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 .
1. Claims 4, 5, 7-10, and 12 have been cancelled. Claims 2 and 22 have been withdrawn. Claims 1, 3, 6, and 11 have been amended.
Claims 1, 3, 6, 11, 13-21, and 23-30 are under examination.
2. All rejections/objections pertaining to claims 7 and 8 are moot because the claims were cancelled with the reply filed on 09/04/2025.
The objections to claims 1, 3, 6 are withdrawn in response to the amendments filed on 09/04/2025.
The rejection of claim 11 under 35 U.S.C. 112(d) is withdrawn in response to the amendment to replace the recitation “checkpoint inhibitor” with “the single domain PDL-1 antibody”.
All obviousness-type rejections set forth in the non-final Office action mailed on 02/04/2025 are withdrawn in response to the amendment to claim 1 introducing the requirement the immune checkpoint inhibitor be encoded by an exogenous mRNA molecule encoding.
New grounds of rejection are set forth below.
New Rejections
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 1, 3, 6, 13-18, 21, and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Klemke et al. (WO 19/032628), in view of both Broos et al. (Cancers, 2019, 11: 1-19) and Golinelli et al. (Cancer Gene Therapy, online 22 November 2018, 27: 558-570).
Klemke et al. teach genetically-engineering MSCs stably expressing homing ligands for targeting to desired sites, where the homing ligand is an anti-PD-L1 antibody; the genetically-engineering MSCs are used to obtain and isolate cytoplasts (enucleated MSCs retaining functional intracellular organelles and stably expressing the homing receptors); the MSC cytoplasts are suitable for treating cancer (such as NSCLC), can be transfected with mRNAs, can be further formulated with a pharmaceutically acceptable carrier, and can be cryopreserved (claims 1, 3, 6, 13, 15-18, 21, 23-25, and 28-30) (see Abstract; p. 2; p. 6, line 31 through p. 7, line 3; p. 29, lines 7-8; p. 32, lines 20-26; p. 33, lines 18-22; p. 34, lines 10-14; p. 38, lines 11-25; p. 40, line 40 through p. 41, line 11; paragraph bridging p. 69 and 70; p. 70, line 11 through p. 71, line 12; p. 75-76; p. 77, first paragraph; Example 6; Fig. 1).
With respect to claim 14, Klemke et al. teaches that the MSC cytoplasts express CD90, CD146, and CD166 (see p. 12, lines 20-25; p. 70, last paragraph; Fig. 4). With respect to claim 26, Klemke et al. teach that the cytoplasts include CD47 on their surface for immune evasion (see p. 20, lines 7-9; p. 52, lines 13-18). With respect to claim 27, Klemke et al. teach that the cytoplasts have an average diameter of 12 µm (see p. 72, lines 18-19; Fig. 15B).
Klemke et al. do not specifically teach that the anti-PD-L1 antibody is a single-domain antibody (sdAb) (claims 1 and 3). Broos et al. teach sdAb K2 (PD-L1 sdAb) having high affinity for PD-L1, where sdAb K2 blocks the binding between PD-L1 and PD-1 and wherein sdAb K2 can target the PD-L1-expressing cancers such as NSCLC and breast cancer (claim 6) (see Abstract; p. 2; p. 7, last paragraph; p. 12, last paragraph). Modifying Klemke et al. by using sdAb K2 as the homing antibody would have been obvious to one of skill in the art to achieve the predictable result of obtaining therapeutic cytoplasts suitable to treat cancer.
Klemke et al. and Broos et al. do not specifically teach a conjugate between sdAb K2 and a transmembrane domain nor do they specifically teach delivering the conjugate via an mRNA (claim 1). However, one of skill in the art would have readily recognized that, in order to function as a homing ligand, sdAb K2 must be exposed on the cytoplast surface. Golinelli et al. teach that truncated CARs (lacking the intracellular signaling domain; tCAR) could be used to tether homing antibodies on the surface (see Abstract; p. 560, paragraph bridging columns 1 and 2, and Fig. 1a). Since Klemke et al. teach that the cytoplasts can be transfected with mRNAs, one of skill in the art would have found obvious to transfect the cytoplasts with an mRNA encoding tCAR comprising sdAb K2 as the extracellular domain, to achieve the predictable result of obtaining therapeutic cytoplasts suitable for treating cancer such as breast cancer and NSCLC.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
5. Claims 1, 3, 6, 11, 13-18, 21, and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Klemke et al. taken with both Broos et al. and Golinelli et al., in further view of Aubrey et al. (Bioconjugate Chem., 2018, 29: 3516-3521).
The teachings of Klemke et al., Broos et al., and Golinelli et al. are applied as above for claims 1, 3, 6, 13-18, 21, and 23-30. Klemke et al., Broos et al., and Golinelli et al. do not teach that sdAb K2 comprises a cytotoxic drug (claim 11). Aubrey et al. teach conjugating auristatin to an scFv for targeting chemotherapeutic drugs to breast cancer cells (see Abstract). Based on these teachings, one of skill in the art would have known that homing receptors could be used to deliver chemotherapeutic drugs to cancer cells of interest. One of skill in the art would have found obvious to further couple a chemotherapeutic drug to sdAb K2 to achieve the predictable result of obtaining a composition exhibiting potent therapeutic effect.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
6. Claims 1, 3, 6, 13-21, and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Klemke et al. taken with both Broos et al. and Golinelli et al., in further view of Skeate et al. (Frontiers in Immunology, 2020, 11: 1-11).
The teachings of Klemke et al., Broos et al., and Golinelli et al. are applied as above for claims 1, 3, 6, 13-18, 21, and 23-30. Klemke et al., Broos et al., and Golinelli et al. do not teach TNFSF14 (LIGHT) (claims 19 and 20). Skeate et al. teach that TNFSF14 acts in synergy with checkpoint inhibitors to greatly improve anti-cancer therapy (see Abstract; p. 7, column 2, first full paragraph). One of skill in the art would have found obvious to modify Klemke et al., Broos et al., and Golinelli et al. by further including TNFSF14 with the reasonable expectation that doing so would result in a composition exhibiting synergistic therapeutic effect.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
7. The arguments are answered below to the extent that they pertain to the new rejections.
The argument that Boos does not teach or suggest combining Golinelli’s tCAR with Klemke’s cytoplasts is not found persuasive because it addresses the reference individually. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, the combined teachings of Klemke and Golinelli suggest using the tCAR to tether sdAb K2 to the cytoplast surface.
For the same reasons, the argument that Aubrey and Skeate fail to provide a motivation to combine tCAR with cytoplasts is not found persuasive.
The applicant argues that one of skill in the art would not have been motivated to use Golinelli’s tCAR-encoding lentiviral vector with cytoplasts because cytoplasts are enucleated, and thus, the tCAR would be nonfunctional.
This is not found persuasive. The rejection is based on using an mRNA to introduce the tCAR into cytoplasts. mRNAs are translated in the cytoplasm, not nuclei. Klemke teaches that cytoplasts retain all cellular organelles, can be successfully transfected with mRNAs and, upon transfection, successfully express the encoded polypeptide.
For these reasons, the argument of lack of reasonable expectation of success is not found persuasive.
Conclusion
8. 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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/ILEANA POPA/Primary Examiner, Art Unit 1633