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 .
Claims Status
Claims 1, 3, 160, and 162 are amended. Claims 7, 54-55, 59, 61 are cancelled. Claims 163-164 are newly added. Claims 1, 3, 113, 118-119, 121, 127, 129-130, 141, and 158-164 are pending and are examined on the merits.
OBJECTIONS WITHDRAWN
All objections to the claims with regard to missing sequence identifiers are withdrawn in view of Applicant’s amendments.
REJECTIONS WITHDRAWN
Claim 7 is cancelled, rendering all previous rejections moot.
REJECTIONS MAINTAINED/NEW REJECTIONS
Claim Rejections - 35 USC § 103
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.
Claims 1, 3, 113, 118-119, 121, 127, 129-130, 141, and 158-162 remain rejected and Claims 163-164 are newly rejected under 35 U.S.C. 103 as being unpatentable over Zah et al. 2016 (Cancer immunology research, 4(6), 498-508.; of record), and in view of Chen et al. 2018 (Leukemia, 32(2), 402-412.; IDS), Ma et al. 2018 (US 2018/0162939 A1; of record), Gogishvili et al. 2017 (Blood, 130(26), 2838-2847.; IDS), and Ali et al. 2016 (Blood, 128(13), 1688-1700.; IDS).
Zah teaches a bispecific tandem CAR (TanCAR) comprising two extracellular scFvs targeting two different antigens linked by a (G4S)4 linker, a short extracellular spacer comprising the IgG4 hinge, a CD28 transmembrane domain, a 4-1BB costimulatory domain, and a CD3ζ signaling domain (Fig. 3).
Zah teaches that tandem CARs are an alternative to expressing two different CARs in one T Cell, and that the Tandem CAR approach has several advantages including a significantly smaller DNA footprint – which is advantageous for viral vector packaging and transduction efficiency relative to the dual CAR format (Pg. 506, ¶1).
Zah teaches that the scFvs are constructed in opposite orientations (scFv #1 (VL-VH) – scFv #2 (VH-VL)) to minimize potential mispairing of VL and VH domains between the two scFvs.
Zah teaches that antigen-specific structural requirements are shared between single-input CARs and bispecific CARs. For example, Zah teaches that single input anti-CD20 CARs function better with a long extracellular spacer (IgG4 Hinge-CH2-CH3) (Pg. 500, ¶1), whereas CD19 CARs function better with a short extracellular spacer (Pg. 499, last ¶). Accordingly, Zah teaches a TanCAR wherein the scFv requiring a short spacer (CD19) is linked to the CAR by a IgG4 hinge-only spacer in the membrane-proximal position, and the scFv requiring a long spacer (CD20) is at the distal position (Fig. 3).
Zah teaches that using a (G4S)4 between the two antigen binding domains of the TanCAR compensated for sub-optimal targeting of the distal scFv caused by the required short extracellular spacer (Pg. 502, ¶1).
Zah teaches that all of the components used to assemble the TanCARs taught therein, including the glycine-serine linkers, extracellular spacers, transmembrane domain, and cytoplasmic signaling domains, have previously been tested in the clinic and therefore the probability of problematic immunogenicity is low (Pg. 506, Col. 2, ¶2).
Zah does not teach a TanCAR wherein the two scFvs target BCMA and CS1 and wherein the anti-BCMA scFv is derived from C11D5.3 (corresponding to a VH/VL of SEQ ID NOs: 17 and 21, respectively) and the anti-CS1 scFv is derived from huLuc63 (corresponding to a VH/VL of SEQ ID NOs: 51 and 55, respectively). These deficiencies are cured by Chen, Ma, Gogishvili, and Ali.
Chen teaches the early successes of BCMA-targeted CAR therapies for patients with multiple myeloma, but notes ongoing issues with antigen escape and relapse (Introduction).
Chen proposes solving this problem by augmenting BCMA-CAR T therapy with an anti-CS1-targeted CAR due to the high expression of CS1 on multiple myeloma cells and promising clinical activity of the anti-CS1 monoclonal antibody elotuzumab (i.e. huLuc63) (Introduction).
Chen teaches a compound CAR T cells comprising a construct expressing both an anti-CS1 CAR and an anti-BCMA CAR (Fig. 1).
