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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed May 08, 2026.
Claims 1-5, 10-19, and 22-26 are currently pending in the application. Claims 11-19, 22 and newly 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/13/2023. Claims 1 and 23-25 are amended, claims 20 and 21 are canceled, and claim 26 is newly added as set forth in the claim set filed 05/08/2026.
Therefore, claims 1-5, 10 and 23-25 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2019/019158, filed February 22, 2019.
Applicant’s claim for the benefit of a prior-filed parent provisional applications 62/635,377 filed 02/26/2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is February 26, 2018.
Response to arguments
Maintained Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 1-5, 10, and 24 remain rejected under 35 U.S.C. 103 as being unpatentable over Mueller (WO2017210617; previously cited) in view of Bai (Pharmacol Ther. 2014 May 16;144(1):82–95) and Krepler (Clin Cancer Res; 19(7); 1784–94)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 05/08/2026.
Regarding claim 1 and 24, Mueller teaches a plurality of T cells modified to express a CAR comprising an anti-CD19 antigen binding domain (p. 2, lines 28-32; p. 3, line 5). Mueller further teaches that the composition comprising the modified T cells is administered with an additional agent such as an Inhibitor of Apoptosis Proteins (IAP) inhibitor or second mitochondria-derived activator of caspases (SMAC) mimetic such as LCL161 (p.341, lines 34-35; p. 342, lines 31-33). The examiner notes that SMAC is “a pro-apoptotic mitochondrial protein that is an endogenous inhibitor of a family of cellular proteins known as the Inhibitor of Apoptosis Proteins (IAPs).” (paragraph [0123] of the published application). Therefore, the composition would comprise both T cells engineered to express a CAR as well as a SMAC mimetic, (e.g., an inhibitor that suppresses IAPs thus freeing caspases to activate apoptosis (Mueller para [0108] of the published application).
However, Mueller does not explicitly disclose birinapant, BV-6 or AZD5582 as required in claim 1.
Bai teaches that SMAC mimetics such as birinapant are similar to other SMAC mimetics and been shown to induce cell death as a single agent in a small subset of human cancer and to achieve synergistic activity when combined with chemotherapeutic agents (p. 88, 1st column). Birinapant has an affinity for cIAP1 like the other SMAC mimetics (p. 88, 1st column). Furthermore, Bai teaches that bivalent SMAC mimetics, such as birinapant, Furthermore, bivalent SMAC mimetics that bind to XIAP containing both BIR2 and BIR3 domains with much higher affinities than monovalent SMAC mimetics (such as LCL161) are much more effective in antagonizing XIAP in cell-free functional assays to activate caspase-3/7
and also more than 100-times more potent than monovalent SMAC mimetics in induction of apoptosis in tumor cells (p. 88, 1st column).
It would have been obvious to one of ordinary skill in the art to substitute the SMAC mimetic LCL161 of Mueller with Birinapant of Bai with a reasonable expectation of success. Birinapant is a known alternate SMAC mimetic compound for the same purpose of binding to cIAP1 thus freeing caspases to activate apoptosis (Fig 4; p. 86, 2nd column, p. 88, 1st column). Moreover, Bai teaches that bivalent SMAC mimetics are more than 100-times more potent than monovalent SMAC mimetics in induction of apoptosis in tumor cells (p. 88, 1st column).
However, Mueller and Bai do not teach that birinapant is in the composition in an amount at least 50 nM.
Krepler teaches utilizing birinapant at amounts of 1 nM, 10 nM, 100 nM, and 1000nM with melanoma cell lines to determine IC50 values and the effect on cell viability (Figure 1).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize birinapant at an amount of at least 50 nM with a reasonable expectation of success. As demonstrated by Krepler is known to be effective in cell viability assays in the art when contacting the compound with cancer cells at the recited range.
Regarding claim 2, the combination of Mueller and Bai make obvious claim 1. Moreover, Mueller teaches that the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain wherein the antigen binding domain bind to an antigen (p. 44, lines 15-23; p. 45, lines 29-35; p. 233, lines 11-15; p. 235, lines 18-24)
Regarding claim 3 and 4, the combination of Mueller and Bai make obvious claim 1. Moreover, Mueller teaches the intercellular signaling domain comprises a costimulatory signaling region such as OX40, CD27, CD28, CDS, ICAM-1, LFA-1, ICOS and CD137 (p. 234, lines 7-9).
Regarding claim 5, the combination of Mueller and Bai make obvious claim 1. Moreover, Mueller teaches that the intracellular domain comprises a CD3 zeta chain (p. 234, lines 24-26).
Regarding claim 10, the combination of Mueller and Bai make obvious claim 1. Moreover, Mueller teaches that the composition further comprises a pharmaceutically acceptable carrier with the CAR expressing cell composition (p. 368, lines 28-31).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Mueller (supra) in view of Bai (supra) as applied to claim 1, and in further view of Li (J Thoric Oncol. 2011;6: 1801–1809)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 05/08/2026.
The combination of Mueller and Bai provide for a plurality of T cells modified to express a CAR comprising an anti-CD19 antigen binding domain which is administered with a bivalent SMAC mimetic such as birinapant as described above and incorporated herein in its entirely.
However, Mueller and Bai do not teach that the bivalent SMAC mimetic is BV-6.
