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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/25/2026 has been entered.
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 06/25/2026, is acknowledged in which:
Claims 1-45 and 47-48 are canceled.
Claims 46, 49, and 54 are currently amended.
Claims 50-53, 55-60, and 61-65 were previously presented.
Claims 46 and 49-65 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 3/25/2026,
Claims 46 was objected to for reciting N297Q where the specification recited N257Q, applicant has chosen to amend the claim to N257Q which has overcome the objection, and the objection is withdrawn.
Claim 49 was objected to for a typographical error. Applicant’s amendment to the claim has overcome the rejection and the rejection is withdrawn.
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. Applicant’s amendment to the claim has overcome the rejection and the rejection is withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims. Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
New - Specification
The disclosure is objected to because of the following informalities:
In ¶ [0107] line 4, “SEQ ID NO:18” should read “SEQ ID NO:19” in reference to IgG4-CH2-CH3 double mutant. Based on the instant disclosure, SEQ ID NO:18 is instead a sequence encoding a CD28 cytoplasmic domain (Table 2).
Appropriate correction is required.
New - 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.
The term “N257Q” in claim 46 is used by the claim to mean “a change from natural asparagine (N) at position 257 to a glutamine (Q).” However, this is inaccurate to the actual sequences disclosed (SEQ ID NO:19 annotated below) wherein the natural residue at position 257 corresponds to a proline (P) not an asparagine (arrowhead). Therefore, the term “N257Q” is inaccurate and used contrary to its ordinary meaning leading to ambiguity in determining the metes and bounds of the claim. Based on the sequences provided, it appears that an asparagine (N) to glutamine (Q) mutation instead appears at residue 297 (as originally claimed; residues 235 and 297 underlined).
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Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
For examination purposes, based on the sequences presented in the instant disclosure (i.e. as shown below) and to avoiding adding new matter (as indicated by Remarks, filed 06/25/2026, pg 5, ¶ 1) examiner has interpreted the mutation of “N257Q” to correspond to residue 297 of SEQ ID NO:19 as described in Table 2 of the instant specification.
New - Claim Rejections - 35 USC § 103
Claims 46, 49-53, 55-59, 60-61, and 64-65 are rejected under 35 U.S.C. 103 as being unpatentable over Ali (Front Immunol. 2020;11:531. Published 2020 Mar 31) and Jonnalagadda (Mol Ther. 2015;23(4):757-768) as evidenced by Hudecek (Cancer Immunol Res. 2015;3(2):125-135).
The applied reference (Ali) has a common inventor with the instant application. Based upon the earlier public disclosure date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). This rejection under 35 U.S.C. 102 might be overcome by (1) an affidavit or declaration under 37 CFR 1.130(a) establishing that the subject matter disclosed was obtained directly or indirectly from the inventor or a joint inventor of the application AND providing a reasonable explanation of the additional joint inventor/author in the reference to overcome the rejection in accordance with 35 U.S.C.102(b)(1)(A); or (2) a showing under 37 CFR 1.130(b) of invoking prior public disclosure exceptions under 35 U.S.C. 102(b)(1)(B). See generally MPEP § 717.02.
Ali teaches lentiviral constructs (i.e. polynucleotide) encoding CD171-specific CE7-CAR comprising: (i) an codon optimized scFv ligand binding domain derived from CD171 specific CE7 mab (ii) fused to a 229-amino acid spacer domain from the human IgG4 hinge (i.e. CH2-CH3) with L235D and N297Q (identical to interpretation of “N257Q” as discussed above) double mutations to reduce FcR binding (identity to instant SEQ ID NO:19), (iii) CD28 transmembrane domain, (iv) and CD3ζ and 4-1BB cytoplasmic signaling domains (pg 2-3 spanning ¶). Ali teaches lentiviral-mediated transduction of CD8+ and CD4+ T-cells using the aforementioned construct (pg 3, left column, ¶ 2). Ali further teaches CAR-T cells targeting the CE7 epitope of CD171 tumor-associated antigen as therapeutics in neuroblastoma models and for patients with recurrent or refractory neuroblastoma (pg 2, right column, ¶ 1).
However, Ali is silent regarding increased persistence and/or efficacy of the disclosed CD171-specific CE7-CAR-T cell to treat a CD171+ cancer in comparison to a CAR-T comprising a spacer having a length less than 120 consecutive amino acid residues.
Jonnalagadda teaches a similar double point mutated (L235E and N297Q - or EQ mutant) IgG4 and CH2-deleted (Ch2Δ+) (i.e. 119 AA spacer as evidenced by Hudecek, Figure 1A) IgG4 spacers exhibit inhibited FcγR binding (Figure 4). While both constructed CARs significantly reduced tumor growth in xenograft mouse models (Figure 7b-c), EQ-specific mutant CARs had increased persistence in vivo 21 days post administration compared to Ch2Δ+ CARs (Figure 7d).
One of ordinary skill in the art would recognize that the glutamic acid (E) or aspartic acid (D) mutations of L235 as taught by Ali and Jonnalagadda, respectively, would be considered conservative mutant variations as both E and D are both categorized as negatively charged amino acids. Therefore, it would be obvious to one of ordinary skill that the CD171-specific CE7-CAR-T cell as taught by Ali, structurally indistinguishable from the instant claims, would have a reasonable expectation of success having inherent increased persistence in comparison to a CAR-T cell having a spacer less than 120 consecutive residues because Jonnalagadda teaches these a conservatively similar mutant spacer has increase persistence in comparison to a CH2-deleted variant (i.e. spacer less than 120 residues as evidenced by Hudecek).