Chen teaches that compound CAR T cells comprising a combination of anti-CS1 CAR and anti-BCMA CAR outperforms single-antigen anti-BCMA CAR in a preclinical mouse model of multiple myeloma (Fig. 7).
Ma 2018 is a patent application disclosing, in part, the same anti-CS1/anti-BCMA compound CAR taught by the above Chen 2018 reference and provides further structural details about the construct.
Regarding instant Claims 1, 158-159, and 161-162, Ma teaches a CS1/BCMA compound CAR comprising scFvs derived from huLuc63 and C11D5.3 (¶1070).
[Note: SEQ ID NO: 56 (VH/VL of SEQ ID NOs: 51/55) and SEQ ID NO: 22 (VH/VL of SEQ ID NOs: 17/21) of the instant Claims correspond to scFvs derived from huLuc63 and C11D5.3, respectively, as evidenced by the instant specification (¶31; ¶23).]
Ma further notes that protein expression from a lentiviral vector drops significantly with each 1 kb of additional length, resulting in lower transduction efficiencies with compound CARs relative to single CARs (¶1063).
Gogishvili teaches anti-CS1 (also known as SLAMF7) CAR T cells comprising an scFv derived from huLuc63/elotuzumab (Abstract).
Gogishvili teaches the CAR further comprises an extracellular spacer consisting of the Fc Hinge-CH2-CH3 domains of IgG4 (Pg. 2839, § Materials and Methods, ¶1), which corresponds to the “long” extracellular spacer taught by Zah.
Gogishvili teaches that the anti-CS1 CAR T cells exhibit strong anti-myeloma activity in a preclinical mouse model (Fig. 3).
Ali teaches an anti-BCMA CAR comprising an scFv derived from the C11D5.3 binding domain and a CD8α hinge (Fig. 1).
Ali teaches teaches the C11D5.3 anti-BCMA CAR exhibited strong anti-myeloma activity in humans (Fig. 1E).
It would have been obvious to one of ordinary skill in the art to substitute the first and second scFv of the TanCAR taught by Zah (Fig. 3) with the scFvs comprising the VH and VL of anti-CS1 binder “huLuc63”, as taught by Ma and Gogishvili, and anti-BCMA binder “C11D5.3”, as taught by Ma and Ali, respectively, in order to construct a dual-target anti-CS1/anti-BCMA TanCAR for use in treating multiple myeloma, wherein the CAR comprises, from N to C terminus, 1) huLuc63 anti-CS1 scFv, 2) (G4S)4 linker, 3) C11D5.3 anti-BCMA scFv, 4) IgG4 hinge domain (“short” extracellular spacer; i.e. SEQ ID NO: 73), 5) a CD28 transmembrane domain (i.e. SEQ ID NO 46) 6) a 4-1BB costimulatory domain (i.e. SEQ ID NO: 77), and a CD3ζ signaling domain (i.e. SEQ ID NO: 78).
The skilled artisan would have been motivated to adapt the compound CAR format taught by Chen/Ma into the TanCAR format taught by Zah because Ma acknowledges challenges with transduction efficiency of the large dual CAR constructs and Zah teaches that the TanCAR format has a smaller DNA footprint and improved transduction efficiency.
The skilled artisan would have been motivated to choose CS1 and BCMA as the two target antigens because Chen teaches that BCMA-targeted CARs have previously demonstrated success in the clinic and that the addition of CS1 targeting could mitigate the risk of antigen escape.
The skilled artisan would have further been motivated to choose this particular pair of binders because Ma explicitly teaches this same pair of scFvs (i.e. C11D5.3 and huLuc63) as a suitable option for an anti-BCMA/anti-CS1 dual CAR T cell (¶1070). In addition, motivation to choose scFvs comprising the VH/VL domains of C11D5.3 and huLuc63 as the particular binders in construction of a BCMA/CS-1 TanCAR is further provided by Zah 2016, which highlights the benefits of using components previously tested in the clinic in order to avoid unexpected immunogenicity (Pg. 506, Col. 2, ¶2). In line with this suggestion, the clinical trials of CARs comprising anti-BCMA binding domain of “C11D5.3” demonstrated strong efficacy against multiple myeloma, as taught by Ali, while the anti-CS1 binding domain “huLuc63” shares its VH/VL sequence with the monoclonal antibody elotuzumab, which was FDA-approved for use in treating multiple myeloma and has since been employed in investigational CAR T constructs, as taught by Gogishvili.
