--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 .
Status of Claims
Applicant’s amendment filed on 10/10/2025 is acknowledged. Following the amendment, claims
1, 3, 12-13, 17, 28, and 33 are currently amended. Claims 2, 4-7, 9-11, 14-16, and 21-27 are canceled. Claim 32 remains withdrawn. Claims 1, 3, 8, 12-13, 17-20, and 28-35 are currently pending and under examination.
Claim Objections
Applicant’s arguments, see pg. 6, filed 10/10/2025, with respect to claim 28 have been fully considered and are persuasive. The objection of 10/10/2025 has been withdrawn. Upon further review of the amended claims, the following objections are noted.
Claim 20 is objected to because of the following informalities: “between about 5,000 molecules per cell and about 10,000 per cell molecules per cell…”. Appropriate correction is required.
Claim 33 is objected to because of the following informalities: “A nucleotide composition…” should read as “a nucleic acid composition” as referenced again in dependent claim 34. Appropriate correction is required.
Claim Rejections - 35 USC § 112
1. Applicant’s arguments, see pg. 6, filed 10/10/2025, with respect to rejection of claims 3-7, 13-16, and 21-25 under 35 U.S.C. 112(a) have been fully considered and are persuasive. The rejection of 10/10/2025 has been withdrawn.
2. Applicant’s arguments, see pgs. 6-7, filed 10/10/2025, with respect to the rejection of claims 5-7 and 15-18 under 35 U.S.C. 112(b) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Applicant’s amendment filed on 10/10/2025 and review of amended claims.
Claims 3, 18, 20, and 28 are 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 3 recites “…the first intracellular signaling domain comprises…or a modified CD3ζ polypeptide comprises…” It is unclear whether the claim means:
1. The first intracellular signaling domain comprises a native CD3ζ polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 135; or
2. The first intracellular signaling domain comprises a modified CD3ζ polypeptide, wherein the modified CD3ζ polypeptide comprises SEQ ID NO: 135.
The current wording of claim 3 renders the scope unascertainable.
Claims 18 and 20 recite the limitation density “on the surface of the target cell,” but claim 1 does not expressly introduce a target cell. There is insufficient antecedent basis for this limitation in the claim.
Claim 28 recites the limitation “wherein the tumor antigen is selected from…”. It is unclear if the “tumor antigen” is referring to only the first tumor antigen; only the second tumor antigen; either of the tumor antigens; or both tumor antigens. Therefore, the scope of the claim is unascertainable
3. Applicant’s arguments, see pg. 7, filed 10/10/2025, with respect to the rejection of claim s 2, 5-12, 15, and 25 under 35 U.S.C. 112(d) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Applicant’s amendment filed on 10/10/2025.
Claims 18 and 28 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18 depends from canceled claim 15 and claim 28 depends from canceled claim 26. Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Rejections - 35 USC § 102
Applicant’s arguments, see pg. 7-8, filed 10/10/2025, with respect to rejection of claims 1, 3-6, 8, 10, 11, 13-19, 21-24, 26-31, and 33-35 under 35 U.S.C 102 have been fully considered and are persuasive. The rejection of 10/10/2025 has been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 10/10/2025 have been fully considered but they are not persuasive.
Claims 1, 3, 8, 12-13, 17-20, and 28-35 remain rejected under 35 U.S.C. 103 as being unpatentable over Orentas et al. (cited in previous Office Action dated 04/10/2025) in view of Watanabe et al. (cited in previous Office Action dated 04/10/2025).
Applicant argues that Orentas teaches a DuoCAR system directed to three leukemia-associated antigens and regards targeting only two antigens as insufficient to prevent tumor relapse and antigen-escape variants. This argument is not commensurate with the scope of the claims. Independent claims 1 and 33 use the open-ended transition “comprising” and require a first CAR having an antigen-binding domain and CD28 costimulatory signaling and a second CAR having an antigen-binding domain and 4-1BB costimulatory signaling. The claims do not require that the cell or nucleic acid composition bind only two antigens, nor do they exclude an additional antigen-binding domain or a third antigen specificity. “Comprising” does not exclude additional, unrecited elements (MPEP 2111.03).
