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.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/01/2025 has been entered.
This action is in response to the papers filed December 01, 2025.
Claims 1-5 and 10-25 are currently pending in the application. Claims 11-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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. Claim 2 is amended, claim 8 is canceled and no claims are newly added as set forth in the claim set filed 12/01/2025.
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
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
The rejection of claims 2-5 and 8 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Applicant’s arguments and amendments filed 12/01/2024 have been considered and are persuasive, particularly, the amendments made to claim 2 in order to eliminate the duplicate terms.
Claim Rejections - 35 USC § 103
A response to Applicant’s arguments with regard to a withdrawn rejection is moot. A response to any argument pertaining to a new or maintained rejection can be found below.
The rejection of claims 1 and 23 under 35 U.S.C. 103 as being unpatentable over Mueller (WO2017210617; previously cited) in view of and Li (J Thoric Oncol. 2011;6: 1801–1809) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2024 have been considered and are persuasive. Applicant in particular argues the lack of motivation to substitute a bivalent for a monovalent SMAC mimetic due to superior results. Examiner has set forth a new rejection below addressing this issue as necessitated by the new grounds of rejection through the filing of an RCE.
The rejection of claims 1 and 25 under 35 U.S.C. 103 as being unpatentable over Mueller (WO2017210617; previously cited) in view of and Hennessy (J. Med. Chem. 2013, 56, 9897−9919) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2024 have been considered and are persuasive. Applicant in particular argues the lack of motivation to substitute a bivalent for a monovalent SMAC mimetic. Examiner has set forth a new rejection below addressing this issue as necessitated by the new grounds of rejection through the filing of an RCE.
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).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 12/01/2025.
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).
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.
Response to Applicants’ Arguments as they apply to rejection of claims 1-5, 10, and 24 under under 35 U.S.C. 103 over Mueller and Bai
Applicant’s arguments and amendments filed 12/01/2025 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.
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.
Furthermore, the applicants are reminded that the motivation for combining the teachings of the prior art may be different from applicants’ motivation to make the disclosed compositions. The fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The office has provided motivation to utilize bivalent SMAC mimetics instead of LCL161.
It is noted that Applicant refers to Fig 11B to support their statement of unexpected results across all bivalent compounds with the CAR T, however, only AZD5582 appear to work at all the claimed concentrations of 10nM to 1uM. The other bivalent SMC, BV6 and Birinapant only work at specific concentration to achieve the desired results.
New grounds of objections/ Rejections in response to Applicants’ arguments or amendments
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.
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.
Claim 23 is newly 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)
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).
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 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)
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.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634