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 81-100, of record 1/2/2026, are pending and subject to prosecution. Claims 81 and 100 are amended.
Status of Prior Rejections/Response to Arguments
RE: Objection to the specification:
The amendment to the specification is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 81, 83-89, and 91-100 under 35 U.S.C. 103 over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019):
The applicant asserts that:
A skilled artisan would not have been motivated to combine the teachings of Frost et al. and Ang et al. because the references focus on different methods and different cells (Applicant Remarks, page 9-11).
Ang et al. teach subcutaneous administration only generally, with no examples or emphasis, which would not have motivated one to modify the method of Frost et al. to comprise the route of delivery (Applicant Remarks, page 10).
Li et al. teach away from the use of T cell aggregates, that there would have been no reasonable expectation of success in combining the teachings of Frost et al. and Li et al., and that such a combination would have been motivated by hindsight (Applicant Remarks, page 11-13).
Unexpected results are demonstrated in the form of superior engraftment and tumor regression through subcutaneous T cell administration versus intravenous administration (Applicant Remarks, page 13-14).
The applicant’s arguments have been fully considered but are not found persuasive. Frost et al. teach transduction of T cells and/or NK cells (See Abstract), and Ang et al. teach methods of expanding immune cells, such as T or NK cells and those expressing CARs, using engineered universal APCs, as well as the use of the expanded cells (See Abstract and ¶0012 and 0018-0019). As both references pertain to the modification and use of T cells, thus representing analogous art, ample motivation exists for one of ordinary skill to combine their teachings. See MPEP 2141.01(a)(I).
That Ang et al. do not emphasize or exemplify subcutaneous delivery of T cells does not lessen any motivation for combining their teachings with those of Frost et al. A reference is prior art for all that it contains and would have reasonably suggested to one of ordinary skill in the art. See MPEP 2123(I).
Li et al. teach that excessively large T cell clusters may be associated with moderate differences in cell proliferation (which Li et al. admit may be due to reduced media changes) and increased checkpoint marker expression (See page 5, full ¶1 and fig. 1-2). Li et al. suggest that increased frequency of disaggregation, to yield smaller aggregates, may increase T cell potency (See page 5, full 2-3), which does not constitute teaching away from the culture of T cells as aggregates.
Regarding the assertion of unexpected results, for such an assertion to overcome a finding of obviousness, the scope of the claims and the experimental conditions used to achieve any unexpected results must be fully commensurate. See MPEP 716.02(d). The experimental results documented in fig. 23 are obtained with a cells modified by 4 h incubation with a single VSV-G-pseudotyped lentiviral construct (F1-3-748GU) displaying the T cell activation element UCHT1-scFvFc-GPI and encoding an anti-CD19 CAR and luciferase (See ¶1056-1057 of the instant application’s PG Pub). The scope of the instant claims are considerably greater than the single method used the achieve the alleged unexpected results. No additional evidence is provided to indicate that any variant would also yield similar results. Further, disclosure of a single, specific method is insufficient to provide a basis that would enable one of ordinary skill in the art to extrapolate such results to other species encompassed by the claims.
The rejection is maintained over claims 81, 83-89, and 91-99 in modified form to address amended limitations. The rejection of claim 100 is withdrawn in light of the amendment to require a depot formulation.
RE: Rejection of claims 81-89 and 91-100 under 35 U.S.C. 103 over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019), further in view of Ren et al. (Oncotarget, 2017):
The applicant asserts that because the teachings of Ren et al. are related to allogeneic CAR-T cell generation and the teachings of Frost et al. a concern autologous therapy, no motivation to combine exists (Applicant Remarks, page 14-15).
This argument is not found persuasive. Frost et al. teach that the cells may be autologous or allogeneic to the subject being treated (See ¶0134), therefore the teachings of Ren et al. could be readily applied to the method of Frost et al.
The rejection is maintained over claims 81-89 and 91-99. The rejection of claim 100 is withdrawn in light of the amendment to require a depot formulation.
RE: Rejection of claims 81 and 83-100 under 35 U.S.C. 103 over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019), further in view of Long et al. (Frontiers in Immunology, 2018):
The applicant asserts that Long et al. teach intratumoral administration of hyaluronidase, not subcutaneously, as required by claim 90 (Applicant Remarks, page 15-16).
This argument is not found persuasive. Long et al. teach that hyaluronidase enhances ECM breakdown for increasing susceptibility to drugs and cell-based therapies (See page 6, col. 2, ¶3). One of ordinary skill in the art would readily appreciate that, like tumors, skin also comprises ECM and that hyaluronidase could be applied to increase penetration and diffusion for subcutaneous administration.
The rejection is maintained over claims 81 and 83-99. The rejection of claim 100 is withdrawn in light of the amendment to require a depot formulation.
