DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response and amendments received August 25, 2026 are acknowledged.
Claims 1 and 13 have been amended.
Claims 1-13 are pending in the instant application.
Claims 1-13 are under examination as they read on anti-CD19 CAR constructs.
The declaration of inventor Terakura under 37 CFR 1.132 received as part of the August 25, 2026 response is acknowledged and will be discussed in conjunction with the rejections for which it was presented.
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 rejection of claim 13 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement has been withdrawn in view of applicant’s claim amendments received as part of the August 25, 2026 response.
Claim Rejections - 35 USC § 102
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.
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.
The rejection of claims 1-13 under 35 U.S.C. 102(a)(1) as being anticipated by Julamanee ’21 (Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival - Mol Ther. 2021 Sep 1;29(9):2677-2690. doi:10.1016/j.ymthe.2021.04.038. Epub 2021 May 1.) has been withdrawn in view of the certified translation of Japanese priority document JP 2020-186414. The art of Julamanee ’21 was published later than the filing date of the priority document and thus Julamanee ’21 no longer qualifies as prior art.
Claim Rejections - 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Hudecek et al. in view of Julamanee ’17 (The Synergistic T-Cell Signal By CD79A/CD40 Costimulatory Endodomain Enhances CD19 Chimeric Antigen Receptor T-Cell Proliferation and Survival – Blood. Volume 130, Supplement 1, 8 December 2017, Page 2061, doi.org/10.1182/blood.V130.Suppl_1.2061.2061).
Hudecek et al. disclose making a panel of anti-ROR1 CAR T cells which varied in the length of the spacer region between the anti-ROR1 scFv and the transmembrane domain (see entire document, particularly the abstract). ROR1 is the receptor tyrosine kinase-like orphan receptor 1 which is a tumor associated molecule expressed on B-cell and epithelial cancers but is not expressed on normal mature B cells or tissues which makes it an attractive target for therapy. They found that the “hinge-only” spacer constructs which comprises just 12 residues between the anti-ROR1 scFv and the transmembrane domain provides the best tumor cell lysis and induction of T cell effector functions in vitro and in vivo (see particularly the abstract, the right column of page 3155, and Figures 1-5). Notably, the costimulatory domain used in the CAR constructs of Hudecek et al. is from CD28 (see particularly the right column of page 3155). These teachings differ from what has been presently claimed in that the intracellular signaling domain in the constructs of Hudecek et al. are not disclosed as comprising CD79A and CD40.
Julamanee ’17 discloses that persistence of CAR T cells is important for therapy, that various costimulatory domains have been used in CARs in an attempt to improve signaling, function, and persistence, and that their construct comprises a CD79A/CD40 costimulatory domain that provided enhanced CAR T cell proliferation and survival as compared to the same construct apart from the use of a conventional CD28 costimulatory domain (see entire document, particularly the introduction and conclusions sections).
Therefore, artisans would have been motivated to replace the costimulatory domains used in the CAR constructs of Hudecek et al with the CD79A/CD40 costimulatory domains found in the CAR constructs of Julamanee ’17. Artisans would be motivated to do so in order to gain the advantages of increased CAR T cell proliferation and persistence that are present in CARs that use CD79A/CD40 costimulatory domains as compared to CD28 costimulatory domains as taught by Julamanee ‘17.
Applicant's arguments filed August 25, 2026 have been fully considered but they are not persuasive. Applicant argues the presence of unexpected results. Specifically, applicant believes that the working examples of the instant specification unexpectedly show superior efficacy in vivo that would not have been expected based upon the prior art . Applicant argues that Figures 4 and 5 demonstrate that an anti-CD19 CAR comprising intracellular CD79A-CD40 domains joined via a short spacer (i.e. 60 AA residues, see most explicitly as discussed in the declaration of inventor Terakura provided as part of the 8/25/2026 response) work better that the same construct having a long spacer or a control construct that binds an irrelevant antigen. Notably, applicant argues that the short spacer yields a tumor size that is 1/10,000 the size of the antigen irrelevant control (i.e. EGFR). Applicant further argues that constructs with a long spacer had equivalent anti-tumor activity when comparing CD79A-CD40 to conventional CD28 intracellular domains, such that extra anti-tumor activity is only observed when a short spacer is paired with the CD79-CD40 intracellular domains. Applicant also has provided the declaration of inventor Terakura et al. that in an otherwise identical constructs, a CD79A-CD40 intracellular domain is superior to a 4-1BB intracellular domain Thus applicant believes the rejection should be withdrawn.