Claims 54 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Ali and Jonnalagadda as evidenced by Hudecek as applied to claims 46 and 61 above, and further in view of US 2018/0009891 A1 (herein Jensen).
Regarding claim 54, The combined teachings of Ali, Jonnalagadda, and Hudecek teach claim 46 as discussed above (a codon optimized CE7-scFv CAR with human IgG4 hinge-CH2-CH3 with double mutations, CD28 transmembrane domain, and CD3ζ and 4-1BB cytoplasmic signaling domains – implicit identity to recited SEQ ID NOs: 1, 19, 4, 7, and 8 as disclosed in the instant specification; Table 2). However, explicit nucleotide (SEQ ID NOs: 1, 7, and 8) and amino acid sequences (SEQ ID NOs: 19 and 4) are not disclosed.
Jensen teaches a plasmid (Jensen SEQ ID NO:54 “long construct”) encoding a nucleotide sequence for a CE7scFv CAR (Figure 13A “Long”) with 100% identity to instant SEQ ID NO:1 (residues 2084-2870 of Jensen SEQ ID NO:54), instant SEQ ID NO:4 (residues 3563-3646 of Jensen SEQ ID NO:54; translation disclosed in Table 1 “CD28tm” – annotated below), instant SEQ ID NO:7 (residues 3647-3772 of Jensen SEQ ID NO:54), and instant SEQ ID NO:8 (residues 3773-4108 of Jensen SEQ ID NO:54) (alignments shown below). Jensen further teaches this CAR has an IgG4-CH2-CH3 (residues 2894-3562 of Jensen SEQ ID NO:54 disclosed as “long spacer” with amino acids disclosed in Table 8 – Jensen SEQ ID NO:60) with 100% identity to instant SEQ ID NO:19 without L235D and “N257Q” mutations.
One of ordinary skill would recognize that the CAR as taught by the combined teachings of Ali, Jonnalagadda, and Hudecek can reasonably constructed using known sequences for respective domains. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to utilize a known functional CE7-CAR as taught by Jensen and include known mutations in residues 235/297 (i.e. 235 and 257 as recited in the instant claims) as taught by Ali and Jonnalagadda with a reasonable expectation of success of reducing IgG Fc receptor binding and thus improving CAR-T cell persistence within scope of the instant claims (See MPEP 2143(I)(E)).
Instant SEQ ID NO:1 aligned with Jenson SEQ ID NO:54
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Fusion of instant SEQ ID NO:7 and 8 aligned with Jenson SEQ ID NO:54
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Instant SEQ ID NO:19 aligned with Jenson SEQ ID NO:60 (long spacer encoded in SEQ ID NO:54)
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Regarding claim 62, The combined teachings of Ali, Jonnalagadda, and Hudecek teach claim 61 as discussed above.
Jensen teaches that designing CAR-T cells to favor proliferation/persistence in vivo may allow the use of lower overall dose T cell, provide a more uniform therapeutic response, and reduce the risk for tumor lysis syndrome and cytokine storm (¶ [0208]).
One of ordinary skill in the art would recognize that persistent CAR-T-cell population could allow lower overall T cell doses because the cells are able to survive longer/proliferate in vivo. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the persistent CD171-specific CE7-CAR-T cell as taught by the combined teachings of Ali, Jonnalagadda, and Hudecek for optimal dosing and test reduced T-cell dosage amount to reasonably prevent adverse effects (i.e. tumor lysis syndrome or cytokine storm) as taught by Jensen.
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Ali and Jonnalagadda as evidenced by Hudecek as applied to claim 62 above, and further in view of Park (Mol Ther. 2007;15(4):825-833) as evidenced by Nair (J Basic Clin Pharm. 2016;7(2):27-31).
Park teaches infusion of T cells expressing CAR constructed from CE7 scFv, IgG1 hinge-CH2-CH3, CD4 transmembrane region, and CD3ζ cytoplasmic domain (page 831, column 2, ¶ 2) for clinical response in patients with recurrent/refractory neuroblastoma with baseline infusion set at 108 cells/m2 (Abstract, Table 3). This amount equates to about 2.7x106 cells/kg based on FDA draft guidelines for humans as disclosed by Nair (Table 1 - typical conversion from dose/m2 to dose/kg based on FDA guidelines for humans is 1.62 m2/60kg). Park suggests the minimal tumor response observed in the study was most likely due to the limited persistence (1-7 days in patients with bulky disease - abstract) of transferred T cells (page 828, column 2, ¶ 2).
One of ordinary skill in the art would recognize that enhancing T cell persistence would likely improve tumor response. Therefore, it would be obvious to one of ordinary skill in the art to administer a cell dosage as previously taught in the art (Park) as a baseline comparison for CAR T cells utilizing a construct with enhanced persistence as taught by the combined teachings of Ali, Jonnalagadda, and Hudecek.
Citation of pertinent prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Hong H, et al. PLoS One. 2016;11(1):e0146885. (IDS cited)
Künkele A, et al. Cancer Immunol Res. 2015;3(4):368-379. (IDS cited)
Taraseviciute A, et al. Cancer Discov. 2018;8(6):750-763. (IDS cited)
Hombach A, et al. Gene Ther. 2010;17(10):1206-1213. (cited in office action dated 3/25/2026)
Conclusion
No claims are allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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