DETAILED ACTION
Notice of Pre-AIA or AIA Status
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to the papers filed on 04/16/2026. Claims 149-153, 156-165, and 167-169 are currently pending as per claims filed on 04/16/2026. Claims 156-158, 161, 162 are withdrawn, claims 149, 151, 156-160, 167, and 168 have been amended, and Claim 169 has been added by Applicants’ amendment filed on 04/16/2026. Claim 149 is an independent claim.
In response to restriction requirement filed 10/02/2025, applicant’s response filed 11/21/2025 elected without traverse Group III, claims 149-150 drawn to a method of reducing CCR antigen-mediated stimulation of T cell signaling. The examiner appreciates the correction. Moreover, in the response filed on 11/21/2025, Applicants elected without traverse the following species:
(A) both: the first hinge region comprises an amino acid substitution at position 27, and the second hinge region comprises an amino acid substitution at position 44 of SEQ ID NO: 2 (an not single aa substitutions at position 27 or 44) . Claims 149-157, 159-161, and 163-168 read on the elected species.
(B) The amino acid sequence of the second hinge region, as set forth in SEQ ID NO: 3 (an not SEQ ID NO:4 or SEQ ID NO:5) . Claims 149-157, 159-161, and 163-168 (claims 131-150 now canceled) read on the elected species.
Note, that in response to the restriction requirement filed on 11/21/2025, Applicant additionally added claims 151-168 and cancelled claims 131-150. Therefore, Applicant elected for (A): The first hinge region comprises an amino acid substitution at position 27, and the second hinge region comprises an amino acid substitution at position 44 of SEQ ID NO: 2, which read on now claim 156-159. Applicant elected for (B): The amino acid sequence of the second hinge region, as set forth in SEQ ID NO: 3, which read on claim 160.
Examiner notes that if newly added claims 156-162 in claims filed 11/25/2025 would have been originally presented, it would have been subjected to restriction requirements. Claim 156-158 read on non-elected species.
Moreover, the sequences listed in claims 161 and 162 are unique and specific sequences and not disclosed as being required for the elected species. Thus, search and examination the beyond the elected sequence as recited in claim 160 would place an undue burden on the examiner. Thus, claims 161 and 162 do not correspond to the elected species; accordingly, claims 161 and 162 remain withdrawn from consideration as being directed to a non-elected species. See 37 CFR 1.142(b) and MPEP § 821.03.
Therefore, claims 149-153, 156-160, 163-165, and 167-169 are pending and under examination are pending and under examination to which the following grounds of rejection are applicable.
Priority
The instant application claims is a 371 of PCT/US2021/027648 filed on 04/16/2021 which claims benefit of US Provisional patent application 63/011,494 filed on 04/17/2020. Thus, the earliest possible priority for the instant application is 04/17/2020.
Response to Arguments
Withdrawn objections/rejection in response to Applicants’ arguments or
Amendment
Drawing Objection
In view of Applicants’ amendment of the drawings, the drawing objection has
been withdrawn.
Claim Objection
In view of Applicants’ amendment of claim 149, the drawing objection has
been withdrawn.
Claim Rejections - 35 USC § 112 (b)
In view of Applicants’ amendment of claim 149 and 151-153 and cancellation of claim 154, the 35 USC § 112 (b) rejection has been withdrawn.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment of claim 149 and arguments, the 103 rejection has been withdrawn.
A response to Applicant’s arguments with regard to a withdrawn rejection is moot.
Applicant’s arguments, see page 16-19, filed 04/16/2026, with respect to the teachings of Chaudhary, Van de Stegen, Schonfeld, and Wu, have been fully considered and are persuasive.
Examiner agrees with the applicant’s arguments and amendments that Chaudhary, Van de Stegen, Schonfeld, and Wu also do not teach both a CAR and CCR each having a CD8α domain and substitution of the cysteine residue at position 44 of SEQ ID NO:2 within the CCR hinge for another residue producing a modified CCR and do not teach any method of reducing T cell stimulation in a T cell comprising both a modified CCR and a CAR. Similarly, examiner agrees that the combined teachings of Chaudhary, Van de Stegen, Schonfeld, and Wu would not be able to predict the surprising result of reducing undesirable effect of CCR antigen-dependent, CAR antigen-independent signaling from the cysteine substitution in the hinge region of the CCR.