RE: Rejection of claims 81 and 93-94 on the ground of nonstatutory double patenting over claims 1, 12, 16-19, and 23-24 of U.S. Patent No. 11325948 in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019):
The arguments directed toward Ang et al. and Li et al. and the assertion of unexpected results are addressed above. Upon further consideration, however, the rejection is withdrawn.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 81, 83-89, and 91-99 remain rejected under 35 U.S.C. 103 as being unpatentable over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019).
Regarding claims 81, 86, 88-89, 92, and 94: Frost et al. teach methods for transducing lymphocytes and their use in adoptive cellular therapy (See Abstract). T cells in PBMCs can be transduced with retroviral or lentiviral particles expressing a polypeptide capable of binding to CD3 (See ¶0008 and 0012-0013). The viral particles can be replication-incompetent (See Abstract and ¶0003-0004 and 0097). The viral particles can encode a transgene such as a CAR, as well as a lymphoproliferative element (which reads on “a second transgene of interest”) (See ¶0306 and 0998). Frost et al. teach that blood can be collected from a subject (which reads on “from the subject”) and that the T cells can be genetically modified ex vivo by contacting with recombinant replication-incompetent retroviral particles and reintroduced to the subject within 12 h (See ¶0097). The retroviral particles can be separated from the T cells after contacting and prior to administration, but the method of Frost et al. does not strictly require it (See ¶0716). Frost et al. do not expressly teach subcutaneous administration of the modified cells or cell aggregates.
Ang et al. teach methods of expanding and using immune cells (See Abstract). The cells can be T cells and can express a CAR (See ¶0016 and 0021). The cells can be administered subcutaneously (See ¶00104).
Li et al. teach that T cells grow in clusters (which read on “cell aggregates”) following activation (See page 4, ¶2). The clusters can reach 2 mm in diameter or 250 µm in diameter (which read on “a diameter greater than 40 µm”) with daily disaggregation via pipette mixing (See page 4, ¶2). Micrographs depict the majority of cells as being part of the clusters (which reads on “at least 5% of the… T cells”) (See fig. 1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Frost et al. to comprise subcutaneous administration, such as is taught by Ang et al., of the modified cells. One would be motivated to make this modification because Ang et al. teach that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer (See ¶00107). There would be a reasonable expectation of success in doing so because the cells of Frost et al. could be readily administered subcutaneously.
It also would have been obvious to administer the at least some of the cells of Frost et al. as aggregates. One would have been motivated to make this modification because Li et al. teach that T cells naturally form clusters during activation and expansion (See page 4, ¶2). There would be a reasonable expectation of success in making this modification because activation of T cells via viral particles expressing a CD3 antibody would result in cell aggregation in vitro.
Regarding claims 83 and 85: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. teach an embodiment wherein mice are dosed with 1 × 107 transduced cells (which reads on “between 3 × 104 and 3 × 108 modified T cells”) in 200 µl DPBS (See ¶0193). Frost et al. do not expressly teach a volume between 0.5-20 ml, however, one of ordinary skill in the art would understand that cell number and/or solution volume would likely need to be increased for a larger subject, such as a human patient, and could readily be carried out through routine optimization. Frost et al. also do not expressly teach delivery within a device.
Ang et al. teach that the immune cells can be administered via reservoir-access device (which reads on “contained within a delivery device”) (See ¶00104).
It would have been obvious to one having ordinary skill in the art to further modify the method of Frost et al. to comprise administration of the cells in a delivery device, such as is taught by Ang et al. One would be motivated to make this modification because Ang et al. teach that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer (See ¶00107). There would be a reasonable expectation of success in doing so because the cells of Frost et al. could be readily administered in a reservoir-access device.
Regarding claims 84 and 95: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. teach that between 5% and 90% of the total lymphocytes collected from the blood are transduced (which reads on “at least 5% of the modified T cells in the cell formulation are genetically modified” and “between 1% and 20% of the modified T cells in the cell formulation are genetically modified”) (See ¶0146).
Regarding claim 87: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. do not expressly teach multiple administrations of the cells.
Ang et al. teach that modified immune cells can be administered in two or more doses (which reads on “administered multiple times”) (See ¶00103-00104).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the metho of Frost et al. to comprise administration of two or more doses of cells. One would be motivated to make this modification because Ang et al. teach that therapeutic dosing is preferably done in cycles (See ¶00104). There would be a reasonable expectation of success in doing so because the cells of Frost et al. could be readily administered in multiple doses.
Regarding claim 91: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. teach an embodiment wherein transduced PBMCs are washed and resuspended in DPBS and 2% HSA (which reads on “up to 5% HSA”) (See ¶1088).
Regarding claim 93: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. teach that the viral particles can comprise a GPI-anchored CD3-binding scFv or scFvFc (which read on “anti-CD3 antibody mimetic”) on their surface (See ¶0678-0680).
Regarding claim 96: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. teach that administration of the modified cells does not require host lymphodepletion (which reads on “the subject is a lymphoreplete subject”) (See ¶0104, 0128, 0147, and 0262).
