considered.
Withdrawn Objections and Rejections
In the office action dated 08/20/2025,
Figure 1 was objected to because only that which is old was illustrated. Applicant’s submission of a corrected drawing with “Prior Art” legend has overcome the objection and the objection is withdrawn
The specification was objected to for informalities in the text and tradenames or marks used in commerce without appropriate symbols. Applicant’s submission of amendments to the specification with appropriate corrections has overcome the objections and the objections are withdrawn.
All rejections regarding claims 47 and 48 are rendered moot in view of claim amendments.
Claim 54 was rejected under 35 USC 112(a) for reciting antibody species without sufficient written description. Applicant’s amendment to the claim to limit identity to those with 100% identity to the claimed antibody species with sufficient written description has overcome the rejection and the rejection is withdrawn.
Claims 61-65 were rejected under 35 USC 112(a) for reciting inhibiting cancer (within scope of prevention) without sufficient enablement. Applicant’s amendment to the claim to remove ‘inhibition’ has overcome the rejections and the rejections are withdrawn.
Claims 46, 49-52, 55-59, 60-61, and 65 were rejected under 35 USC 102a1 as being anticipated by Hong as evidenced by Hudecek. Applicant’s amendment to the claim to incorporate the limitations of newly cancelled claims 47 and 48 and reciting a new negative limitation “lacks an N297Q substitution” has overcome the rejections of record and the rejections are withdrawn.
Claim 53 and 54 were rejected under 35 USC 103 as being unpatentable over Hong in view of Salter. Applicant’s amendment to the limitations of the base claim have overcome the rejections and the rejections are withdrawn
Claim 62 was rejected under 35 USC 103 as being unpatentable over Hong in view of Jensen and Jonnalagadda. Applicant’s amendment to the limitations of the base claim have overcome the rejections and the rejections are withdrawn
Claim 63 was rejected under 35 USC 103 as being unpatentable over Hong, Jensen, and Jonnalagadda, and further in view of Park and Nair. Applicant’s amendment to the limitations of the base claim have overcome the rejections and the rejections are withdrawn
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
New Claim Objections
Claims 46 and 49 are objected to because of the following informalities:
Claim 46, line 7 - the instant claim recites “N297Q substitution” where in the specification the substitution is referred to as “N257Q” (¶ [0107]; Table 2, pg 28). Appropriate correction to either the claim or the specification is required.
Claim 49, line 1 - “claims 46” should read “claim 46”
Appropriate corrections are required.
New Claim Rejections - 35 USC § 112(a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 46 and 49-65 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 46, the instant claim is drawn to a nucleic acid encoding a CAR comprising a CD171 binding domain, a spacer comprising a modified IgG4 hinge between 120 and 230 residues in length comprising “an L235D substitution and lacks an N297Q substitution”, a transmembrane domain, and an intracellular signaling domain, wherein a T cell comprising the CAR has an increased persistence and/or efficacy to treat or ameliorate a CD171 cancer in a subject administered the T cell compared to a T cell having a spacer less than 120 residues in length (i.e. short spacer).
The specification provides sequence information for substitutions only at residues L235 (SEQ ID NO: 2) or dual L235 and N297 (SEQ ID NO: 19), and has sufficient written description for the aforementioned CD171 CAR with a double mutation (L235D and N297Q substitutions) reducing tumor progression (Figure 4) (i.e. increased efficiency), the claim limitation of having only a single L235D substitution (i.e. at least 95% identity to SEQ ID NO: 2 without an N297Q substitution) improving persistence and/or efficiency in comparison to a short spacer is not supported by the specification.
The state of the prior art near the effective filing date of the claimed invention demonstrates that T cell persistence, and therefore efficiency in treating a tumor in vivo, can be drastically impacted by hinge domain composition.
Jonnalagadda (Mol Ther. 2015;23(4):757-768) teaches in vivo engraftment in CD19 CAR T cells is impaired in single hinge mutants (L235E or N297Q) in comparison with a CH2-deleted spacer (Ch2Δ+) (i.e. spacer less than 120 residues in length) (Figure 5a). The improved persistence in comparison with a short spacer was only observed with L235 and N297 dual substitutions.
Hudecek (Cancer Immunol Res. 2015;3(2):125-135) similarly teaches that antitumor activity at 1 week post-injection and persistence at 3 days for CD19-CAR-T cells at levels comparable to short hinge domain required both L235 and N297 mutations (L235A and N297Q substitutions with additional E233P and F234V substitutions; “Long4/2NQ”), which was not replicated with substitutions in only residues 233-235 (Figure 6A, 6F, and 6H).
Hombach (Gene Ther. 2010;17(10):1206-1213) teaches a mutated IgG1 hinge domain with multiple substitutions in residues 233-236 and 254 (i.e. without N297 substitution) can prevent cross activation with THP-1 cells (i.e. abolish interaction with Fc receptors expressed by THP-1 cells), however persistence and/or efficiency in vivo were not tested. Further, Hombach does not teach the suitability of an individual L235 substitution.
Overall, aside from dual substitutions no longer supported by the amended base claim, neither the disclosure nor the prior art recognize a strict mutational landscape within the residues of the IgG4 hinge that would allow a priori determination of substitutions in the hinge domain within the breadth of the claimed genus (comprising an L235D substitution without an N297Q) that would predictably fulfill the claimed function of increased persistence and/or efficiency in comparison with a short spacer without undue experimentation (i.e. testing additional alternative residue mutations to support an L235 substitution). Therefore the instant claim and subsequent dependent claims 49-65 that do not resolve this issue were found not to meet written description requirements.
Conclusion
No claims are allowed.
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 HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647