As applicants concede “for the first time, that certain CCRs are able to interact with the corresponding CAR via disulfide bonding of cysteine residues between the CAR and CCR hinge regions, which induces CAR-mediated T cell signaling in the absence CAR antigen. The Applicant has also surprisingly discovered that CAR antigen-independent signaling can be driven by the CCR, and such signaling can be solved by mutating cysteine residues within the CCR hinge region. Indeed, the applicant demonstrated that one or more cysteine residues in the hinge region of the CCR is shown to eliminate the undesirable effect of CCR antigen-dependent, CAR antigen-independent signaling, with T cells showing cytotoxicity only against targets expressing both antigens”. Hence, applicant has persuaded applicant of the novelty of the cysteine modification to the hinge region of the CCR eliciting a surprising outcome of reduced CCR antigen-mediated stimulation of T cell signaling in the absence of CAR antigen.
New rejections in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 112 (b)
Claims 149-153, 156-160, 163-165, and 167-169 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 applicant regards as the invention. This is a new rejection necessitated by amendment of the claims in the response filed 04/16/2026.
Claim 149 is indefinite because of the recitation “substituting the cysteine residue at position 44 of SEQ ID NO: 2”. It is unclear if the claimed SEQ ID NO:2 corresponds to the CD8a hinge domain of CAR and CCR polypeptides recited claim 1 subpart a) or a different CD8a hinge domain. As such the metes and bounds of the claim are indefinite.
Claim 149 recites the limitation "the cysteine residue" in line 7. There is insufficient antecedent basis for this limitation in the claim.
Claim 150, 152 and 153, is indefinite because of the recitation “one or more cysteines”. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the term “and/or” in line 18. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only CD3+, CD4+, and CD8+ cells, or all of the expressions, “or” would imply that the expression types are in the alternative. Appropriate correction is required.
Claims 150-153, 156-165, 167-169 are also included in the rejection as they directly or indirectly depend on claim 149.
Maintained and/or modified rejections in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 112 (a) – Scope of Enablement
Claims 149-153, 156-160 and 163-165, 167-169 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of reducing CCR antigen-mediated stimulation of T cell signaling in the absence of a CAR antigen, the method comprising:
• obtaining anti-BCMA CAR and anti-EGFR CCR polypeptides each having a CD8a hinge domain;
• wherein the CAR contains a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2,;
• wherein the CCR contains a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2, a CD8α transmembrane domain, and a CD28 cytoplasmic domain
• expressing the CAR and modified CCR in a T cell;
wherein, in the absence of CAR antigen, CCR antigen-mediated stimulation of T cell signaling by the modified CCR is reduced in the T cell compared to CCR antigen-mediated stimulation of a T cell comprising the same CCR without the substitution of the cysteine residue at position 27 and 44 of SEQ ID NO: 2 within the CCR hinge domain.
does not reasonably provide enablement for a method comprising a genus of CAR and CCR polypeptides having a CD8α hinge domain comprising substituting the cysteine residue at position 44 of SEQ ID NO: 2 within the CCR hinge for another residue, thereby producing a modified CCR. Note that the claims are examined as they read on the elected species, i.e., the first hinge region comprises an amino acid substitution at position 27, and the second hinge region comprises an amino acid substitution at position 44 of SEQ ID NO: 2. The claims are not enabling for any antigen to be able to bind to the CAR and CCR polypeptides but only for the CAR and CCR polypeptides being able to bind to different antigens. Moreover, the claims are not enabling for any structure of a CCR. In other words, the claims are only enabled for the CCR comprising an EGFR binding domain, a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2, a CD8α transmembrane domain, and a CD28 cytoplasmic domain
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
This rejection has been modified in consideration of the applicant's amendment filed on 04/16/2026.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
the breadth of the claims; the nature of the invention:
The claims are directed to a method that comprises a vast genus of CAR and CCR polypeptides each having a CD8α hinge domain and substituting the cysteine residue at position 44 of SEQ ID NO: 2 within the CCR hinge for another residue, thereby producing a modified CCR, compared to a CCR comprising a CD8α hinge domain without substitutions. The claims broadly encompass any CAR and CCR polypeptides with a CD8α hinge domain and substituting the cysteine residue at position 44 of SEQ ID NO: 2 within the CCR hinge with any amino acids to reduce CCR antigen-mediated stimulation of T cell signaling in the absence of CAR antigen, compared to a CCR comprising a CD8α hinge domain without the substitution.