The skilled artisan would have been motivated to choose the particular order of antigens binding domains – wherein the anti-BCMA binder is more membrane proximal – because Zah teaches that antigen-specific structural requirements are shared between single-input CARs and bispecific CARs. To match the relative positions of the two binding domains in the TanCAR with their positions in each of the single-input CARs taught by the prior art – employing the same logic taught by Zah – it would have been obvious to one of ordinary skill in the art that the huLuc63 binding domain should occupy the membrane-distal position in the TanCAR because Gogishvili teaches a single-input huLuc63 CAR comprising a “long” IgG4 spacer (Hinge-CH2-CH3) – while the CD11D5.3 binder should occupy the membrane proximal position because Ali teaches an effective anti-BCMA CAR comprising a shorter CD8 hinge.
The skilled artisan would have been motivated to link these two binding domains by a (G4S)4 linker because Zah teaches such a linker compensates for suboptimal positioning of the two binding domains relative to a shorter linker. Moreover, the inverse arrangement of variable domains within the sequential scFvs (huLuc63 (VL-VH) – linker – C11D5.3 (VH-VL)) as exemplified in Claim 162 (SEQ ID NOs 56 and 22) would have been obvious because Zah teaches that arranging the scFvs in such a way minimize potential mispairing of VH/VL domains.
There would have been a reasonable expectation of success because 1) Chen teaches compound CAR T cells comprising both anti-CS1 and anti-BCMA CARs outperform single-input anti-BCMA CARs in a preclinical mouse model, 2) Ma teaches the specific pair of scFvs derived from huLuc63 and C11D5.3 in a compound CAR format, 3) Zah teaches that a tandem CAR format has a significantly smaller DNA footprint and increased transduction efficiency relative to a dual CAR format 4) Gogishvili teaches a potent anti-CS1 CAR a huLuc63-derived scFv and a long extracellular spacer, 5) Ali teaches an anti-BCMA CAR comprising a C11D5.3-derived scFv with “impressive activity against MM”, and 6) Zah teaches both the benefits of incorporating CAR components previously tested in the clinic and that the structural requirements of a single-input CAR and TanCAR are shared.
Response to Arguments
Applicant's arguments filed 08/22/2025 have been fully considered but they are not persuasive.
Applicant has amended the claims to require “an extracellular spacer comprising less than 20 amino acids”, and newly added Claims 163-164 both specify a 4-1BB costimulatory domain. However, the art as applied in the previous 103 rejection (and reproduced above) already encompassed these limitations (the IgG4 hinge domain according to the primary reference Zah is identical to the 12aa hinge of SEQ ID NO: 73). In addition, the instant application does not demonstrate the criticality of a short extracellular spacer “less than 20 amino acids”. As acknowledged in the specification, “All OR-gate CARs...contained a short (12-amino acid) extracellular spacer” (Pg. 131, ¶313), and no comparison is made to a bispecific CAR comprising the CD8α hinge or indeed any other hinge of any other length.
Instead, Applicant’s arguments to support the non-obviousness of an extracellular spacer “less than 20 amino acids” relies on the notion that the primary reference “Zah” (Cancer immunology research, 4(6), 498-508.) teaches away from combining the bispecific tandem CAR taught therein with the CS1 and BCMA binding domains of the prior art because the “short” IgG4 spacer of Zah differs from the CD8α spacer of, for example, the BCMA CAR taught by Ma (US 2018/0162939 A1).
In response, it is first noted that, as previously pointed out (see Response to Arguments in the Non-Final dated 05/22/2025; pg. 15, ¶3), only Claim 162 specifies the relative position of the anti-CS1 and anti-BCMA binders in addition to requiring all of the structure present in the CAR of the disclosed examples. Therefore, any arguments regarding unexpected results are relevant only to Claim 162.
