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 05/06/2026. 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 Claims 11-12, 28-35, and 41-45 are withdrawn from prosecution as being drawn to non-elected subject matter.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.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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 23 and 25 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.
Claims 23 and 25 both recite the limitation "the…non-CD3 subunit chain”. Claim 1, from which both claims depend, does not recite a non-CD3 subunit chain. There is insufficient antecedent basis for this limitation in the claim.
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.
Claim 1, 4, 7, 14, 16-19, 22, 23, and 25-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hwang (Hwang et al. TCR ITAM multiplicity is required for the generation of follicular helper T-cells. Nat Commun. 2015 May 11:6:6982.; of record, cited on an IDS).
Regarding claim 1, Hwang teaches a genetically modified cell expressing a modified CD3 subunit chain (p. 2):
we analysed two lines of ‘knock-in’ mice generated by gene targeting in embryonic stem cells: 6Y/6Y, which encodes a ‘wild-type’ CD3z chain, and 6F/6F, which encodes a CD3z protein where each of the 6 ITAM Y residues was mutated to Phenylalanine (F), rendering these ITAMs non-functional for signal transduction
Please see also Figure 1a, which, on the right, shows a schematic of a T cell receptor (TCR) complex comprising the modified CD3ζ subunit chain.
Also in Figure 1, Hwang teaches staining profiles of cells isolated from 6F/6F transgenic mice (i.e., isolated cells expressing the modified CD3 subunit chain) (b, c).
Hwang further teaches the modified CD3 subunit chain comprising at least one modified ITAM comprising an amino acid sequence of Formula I:
Each of the invariant TCR subunits (CD3g, CD3d, CD3e and CD3z) contains one or more copies of a semi-conserved sequence, the Immunoreceptor Tyrosine-based Activation Motif (ITAM), within their cytoplasmic domains that are composed of
two YxxL/I cassettes (Y = tyrosine, L = leucine, I = isoleucine, x = any amino acid) separated by 6–8 amino acids.
Above, the two YxxL/I cassettes are equivalent to X1-4 and X6-9 of Formula I, while the 6-8 amino acids separating the two YxxL/I cassettes are equivalent to (X5)m of Formula I. As noted above, Hwang modified these ITAMs by mutating the tyrosines (Y) to phenylalanines (F), as described above and shown in Figure 1a – i.e., Formula I with the proviso that at least one of X1 and X6 is not tyrosine.
Hwang further teaches wherein the cell expresses an antigen-specific receptor (a CD3/TCR complex, such as that shown in Figure 1a), that the cell is not immortalized (it is either an embryonic stem cell or an isolated T cell derived from the stem cell), and the modified CD3 subunit chain is not comprised in a CAR (it is comprised in a CD3/TCR complex).
Lastly, Hwang teaches that, “Subunits of the TCR complex can be classified into two distinct functional groups: ligand binding or signal transduction…TCRα/β dimers confer ligand-binding specificity and associate non-covalently with dimers composed of the invariant signal transducing subunits: CD3γ, CD3δ, CD3ε, and CD3ζ” (p. 2 1st ¶). Thus, insofar as Hwang teaches the transducing, non-ligand-binding CD3ζ subunit with tyrosine-to-phenylalanine substitutions but does not teach any other mutations which would confer an antigen-binding domain or antigen-recognition moiety on the subunits, it is assumed that these subunits do not comprise exogenous antigen-binding domains or extracellular fusions to an antigen recognition moiety, and antigen recognition is not mediated by the modified subunit.
Regarding claim 4, Hwang teaches wherein the antigen-specific receptor is a TCR, as described above.
Regarding claim 7, Hwang teaches wherein the cell is a T cell, as described above.
Regarding claim 14, Hwang teaches wherein the modified CD3 subunit chain is a CD3zeta chain, as described above.
Regarding claims 16-19, Hwang teaches wherein the CD3zeta chain comprises one, two or three modified ITAMs wherein each of X1 and X6 is phenylalanine, as described above and shown in Figure 1a.
Regarding claim 22, Hwang teaches wherein the cell (T cell) is derived from an embryonic stem cell and wherein the modified chain is introduced into the embryonic stem cell prior to differentiation into the T cell expressing the modified CD3 subunit chain, as described above.
Regarding claims 23 and 25: claim 1, from which both claims depend, recites alternative embodiments of the CD3 subunit chain comprising one of any of the following: an ITAM deletion, an exogenous intracellular hematopoietic, and/or at least one modified ITAM of Formula I. Claims 23 and 25 recite the “modified CD3 subunit chain…comprising at least one ITAM deletion”. Thus, they further limit that alternative embodiment. However, claims 23 and 25 do not recite or further limit the modified CD3 subunit comprising at least one modified ITAM. As a result, insofar as Hwang teaches the modified ITAM embodiment, and claims 23 and 25 encompass but do not further limit that embodiment, Hwang teaches those limitations of claims 23 and 25.
Regarding claim 26, Hwang teaches a population of the T cells and/or embryonic stem cells as described above.
Regarding claim 27, Hwang teaches injecting donor bone marrow cells from 6F/6F mice into recipient mice, in vivo, i.e., the cells in a pharmaceutical composition.
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 24 is rejected under 35 U.S.C. 103 as being unpatentable over Hwang (cited above), as applied to claims 1, 7, 14, in view of Wu (Wu et al. Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy. Cell, 2020; 182, 855-871.e23.; publicly available August 20, 2020).
Hwang teaches the cell expressing a modified CD3ζ subunit chain of claim 1, from which claim 24 depends.
Hwang does not teach wherein the modified CD3 subunit chain is a CD3zeta chain comprising an intracellular T-cell signaling domain of a CD3epsilon chain.
Wu teaches a modified CD3 subunit chain comprising a CD3zeta chain and an intracellular T-cell signaling domain of a CD3epsilon chain (Figure 5a, the relevant portion reproduced below):
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Wu further notes that, “The CD3 sub units...use tyrosine phosphorylation as a functional switch to trigger downstream signaling” (p. 855) and that, “CD3ε incorporation enhanced basal phosphorylation level of the CD3z module, which might be explained by the Lck recruitment function of CD3ε BRS” (p. 868). However, “It is still unclear how CD3ε BRS coordinates interactions with Lck and p85.”. Thus, Wu teaches that incorporating CD3ε in a construct with CD3ζ increased CD3ζ phosphorylation, which may increase downstream signaling. Wu further provides a teaching, suggestion or motivation to further explore this relationship given the lack of clarity regarding how the CD3ε BRS (i.e., an intracellular signaling domain having “ionic interaction with Lck regulatory domains”; p. 860) coordinates interactions with Lck and p85, and how that affects CD3ζ.
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 Hwang, to also comprise an intracellular signaling domain of CD3ε, as taught by Wu, to achieve the predictable result of a CD3 subunit chain suitable for further studying the role of the CD3ε BRS in TCR functionality and its interactions with CD3ζ. Given the clinical relevance of therapeutic T cells with engineered receptors, as taught by Hwang and Wu, in combination with Wu’s disclosures that there was an unmet need to further clarify the function of the CD3 complex and the interactions among the components and their signaling domains, the ordinary artisan would have been motivated to synthesize said construct to further study those interactions.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1, 4, 7, 14, 16-19, and 22-27 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