Regarding claims 97-98: Following the discussion of claims 81, 86-89, 92, and 94, Frost et al., modified by Ang et al. and Li et al., render obvious the administration of multiple doses of PBMCs wherein the cells are transduced to express a CAR. Frost et al. teach that the CAR can target antigens such as CD19 and CD20 (See ¶0167), which would inherently be expressed on at least some of the cells re-introduced into a subject and would read on “the second formulation comprises… a source of the cognate antigen recognized by the CAR” and “the cell formulation comprises a source of a cognate antigen for the CAR”.
Regarding claim 99: Following the discussion of claims 81, 86, 88-89, 92, and 94, Frost et al. do not expressly teach formulation of the cells as including a cytokine.
Ang et al. teach that the immune cells can comprise IL-15 (which reads on “the cell formulation comprises a cytokine and wherein the cytokine is… IL-15”) (See ¶0016).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cells of Frost et al. to comprise IL-15. One would be motivated to make this modification because Ang et al. teach that IL-15 can induce T cell proliferation (See ¶0055). There would be a reasonable expectation of success in doing so because the cells of Frost et al. could be readily engineered to comprise IL-15.
Claims 81-89 and 91-99 remain rejected under 35 U.S.C. 103 as being unpatentable over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019), further in view of Ren et al. (Oncotarget, 2017).
The teachings of Frost et al., Ang et al., and Li et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 82: Following the discussion of claims 81, 83-89, and 91-99, Frost et al., modified by Ang et al. and Li et al., render obvious the administration of modified T cell clusters but do not teach most of the T cells as being negative for surface CD3.
Ren et al. teach CRISPR-mediated knockout of CD3 and HLA-I for generating universal CAR-T cells (See Abstract). Lentiviral vectors were used for delivery of the CAR and gRNAs (See page 17007, col. 2, full ¶3; page 17008, col. 1, ¶1; and fig. 1). Ren et al. teach enrichment of TCR/CD3-negative cells to obtain a pure population (which reads on “at least 50% of the T cells in the cell formulation are surface CD3-“) (See page 17003, col. 2, ¶1)
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Frost et al., modified by Ang et al. and Li et al., to comprise disruption of CD3 and HLA-I and enrichment for CD3-negative cells, as taught by Ren et al. One would be motivated to make this modification because Ren et al. teach that disruption of these loci can generate allogeneic CAR-T cells (See Abstract). There would be a reasonable expectation of success in doing so because the cells of Frost et al., modified by Ang et al. and Li et al., could be readily modified to disrupt CD3 expression following contacting with replication-incompetent lentivirus.
Claims 81 and 83-99 remain rejected under 35 U.S.C. 103 as being unpatentable over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019), further in view of Long et al. (Frontiers in Immunology, 2018).
The teachings of Frost et al., Ang et al., and Li et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 90: Following the discussion of claims 81, 83-89, and 91-99, Frost et al., modified by Ang et al. and Li et al., render obvious the administration of modified T cell clusters but do not teach the T cells as administered with hyaluronidase.
Long et al. review strategies for improving therapeutic outcomes using CAR-T cells (See Abstract). Long et al. teach that physical barriers such as extracellular matrix components can reduce tumor accessibility by CAR-T cells and that administration of hyaluronidase can render solid tumors more accessible to cell-based therapies (See page 6, col. 2, ¶2-3).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Frost et al. to comprise co-administration of hyaluronidase with the modified cells. One would be motivated to make this modification because Long et al. suggest that hyaluronidase could be used for enabling greater CAR-T cell access to tumor cells (See page 6, col. 2, ¶2-3). There would be a reasonable expectation of success in doing so because the method of Frost et al., modified by Ang et al. and Li et al., could readily comprise co-administration of hyaluronidase.
Claims 81, 83-89, and 91-100 are rejected under 35 U.S.C. 103 as being unpatentable over Frost et al. (WO 2018161064 A1) in view of Ang et al. (WO 2019165097 A1) and Li et al. (Autoimmunity, 2019), further in view of van Buuren et al. (US 20220280621 A1).
The teachings of Frost et al., Ang et al., and Li et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 100: Following the discussion of claims 81, 83-89, and 91-99, Frost et al., modified by Ang et al. and Li et al., render obvious the subcutaneous administration of T cell clusters wherein the T cells are contacted with replication incompetent recombinant retroviral particles comprising anti-CD3 scFvFc, but they do not expressly teach a depot formulation.
Van Buuren et al. teach methods for manufacturing and using antigen-specific T cells (See Abstract). The cells can be formulated as long-acting depot preparations for subcutaneous delivery (See ¶0539).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method rendered obvious by Frost et al., modified by Ang et al. and Li et al., to comprise a depot formulation. One would have been motivated to make this modification because van Buuren et al. teach that such a formulation enables long-acting delivery (See 0539). There would be a reasonable expectation of success in doing so because the modified T cell aggregates could be readily prepared in a depot formulation.
Conclusion
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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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633