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 .
Application Status
This action is written in response to applicant’s correspondence received 02/27/2026. Claims 1, 4, 7, 11-12, 14, 16-19, 22-35, and 41-45 are currently pending. Claims 11-12, 28-35, and 41-45 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 4, 7, 14, 16-19, and 22-27 are examined herein. The restriction requirement mailed 01/05/2026 is still deemed proper. Applicant elected the invention of Group I with traverse in the reply filed 02/2027/2026.
Election/Restrictions
Applicant's election with traverse of the invention of Group I in the reply filed on 02/27/2026 is acknowledged. The traversal is on the ground(s) that, “According to 37 CFR 1.475(b)(1), a national stage application claims to a product and a process will be considered to have unity of invention”. This is not found persuasive for two reasons. One, as stated in 37 CFR 1.475, “Where a group of inventions is claimed in an application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression "special technical features" shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.”. As discussed in the restriction requirement of 01/05/2026, the separate inventions share a technical feature which is not a special technical feature in view of the prior art, so does not fulfill the requirement for unity of invention. Two, it is respectfully noted that while the Applicant states that “national stage application claims to a product and process will be considered to have unity of invention”, the text of 37 CFR 1.475 states that a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to the five specific combinations of categories listed in part (b). Attention is drawn to the distinction between the specific combination of products and processes listed in 37 CFR 1.475 (b) 1-5 compared to merely any generic product and process.
Applicant further argues that, “searching and examination of all the pending claims would not cause a serious or undue burden on the Office”. Respectfully, this is not persuasive because this application is a national stage filing of an international application. Restriction in such applications is based on lack of unity practice and the provisions of MPEP 800 do not apply.
Regarding Applicant’s observation that “the subject matter covered by the instant claims was not considered lacking unity of invention during the international phase”, it is noted that the determination of lack of unity is made on a case-by-case basis
The requirement is still deemed proper and is therefore made FINAL.
Claims 11-12, 28-35, and 41-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/27/2026.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1, 4, 7, 14, 16-19,and 22-26 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 1 is drawn to a cell expressing a modified CD3 subunit chain comprising one or more of at least one ITAM deletion, exogenous intracellular hematopoietic cell signaling domain, and at least one modified ITAM in which at least one of X1 and X6 is not tyrosine. The claim does not recite that the cell is an isolated cell. The specification discloses that the invention is contemplated for use in clinical applications in humans, and may be administered to a human subject as a form of cell therapy:
[0074] Non-limiting examples of amino acid sequences which may be included in modified CD3 subunit chains according to aspects of the invention are shown in Table 1. Shown in Table 1 are constructs using mouse sequences designed for proof of concept experiments in the mouse model. For experiments in human cells and for clinical applications, constructs will be designed that contain the corresponding human sequences to those shown for mouse.
[0112] Preferably, the inventive particular cell(s) is/are administered by injection, e.g., intravenously…The dose will be determined by the efficacy of the particular inventive cell(s) and the condition of the subject (e.g., human), as well as the body weight of the subject (e.g., human) to be treated.
[0130] For purposes of the inventive methods, wherein populations of cells are administered, the cells can be cells that are allogeneic or autologous to the subject. Preferably, the cells are autologous to the subject to avoid graft vs host disease or graft rejection.
Therefore, the broadest reasonable interpretation of the claim as a whole encompasses a genetically modified cell or population of cells present and growing in a living human organism.
The dependent claims specify various structural limitations of the cell, but do not recite limitations which would limit the cell to one which is not part of a human organism. The exception is claim 27, which limits the cell to one present in a pharmaceutical composition. A pharmaceutical composition is interpreted as encompassing compositions suitable for administration to a living subject but not compositions present in a living subject.
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.
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, 4, 7, 14, 16-19, 23 and 25-27 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as anticipated by U.S. PGPUB 2018/0230193 to Loew (hereinafter ‘Loew’).
A note on claim interpretation: Given the similarities between engineered TCRs and CARs (i.e., both are engineered antigen-specific T cell receptors), it is not entirely clear what specific structures the Applicant intends to exclude with the limitation that the modified CD3 subunit is not comprised within a CAR, as recited in claim 1. While the instant specification does not provide an explicit definition of what the inventors regard “chimeric antigen receptor” (CAR) to mean, it does state the following:
[0084] Unlike CARs, T cell receptor fusion constructs become a functional component of the endogenous TCR complex.