Next, in response to Applicant’s assertion that the CD8α hinge region is 67 amino acids in length, Examiner points out that this is incorrect. The translated nucleotide sequence from Applicant’s Exhibit A is indeed 67 amino acids in length:
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC
Hinge Transmembrane Cytoplasmic
However, this sequence comprises not only the CD8α hinge region, but also the transmembrane domain and a portion of the intracellular domain (annotated above and as evidenced by the UniProt entry for human CD8α; https://www.uniprot.org/uniprotkb/P01732/entry; PTO-892; screenshot below).
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614
1296
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Greyscale
In reality, the CD8α hinge region described in Applicant’s Exhibit A is only 45 amino acids in length, and is the same as that used in the anti-BCMA CAR of Ma. Below is the partial sequence for the anti-BCMA CAR of Ma (SEQ ID NO: 178) annotated for the hinge and transmembrane domains:
...VSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT...
← BCMA scFv CD8α Hinge CD8α TM ICD →
Applicant further asserts that Gogishvili (Blood, 130(26), 2838-2847.) teaches a single-input CS1 CAR comprising a CD8α extracellular spacer (Remarks, Pg. 7, lines 5-6). This is also incorrect. As stated in the rejection of record, the anti-CS1 CAR of Gogishvili comprises extracellular spacer consisting of the Fc Hinge-CH2-CH3 domains of IgG4 (see Gogishvili Pg. 2839, § Materials and Methods, ¶1), – therefore providing an expectation of success when placing this CS1 binding domain in the membrane-distal position of the bispecific tandem CAR format taught by Zah.
Finally, the Zah reference does not “teach away” from the use of binding domains originally paired with a CD8α extracellular spacer, as asserted by Applicant. Instead, Zah focuses on comparing short, medium, and long spacers all derived from IgG4 – conceivably for convenience of the IgG4 domain architecture in producing spacers of three discrete lengths while maintaining some common sequences between each of the spacers tested. Nowhere in Zah is there a suggestion that a binding domain from a functional single-input CAR comprising a CD8α hinge could not be adapted for use in a tandem bispecific CAR comprising a short IgG4 spacer.
In fact, the reference cited by Zah that previously established a “CD19 CAR has superior activity when constructed with a short extracellular spacer” (Zah pg. 499, last ¶) categorizes the CD8α as a “short” spacer, and highlights that, similar to CD19 CAR comprising the “short” IgG4 spacer, a CD19 CAR comprising the CD8α hinge displayed potent anti-tumor activity. Below is a quote from said reference, emphasis added (Hudecek et al. 2015; Cancer immunology research, 3(2), 125-135.; Pg. 126, ¶1; PTO-892):
“...potent antitumor activity in patients with advanced chronic lymphocytic leukemia contained a short spacer sequence derived from CD8a that linked the scFv to the intracellular signaling domains (1, 18). By contrast, in another trial in which antitumor efficacy and CD19-CAR-T-cell survival were less impressive, the spacer domain was longer and derived from the IgG1 hinge and Fc...”
Consistent with this understanding, the instant specification categorizes a short spacer as “less than 50...amino acids” and a long spacer as “at least 50...amino acids” (Specification ¶0152). Indeed, the 45aa CD8α hinge is more similar in length to the short spacer of Zah (12aa) than the “medium” (119aa) or “long” spacers (229aa). Accordingly, the particular format taught by Zah comprising the short IgG4 hinge is the closest match to existing single-input anti-BCMA CAR architecture. As pointed out in the previous office action, substituting the VH and VL domains of the CD19/CD20 T results in a CAR comprising an identical structure to the species “huLuc63-c11D5.3 Short” of the instant disclosure (see Response to Arguments in the Non-Final dated 05/22/2025, last ¶), which meets all of the limitations of the claims – including an extracellular spacer comprising less than 20 amino acids.
Because the CD8α hinge was generally considered by the prior art (and the instant application) to be “short” in length – and because Zah provides no compelling reason to further modify or substitute the hinge region of the disclosed bispecific CAR format – the most straightforward and obvious construction of a bispecific tandem CAR comprising anti-CS1 and anti-BCMA binding domains would be simple substitution of the VH and VL domains as described above. Accordingly, the instant invention as claimed remains obvious over the prior art of record.
Conclusion
No claim is allowed.
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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/BRYAN WILLIAM HECK/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643
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