the amount of direction provided by the inventor; the existence of working examples:
However, the specification does not disclose a reduction to practice of a method of reducing CCR antigen-mediated stimulation of T cell signaling in the absence of CAR antigen, compared to a CCR comprising a CD8α hinge domain without the cysteine substitution at position 44. Note that claim 152 further limits claim 149 to a CAR hinge domain that has been modified at cysteine residues with any other choice of the 20 naturally occurring amino acids. The specification describes a method that uses a CAR and CCR wherein the CAR is an anti-BCMA and the CCR is an anti-EGFR, thus binding to two different antigens, and wherein the CAR and CCR CD8α hinges have serines in place of cysteines corresponding to positions 27, 44, and 27 and 44 of SEQ ID NO: 2 and were transduced into T-cells (Specification: Example 4 and 5 page 114 and 115). Specification does not exemplify that any CAR and any CCR binding domain, other than BCMA for CAR and EGFR for CCRwould result in eliminating the undesirable effect of CCR antigen-dependent, CAR antigen-independent signaling in T-cells. Moreover, the structure of the CCR comprises a CD8α transmembrane domain and a CD28 cytoplasmic domain.
The specification discloses 6 constructs (C1-C6), as shown in example 3 and Figure 4A wherein C1 is the parental CAR + CCR construct that utilizes cysteines in all four positions. C2 contains two serines in the CAR and two cysteines in the CCR. C3 contains two cysteines in the CAR and two serines in the CCR. C4 contains a serine at position 27 of SEQ ID NO: 2 and a cysteine at position 44 of SEQ ID NO: 2 of the CAR; and a cysteine at position 27 of SEQ ID NO: 2 and a serine at position 44 of SEQ ID NO: 2 of the CCR. C5 contains a cysteine at position 27 of SEQ ID NO: 2 and a serine at position 44 of SEQ ID NO: 2 of the CAR and serine at position 27 of SEQ ID NO: 2 and a cysteine at position 44 of SEQ ID NO: 2 of the CCR. C6 utilizes serines in all four positions. Figure 4A-C show that the C2-6 mitigate/eliminate cytokine release when engineered T cells are exposed to EGF-presenting cells only, thus showing that cysteine substitutions in the hinge of the CCR, CAR, and both CAR and CCR at either position 27, 44, and at both 27 and 44, can elicit the claimed function of eliminating the undesirable effect of CCR antigen-dependent, CAR antigen-independent signaling in T-cells.
Outside of this scope of enablement, there is no minimal or maximal physiological or phenotypic result which would necessarily tell a skilled artisan the method would give the desired result of reducing CCR-antigen-mediated stimulation of T cell signaling in the absence of CAR antigen when any CCR having any structure, other than a CD8α hinge, a CD8α transmembrane domain, and a CD28 cytoplasmic domain for signaling.is used.