Orentas expressly discloses the claimed two-CAR signaling arrangement. In particular, Orentas describes a DuoCAR product containing: 1. A first CAR having tandem CD20 and CD19 binding domains linked to CD28 and CD3ζ intracellular signaling domains (pg. 17); and
2. A second CAR having a CD22 binding domain linked to 4-1BB and CD3ζ intracellular signaling domains. Orentas further expressly characterizes the disclosed system as a “DuoSet comprised of two CAR-T vectors” (pg. 78). Thus, Orentas discloses an immunoresponsive cell having a first CD28 containing CAR and a second 4-1BB containing CAR, as presently claimed. The fact that the first CAR additionally contains a second antigen-binding domain directed CD19 does not distinguish the claimed subject matter because the claims do not exclude that additional binding domain. Nor does Orentas teach away from the claimed subject matter. Although Orentas states that targeting three or more antigens is superior for reducing antigen-escape variants (pg. 22), this statement expresses a preference for greater antigen coverage. It does not discredit or render inoperative the use of the first and second CARs recited in the claims, nor does it discourage using a CD28 containing CAR against a low-density tumor antigen. A known arrangement does not become nonobvious merely because the reference describes another arrangement as superior (MPEP 2145, citing In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Watanabe is relied upon for the feature not expressly quantified by Orentas – namely, that the tumor antigen bound by the CD28 containing CAR may be present at fewer than about 5,000 molecules per cell. Watanabe investigated an anti-CD20 CAR containing CD28 and CD3ζ intracellular signaling domains and determined that CAR-T cell cytolytic activity occurred at a CD20 density of approximately 200 molecules per target cell, with other activation responses occurring at densities in the range of a few thousand molecules per cell (Abstract). These values fall within the presently claimed density of less than about 5,000 molecules per cell.
Accordingly, a person of ordinary skill in the art would have had reason to employ the CD20 binding, CD28 containing first CAR taught by Orentas for recognition of tumor cells having low CD 20 expression, as taught by Watanabe. The motivation would have been to retain CAR mediated recognition and cytolytic activity when expression of a tumor antigen is reduced, thereby addressing the recognized problem of antigen downregulation an antigen escape variants. Watanabe’s experimental demonstration of CD28-CD3ζ activity at antigen densities substantially below 5,000 molecules per cell would also have provided a reasonable expectation of success.
Accordingly, Applicant’s arguments do not overcome the rejection. The rejection under 35 U.S.C 103 over Orentas in view of Watanabe is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 13, 17, 84, and 86 of U.S. Patent No. 11267901 (‘901) in view of Orentas et al. (cited above) and Watanabe et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant application and patent ‘901 teach a T-cell comprising multiple chimeric antigen receptors, with an intracellular signaling domain including CD28 as co-stimulatory molecule, means of recombinant expression and a pharmaceutical composition comprising these CAR-T cells against antigens CD19 and CD22. However, patent ‘901 does not specifically teach the use of ITAM variants within the CD3ζ polypeptide portion of the intracellular signaling domain nor the values for antigen density. The teachings of Orentas and Watanabe as discussed above address these deficiencies.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the CAR-T cell composition known from patent ‘901 and combine it with the teachings of Orentas and Watanabe that show the use of ITAM variants within the CD3ζ polypeptide portion of the intracellular signaling domain and effective antigen density per molecule at values below and above 5000 molecules per cell. One of ordinary skill in the art would have been motivated to do so to achieve optimal CAR-T response to targeted antigens as well as optimizing the pharmaceutical CAR-T composition for drug dosage, efficacy, side effects, and drug compliance. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made and the conflicting claims are not patentably distinct from each other.
2. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25, 27-28, and 31 of U.S. Patent No. 12018077 (‘077) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
3. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-23, 29-30, 32-34, and 38 of U.S. Patent No. 12263220 (‘220) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
4. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9, and 20 of copending Application No. 17/583,117 (‘117) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
5. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11, 14-15, and 18 of copending Application No. 19/076,055 (‘055) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
6. Claims 1-31, and 33-35 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-20, 22-23, and 26 of copending Application No. 18/622,315 (‘315) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above. In addition, while application ‘315 targets CD56 as target antigen for the first CAR, it would have been obvious to one of ordinary skill in the art to use the teachings of Orentas et al. and Watanabe et al. to modify the first CAR target antigen from CD56 to CD19 in order to more specifically target certain tumor antigens. This is a provisional nonstatutory double patenting rejection.
Applicant’s request that the provisional nonstatutory double patenting rejection be held in abeyance until allowable subject matter is identified has been considered but is not accepted. Applicant’s request to defer consideration of the rejection neither establishes that the presently pending claims are patentably distinct from the reference claims nor includes a terminal disclaimer that obviates the rejection. Accordingly, Applicant has not overcome the provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowable.
Applicant's amendment necessitated the new ground 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 DENNIS GEORGE whose telephone number is (571)270-0340. The examiner can normally be reached M-F 8:30am - 5pm 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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/DENNIS GEORGE/Examiner, Art Unit 1644
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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