Loew describes their construct as follows:
The present disclosure features the use of chimeric CD3 proteins to modulate T cell Receptor (TCR) signaling. Specifically, the disclosure is based, in part, on the discovery that chimeric CD3 proteins (e.g., CD3delta, CD3gamma, and CD3epsilon) having all or most of their extracellular domain fused to an antigen binding domain can activate the TCR in the presence of a cognate antigen. (Abstract)
The front page figure of Loew supports this interpretation, showing a modified CD3 subunit complexed with other, unmodified CD3 subunits and TCRα/β chains. Based on those disclosures, Loew’s construct aligns with Applicant’s description of a T cell receptor fusion construct, not a CAR.
Regarding claim 1, Loew teaches non-immortalized cells (primary human T cells) comprising TCARs comprising modified CD3 subunit chains comprising a tyrosine-to-phenylalanine mutation in the ITAM motif (i.e., a modified ITAM of Formula I, wherein X1 and X6 are not tyrosine), or, alternatively, comprising an ITAM deletion (constructs with “no CD3 zeta signaling domain”, or which lack “internal endogenous ITAM domains”; see below):
[0493] FusTCARs were also tested in primary human T-Cells for their activity…A second construct (SEQ ID NO: 11) was similarly cloned, excepting that all intracellular tyrosine residues within CD3 zeta annotated to be phosphorylated were switched to phenylalanine in order to abbrogate intracellular phosphotyrosine signaling. As a combination of a intracellular costimulatory domain with intracellular signaling domain has previously been demonstrated to be beneficial for typical CAR constructs, a final construct was cloned whereby CD19 scFv was a N-terminal fusion to the CD8a linker and transmembrane domain followed by 4-1BB; no CD3 zeta signaling domain was included in this construct (SEQ ID NO: 12). Finally, an analogous fusTCAR was synthesized to CD19scFV-Zeta_7YtoF. “FusTCAR4” lacks internal endogenous ITAM domains. CD19scFv, SEQ ID NO: 13 was cloned as a N-terminal fusion to the complete CD3 epsilon protein except those tyrosines annotated to be phosphorylated were mutated to phenylalanine rendering the instrinic signaling pathways associated with CD3 epsilon ITAMs inactive.
[0485] “FusTCAR3” (FIG. 14) lacks internal endogenous ITAM domains. CD19 scFv was cloned onto the N-terminus of the CD3 extracellular and transmembrane domains followed by the intracellular costimulatory domain 4-1BB (SEQ ID NO: 9).
[0551] As described in Example 1, lentivirus were produced for fusTCAR3, fusTCAR16, fusTCAR19 and fusTCAR22 and transduced into isolated primary human T-cells. Transduced T-cells and non-transduced control T-cells were expanded and frozen for subsequent analysis.
It is relevant to note, as disclosed by the instant specification, that Formula I is merely a mutant of the wild-type ITAM as provided by Formula II (para [0063]: The wild-type (unsubstituted) consensus sequence for ITAMs is provided by Formula II: YX1X2L/I-(X3)p-YX4X5L/I) in which the tyrosines (Y) at positions corresponding to X1 and X6 of Formula I have been substituted. Therefore, insofar as Loew teaches wild-type ITAMs modified such that the tyrosines have been substituted by phenylalanine, as described above, Loew also teaches modified CD3 subunit chains comprising ITAMs of Formula I.
Loew teaches that the TCARs are antigen-specific receptor which targets a cancer antigen (i.e., CD19, which Loews confirms is a tumor antigen):
[0239] Accordingly, the present invention provides proteins that target the following cancer associated antigens (tumor antigens): CD19
Regarding claim 4, Loew teaches that the antigen-specific receptor is a TCR (see above).
Regarding claim 7, Loew teaches that the cell is a T cell (see para [0493] quoted above).
Regarding claim 14, Loew teaches that the modified CD3 subunit chain is CD3zeta, gamma, CD3delta or CD3epsilon (see para [0493] quoted above for CD3epsilon, and below for the other subunits):
[0542] In “fusTCAR16” the CD19 scFv was cloned as an N-terminal fusion to the CD3 delta extracellular and transmembrane domains followed by the intracellular costimulatory domain 4-1BB (SEQ ID NO: 28).
[0543] In “fusTCAR19” the CD19 scFv was cloned as an N-terminal fusion to the CD3 gamma extracellular and transmembrane domains followed by the intracellular costimulatory domain 4-1BB (SEQ ID NO: 31).
[0549] In “fusTCAR22” the CD19 scFv was cloned as an N-terminal fusion to the CD3 zeta extracellular and transmembrane domains followed by the intracellular costimulatory domain 4-1BB (SEQ ID NO: 34).
Regarding claims 16-19, Loew teaches constructs in which all tyrosines in the ITAM motifs have been substituted with phenylalanine (see at least para [0493] quoted above).
Regarding claim 23, Loew teaches wherein the modified CD3 subunit chain comprises at least a 4-1BB intracellular hematopoietic signaling domain (see above).