the state of the prior art; the level of predictability in the art:
Sadalain et al (Cancer Discovery 2013; page 388-398, as cited in the IDS) teaches that CCRs mimic costimulatory signals, but unlike CARs, do not provide A T-cell activation signal. Their purpose is to provide costimulation in the absence of the natural costimulatory ligand on the antigen-presenting cell and they are used in conjunction with a TCR or a CAR to augment T cell reactivity (page 6, para 2). Sadalain do not teach that modifying the cysteines of the hinge domain of CCRs would permit reduced antigen-mediated stimulation of T cell signaling, let alone reduced association with a CAR via a hinge. Similarly, Kloss et al (Nat Biotechnol. 2013; page 71-76, as cited in the IDS) teaches transducing T cells with both a CAR and a CCR where each one recognizes separate antigens and using the prostate tumor antigens PSMA and PSCA, co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone (abstract, page 1). Kloss teaches that dual chimeric receptor-mediated activation and costimulation of human T cells facilitates robust cytotoxicity, proliferation and tumor eradication; (page 70, legend Figure 1).Kloss also teaches methods of reducing T cell activation by changing CARs from CD19 and PSMA to PSCA and PSMA (page 72 (col 2 para 2) – page 73 (col 1 para 1) and demonstrates that three different scFvs specific for PSCA (Hzl, Mzl , Lzl) when express in T cells as CARs by linking them to CD31; cytoplasmic domains exhibit different activities in cytotoxicity assays (page 73; col. 1) supporting a model of combinatorial PSCA/PSMA targeting in prostate cancer reducing reactivity against healthy tissues expressing either antigen alone (page 74; col.2). . The author does not teach reducing the T cell activation by substituting amino residues in the hinges of the CAR and/or CCR. Bernard teaches that “Seemingly minor structural changes to a CAR can impart strong functional characteristics. To design an efficient receptor, a deep understanding of the individual CAR modular elements, the characteristics of the antigen of interest, and the intersection of these properties is required. Decisions about which structural components to select can have profound consequences regarding the susceptibility to tonic signaling, interaction with or exclusion of endogenous molecules from the signalosome, and can tune the signal strength and threshold of required antigen density for activity.” (page 6, right col, Discussion). Bernard teaches “The properties of the hinge, including its identity and length, shape how the CAR responds to antigen density and epitope position, ultimately affecting sensitivity and signaling strength.” (page 3, right col, 3.2 Hinge Domain). Hence, differences in CAR binding domain, for example, can impart drastic alterations in downstream signaling and ultimately function of the CAR. Finally, Ying et al (Nature Medicine 2019), teaches generating a safe CAR-T cell therapy where genetically altering sequences encoding the extracellular and intracellular domains of the CD8alpha molecule leads to reduced ability to produce cytokines (i.e. decreased T cell activation) (page 1, col 1 and 2, para 1). They found that changing the length of the amino acid sequence of the CD8alpha domain such that the intracellular and extracellular domains were longer than original polypeptide sequences resulted in reduced cytokine production (page 1, col 2, para 1). Indeed, there is no teaching of modification of the CD8alpha hinge domain such that cysteines can be substituted and length can be maintained and result in reduced stimulation of T-cell signaling. Schonfeld (US 9212229 B2) teaches cysteine modifications/or increasing surface expression of CARs, which is completely different than for the claimed purpose of reducing disulfide binding between the CAR and CCR hinge regions in order to reduce CCR antigen mediated stimulation of T cell signaling. However, Schonfeld do not teach “that certain CC Rs are able to interact with the corresponding CAR via disulfide bonding of cysteine residues between the CAR and CCR hinge regions, which induces CAR-mediated T cell signaling in the absence CAR antigen” (page 18 of Applicants’ remarks filed 04/16/2026)
the quantity of experimentation needed to make or use the invention based on the content of the disclosure: The skilled artisan would be required to perform under levels of experimentation in order to practice the claimed invention. The instant specification does not reduce to practice the claimed invention; the instant specification does not provide guidance on how to reasonably predict the genus of CCRs polypeptides (i.e. determine the structure which may comprise the ligand binding domain, transmembrane domain, cytoplasmic signaling domain, and hinge), other than anti-EGFR and anti-BCMA, respectively would permit the desired result of reducing antigen-mediated stimulation of T cell signaling. Thus, the skilled artisan would be forced to 1) which CCR and CAR antigen binding domain to use (i.e. the same or different antigens) 2) the structure of the CCR, and 3) generate the cell harboring a CAR and modified CCR and determine if the modification was sufficient to reduce CCR antigen-mediated stimulation of T cell signaling by running various experiments to demonstrate reduced cytokine levels.