These argument have been considered and are not persuasive. With regard to the 1/10,000 tumor size, such a result was obtained against essentially doing nothing (i.e. the tEGFR-T cells) as the comparator cells do not target the B cell tumor experimentally introduced into the mice and thus such data show, unsurprisingly, that CAR constructs kill tumors expressing the antigenic target of the chimeric antigen receptor. It is true that the data indicate that a short spacer length works better than a longer spacer (for example the “long” spacer of the working examples appears to be an IgG hinge, CH2 and CH3 domain, so about 250 residues or so) but given the data reported by Hudecek et al. who compared spacer lengths in a CAR of different antigen specificity (i.e. the CAR of Hudecek et al bound ROR while the instant working example CAR bind CD19) and very clearly identified that short spacers (i.e. ones 60 residues or less as this is what applicant is claiming and arguing, see claim 1 as amended 8/25/2026) work better than medium spacers which work better than long spacers (see most explicitly Figure 1 of Hudecek et al. and note that the long spacer of Hudecek et al. is highly comparable to the long spacer of the instant application (see the bottom of the right column of page 3154 of Hudecek et al)). Given the clear trend of efficacy when comparing spacer lengths as disclosed by Hudecek et al., using a short spacer reasonably is expected to provide more effective anti-tumor efficacy as compared to other lengths. Given such expectation of increased efficacy when using a short spacer, applicant’s arguments that it is unexpected that combining CD79A-CD40 intracellular domains with a short spacer in an anti-CD19 CAR would yield better efficacy is not persuasive. Note that if applicant is trying to argue a specific degree of increased efficacy by arguing the 1/10,000 tumor size, applicant is reminded that a) no claim recites any amount of efficacy and thus such an argument reasonably is arguing a limitation not claimed, and b) there is no evidence that such a numerical advantage can or will be maintained when using other anti-tumor antigen specificities or other cell types (e.g. T cell versus NK cell, or different types of T cell like a/b versus g/d, etc., see for example Ruppel et al.). Indeed, it is known that the structure of the antigen binding domain can strongly impact efficacy even when targeting the same tumor antigen as Zhang et al. demonstrated that different anti-CEA antibodies were non-equivalent in efficacy when converted into a CAR format (see entire document). Thus the level of efficacy based upon specific numerical results do not appear to be reasonably extrapolatable to the breadth of what has been claimed as no claims are limited to the exact anti-CD19 CAR constructs as disclosed and used in the working examples.
With regard to the declaration of inventor Terakura, given that Julamanee ’17 disclose that the use of a CD79A-CD40 intracellular domain was superior to a conventional CD28 intracellular domain with regard to CAR T cell proliferation and survival, the fact that inventor Terakura observed better proliferation when using CD79A-CD40 intracellular domains as compared to other intracellular domains in CAR T cells is not surprising as it simply confirms the earlier finding of Julamanee ’17 concerning proliferation and survival in a non-anti-CD19 CAR setting. The rejection is maintained.
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Julamanee ’17 (The Synergistic T-Cell Signal By CD79A/CD40 Costimulatory Endodomain Enhances CD19 Chimeric Antigen Receptor T-Cell Proliferation and Survival – Blood. Volume 130, Supplement 1, 8 December 2017, Page 2061, doi.org/10.1182/blood.V130.Suppl_1.2061.2061) in view of Hudecek et al.
Julamanee ’17 discloses CD19 CAR constructs wherein the convention CD28 costimulatory domain was replaced with a CD79A/CD40 costimulatory domain in an effort to improve the signaling, function and persistence of CAR T cells (see entire document, particularly the introduction). It is disclosed that constructs comprising the CD79A/CD40 costimulatory domain demonstrated enhanced CAR T cell proliferation and survival as compared to control constructs comprising the CD28 costimulatory domain. These teachings differ from what is presently claimed in that the constructs of Julamanee ’17 have more than 100 amino acid residues between the anti-CD19 scFv and the transmembrane domain as the spacer comprises an immunoglobulin hinge, CH2, and CH3 domain.
Hudecek et al. disclose making a panel of CAR T cells which varied in the length of the spacer region between the scFv of the antigen binding domain and the transmembrane domain of the CAR construct (see entire document, particularly the abstract). They found that the “hinge-only” spacer constructs which comprises just 12 residues between the scFv and the transmembrane domain demonstrated the best tumor cell lysis and induction of T cell effector functions in vitro and in vivo (see particularly the abstract, the right column of page 3155, and Figures 1-5).
Therefore it would have been obvious to ordinary artisans to shorten the spacer region in the anti-CD19 CAR constructs of Julamanee ’17 to comprise just 12 amino acid residues. Artisans would be motivated to do so based upon the data a Hudecek et al. demonstrating that CAR constructs wherein the spacer was only 12 amino acid residues from the hinge of an immunoglobulin provided the best level of tumor cell lysis and effector cell function as compared to longer spacers.
Applicant's arguments filed August 25, 2026 have been fully considered but they are not persuasive. Applicant repeats arguments concerning the presence of unexpected results as set forth concerning the earlier obviousness rejection. Applicant further argues there is an extreme difference in activity of CARs on tumor size when a short spacer is used as shown in Figures 4 and 5.
These arguments have been considered and are not persuasive. While applicant is correct that the instant data demonstrate a short spacer is more efficacious, such information was already known in the art, such as that of Hudecek et al. who essentially titrate efficacy based upon CAR spacer length (see Figure 1 of Hudecek in particular). Thus applicant’s allegations of unexpected results are not persuasive as discussed in greater detail earlier in this office action. With regard to the “extreme difference” on anti-tumor efficacy, applicant has not supplied any data indicating such “extreme” efficacy is to be found in other setting. Notably, the data of the Terakura declaration speaks only of proliferation, NOT tumor size, and it is known that simply changing the antigen recognition domain of the CAR can impact activity as taught by Zhang et al. None of the instant claims are limited to the exact construct or cell type as argued by applicant as demonstrating “extreme” anti-tumor efficacy and it is known that the use of different antigen binding domains binding the same antigen (Zhang et al.) as well as different cell types (T versus NK for example, see Ruppel et al.) can all impact CAR efficacy. In the absence of data in other model systems demonstrating the same numerical amount of “extreme” impact on tumor size, such results cannot be said to be widely applicable to other settings. Indeed, if such results reasonably could be extrapolated to unrelated systems the results would necessarily be “expected” which is the very anthesis of an “unexpected” result as argued by applicant. The rejection is maintained.
No claims are allowable.
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.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