Regarding claim 25, Loew teaches constructs such as FusTCAR3, where the CD3 epsilon intracellular domain is truncated and lacks any ITAMs (intracellular T-cell signaling domain) (see above).
Regarding claims 26-27, Loew teaches a population of the cells comprised in a pharmaceutical composition:
[0446] Pharmaceutical compositions of the present invention may comprise a chimeric protein-expressing cell, e.g., a plurality of chimeric protein-expressing cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
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.
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.
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.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Loew (cited above).
Loew teaches the cell comprising a modified CD3 subunit chain of claim 1, from which claim 22 depends.
Loew does not explicitly teach that the particular constructs described in the rejection of claim 1 under 35 U.S.C. 102 were derived from hematopoietic stem cells.
However, Loew does teach routine procedures for ex vivo expansion of T cells derived from hematopoietic stem cells, and that it can be applied to those cells:
[0437] The procedure for ex vivo expansion of hematopoietic stem and progenitor cells is described in U.S. Pat. No. 5,199,942, incorporated herein by reference, can be applied to the cells of the present invention. Other suitable methods are known in the art, therefore the present invention is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of immune effector cells (e.g., T cells, NK cells) comprises: (1) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo. In addition to the cellular growth factors described in U.S. Pat. No. 5,199,942, other factors such as flt3-L, IL-1, IL-3 and c-kit ligand, can be used for culturing and expansion of the cells
Loew provides a teaching, suggestion or motivation to obtain the T cells in the above manner, because doing so would have yielded a population of patient-derived therapeutic T cells suitable for ex vivo expansion and manipulation followed by enhanced engraftment and in vivo expansion:
[0394] In a further aspect of the present invention, T cells are obtained from a patient directly following treatment that leaves the subject with functional T cells. In this regard, it has been observed that following certain cancer treatments, in particular treatments with drugs that damage the immune system, shortly after treatment during the period when patients would normally be recovering from the treatment, the quality of T cells obtained may be optimal or improved for their ability to expand ex vivo. Likewise, following ex vivo manipulation using the methods described herein, these cells may be in a preferred state for enhanced engraftment and in vivo expansion.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have derived the primary T cells comprising the modified CD3 subunit chains, as taught by Loew, from the peripheral blood or bone marrow of a patient in need of cell therapy with the transduced T cells. The ordinary artisan would have been motivated by Loew’s teachings that this approach yielded T cells of improved quality for expansion and therapeutic use, and would have had a reasonable expectation of success based on Loew’s disclosure that suitable methods were known in the art.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Loew (cited above), as applied to claims 1, 4, 7, 14, 16-19, 23, and 25-27 above, in view of Law (Expression and characterization of recombinant soluble human CD3 molecules: presentation of antigenic epitopes defined on the native TCR–CD3 complex. International Immunology, Volume 14, Issue 4, April 2002, Pages 389–400.).
Loew teaches the cell comprising a modified of claim 1, from which instantly rejected claim depends, as described above.
Loew does not teach wherein the modified CD3 subunit chain is a combination of a CD3zeta,gamma, delta or epsilon chain comprising an ITAM deletion, and an intracellular T-cell signaling domain of any of the other CD3 chains. This is interpreted as a chimeric construct where some portion of, to provide one example, a CD3zeta chain is fused or linked to some portion of a CD3 delta chain.
Law teaches, “a single-chain (sc) construct encoding the CD3δ chain linked to the CD3ε chain with a flexible linker” (Abstract).
Law further provides several motivations to express and use these constructs, stating (p. 398):
The availability of soluble recombinant human CD3ϵδ fusion proteins resembling the native proteins in the TCR–CD3 complex provides us with the starting materials for three‐dimensional structural determination of the CD3ϵδ subunits. This could be the first step to elucidate how the EC domains of CD3 subunits interact with each other and the TCRαβ/δγ chains. Such information would facilitate the screening and identification of high potency molecules that can disrupt the native TCR–CD3 complexes expressed on T cells. Such agents could be small molecules or biologics like new anti‐CD3 mAb directed against specific regions of the CD3 chains. Not only can these molecules be applied to further our understanding in the signaling function of the TCR–CD3 complex during T cell development, they can also be tested as immunosuppressive agents in the clinic.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the TCRs comprising mutated CD3 subunit chains, as taught by Loew, by creating fusion constructs between various combinations of CD3 chains, as taught by Law. The ordinary artisan would have had a reasonable expectation that the construct could successfully be synthesized based on Law’s guidance regarding their construction, and would have been motivated to do so based on Law’s teachings that said constructs would have been useful for furthering the understanding of the modified TCR-CD3 complex and how the modified CD3 subunits interact with each other.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
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