the level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion
When all of the Wands factors are considered together, they establish a prima facie case that the specification is not enabling for the claims. The specification is only enabling for a method of reducing CCR antigen-mediated stimulation of T cell signaling in the absence of a CAR antigen, compared to a CCR comprising a hinge domain without substitutions, the method comprising: obtaining anti-BCMA CAR and anti-EGFR CCR polypeptides each having a CD8a hinge domain; wherein the CAR contains a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2, and the CCR contains a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2, a CD8α transmembrane domain, and a CD28 cytoplasmic domain, and expressing the CAR and modified CCR in a T cell;
While a lack of a working embodiment cannot be a sole factor in determining enablement, the lack of any working examples, in light of the unpredictable nature of the art and the lack of direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have had a reasonable expectation of success in making or using the claimed invention.
Response to Applicant’s arguments as they apply to rejection of claims 149-153, 156-160 and 163-165, 167-169 under 35 USC § 112(a)
Applicant's amendments to the claims and arguments filed 04/16/2026 have
been fully considered but have not been found persuasive in overcoming the rejection
for reasons of record as discussed in detail below.
On page 11-15 of applicant’s remarks filed 04/16/2026, applicant argues that 1) one of ordinary skill in the art would understand that by substituting cysteine with another amino acid, disulfide bonding is reduced between the CAR and CCR hinge regions and that SEQ ID NO: 2 only comprises two cysteine residues at position 27 and 44, hence the scope of the claims is not too broad and 2) the binding domain of the CAR and the CCR are irrelevant to the claimed invention as the binding target is irrelevant with respect to disulfide binding.
Regarding arguments 1, while applicant asserts that it is well known in the art that disulfide bonds form between cysteines residues and that the mutation of a cysteine residue to any other amino acid besides cysteine would also achieve the same result of reducing disulfide binding, the examiner notes that the claims, as written, recite “for another residue” which could also include artificial amino acid residues which could exhibit disulfide binding. Therefore, examiner suggests applicant amend claims to recite “substituting the cysteine residue...for another amino acid that is not capable of disulfide binding”.
Regarding arguments 2, applicant is directed to the teachings of Bernard included in the 112(a) rejection above which teach that minor structural changes to a CAR (and a CCR since they have similar structure) can impart strong functional characteristics. Bernard teaches “To design an efficient receptor, a deep understanding of the individual CAR modular elements, the characteristics of the antigen of interest, and the intersection of these properties is required. Decisions about which structural components to select can have profound consequences regarding the susceptibility to tonic signaling, interaction with or exclusion of endogenous molecules from the signalosome, and can tune the signal strength and threshold of required antigen density for activity.” (page 6, right col, Discussion). Bernard teaches “The properties of the hinge, including its identity and length, shape how the CAR responds to antigen density and epitope position, ultimately affecting sensitivity and signaling strength.” (page 3, right col, 3.2 Hinge Domain). Hence, Bernard teaches thatmodification to the structure of a CAR, and therefore a CCR as they are similarly structured, , can impart drastic alterations in downstream signaling and ultimately function of the CAR and CCR. Furthermore, it is unclear by the claims if the CAR and CCR can bind to the same antigen. The applicant asserted on page 18 in the Remarks filed 04/16/2026, that the working examples of the specification demonstrated “for the first time, that certain CCRs are able to interact with the corresponding CAR via disulfide bonding of the cysteine residues between the CAR and CCR hinge regions, further indicating that the specification is only enabling fora specific structure to the CCR (i.e contains a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2, a CD8α transmembrane domain, and a CD28 cytoplasmic domain).
Therefore, applicant’s argument that changes in the binding domain (i.e. a BCMA CAR and EGFR CCR) are persuasive only to the extent that the binding domains at least have to be different between the CCR and the CAR and the structure of the CCR must be defined as the only structure enabled for the CCR is that disclosed in the specification. Therefore, theExaminer has modified the scope of enablement to be for a CAR and CCR with different binding domains and the CCR has a specific structure (i.e contains a CD8a hinge domain comprising a cysteine for a serine substitution at position 27, position 44, and position 27 and 44 of SEQ ID NO: 2, a CD8α transmembrane domain, and a CD28 cytoplasmic domain).
Conclusion
Claims 149-153, 156-160, 163-165, 167-169 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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