Li teaches BV-6 is an antagonist of cIAP1 and XIAP (Introduction, p. 1801, 3rd paragraph). As further taught by Li, BV-6 is a SMAC mimetic and it along with other bivalent SMAC mimetics have shown to induce proteasomal degradation of cIAP1 and cIAP2 (p. 1802, 1st column). Overall, Li teaches that BV-6 is capable of sensitizing different cell lines to radiation (p. 1807, 4th paragraph; p. 1808, last paragraph). Moreover, Li teaches utilizing BV-6 at amounts of 1 micromolar and 5 micromolar (i.e. 1000 nM and 5000 nM; at least 10 nM) (p. 1802, 2nd column).
It would have been obvious to one of ordinary skill in the art to substitute the bivalent SMAC mimetic birinapant of Mueller and Bai with BV-6 at the claimed concentration as taught by Li with a reasonable expectation of success. BV-6 is a known alternate bivalent SMAC mimetic compound for the same purpose of binding to cIAP1 and XIAP to produce proteasomal degradation of cIAP1 and cIAP2 (e.g., an inhibitor that suppresses IAPs thus freeing caspases to activate apoptosis (Mueller para [0108] of the published application).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Mueller (supra) in view of Bai (supra) as applied to claim 1, and in further view of Hennessy (J. Med. Chem. 2013, 56, 9897−9919) and Moon (2015, Oncotarget, Vol. 6, No. 29).
The combination of Mueller and Bai provide for a plurality of T cells modified to express a CAR comprising an anti-CD19 antigen binding domain which is administered with a bivalent SMAC mimetic such as birinapant as described above and incorporated herein in its entirely.
However, Mueller and Bai do not teach that the bivalent SMAC mimetic is AZD5582.
Hennessy teaches ADZ5582 (also known as Compound 14 in the reference) as a potent SMAC mimetic which is based on the AVPI motif of SMAC (Abstract; p.9904, 2nd column; p. 9910, 1st paragraph). ADZ5582, a dimeric (bivalent) SMAC memetic, binds with high affinity to cIAP1, cIAP2 and additional binding to XIAP (Table 8, p. 9905, 2nd column).
It would have been obvious to one of ordinary skill in the art to substitute the bivalent SMAC mimetic birinapant of Mueller and Bai with ADZ5582 as taught by Hennessy with a reasonable expectation of success. As taught above, AZD5582 is a known alternate bivalent SMAC mimetic compound for the same purpose of binding to cIAP1, cIAP2 and XIAP in tumor cells.
However, Mueller, Bai and Hennessy do not teach the amount utilized in compositions.
Moon teaches treating cancer cells with a composition comprising 100 nM AZD5582 as well as contacting cells with between 39 nM to 10 micromolar of AZD5582 (Figure 1).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize the AZD5582 compound at an amount of at least 10 mM with a reasonable expectation of success. As demonstrated by Moon, AZD5582 is known to be effective in the art when contacting the compound with cancer cells at the recited range.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Applicants’ Arguments as they apply to rejection of claims 1-5, 10, and 24 under 35 U.S.C. 103
Applicant’s arguments and amendments filed 05/08/2026 have been considered but are not persuasive. Applicant argues unexpected results in that the combination of the compounds and the CAR T cells would be expected to be better than monomeric SMAC let alone LCL161 of Mueller. Moreover, Applicant argues that an artisan would not substitute a bivalent for a monovalent SMAC mimetic.
Examiner disagrees. As seen in the modified rejection above, Bai shows that it is expected the tumor cells are killed more potently by bivalent/dimeric SMAC mimetics. Therefore, the results described by Applicant are not unexpected and there would be motivation to utilize bivalent SMAC mimetics over monovalent SMAC mimetics due to their increased potency on cancer cells.
Applicant argues that none of the references demonstrate the enhanced CAR T 19 killing when combining the bivalent compounds with the CAR T cell therapy and do not suggest the claimed concentrations.
Examiner has modified the rejections above to address the newly claimed amount limitations for the SMAC mimetics. Additionally, it is stated that the unexpected results are not directed towards the compound, but the effects of a compound on tumor cell cultures. The tumor cells are not claimed and method claims are withdrawn. Therefore, the unexpected results, if present, would be directed towards withdrawn claims. The claims which are being examined are of a composition with two components at specific amounts, the combination of references above provide teaching, suggestion and motivation to combine the SMAC mimetic and CAR T therapy with a bivalent SMAC mimetic at the claimed amounts for in vitro culture with tumor cells.
New grounds of rejection
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.
Claims 1-5, 10 and 23-25 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 applicant regards as the invention.
This is a new rejection necessitated by amendment of the claims in the response filed 5/8/2026.
Claims 1, 23, 24 and 25 are indefinite for recitation of the phrase “at least” since it is unclear how the phrase “at least” is defined, what its metes and bounds are, or to what the term is directed towards in reference to the concentration of a component in the composition. The phrase “at least” fails to define an upper limit, and it is unclear what constitutes the maximum allowable concentration. As a result, the claims do not set forth the metes and bounds of the invention with reasonable clarity
The claims should be redrafted to specify the full range (i.e., both lower and upper limits) of the concentrations or, where appropriate, the absolute amounts of the components within the composition, to allow one of ordinary skill in the art to determine the scope of the claimed invention
Claims 2-5, 10 are indefinite insofar as they depend from claim 1.
Conclusion
No claims are 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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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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