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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29 June 2026 has been entered.
Status of the Claims
Applicant’s submission filed 29 June 2026 has been entered. Claims 1-6, 8-18, 20-21, 23-25, 27, 29, and 31-37 are pending. Claims 1, 10-11, and 25 have been amended. Therefore, prosecution on the merits continues for claims 1-6, 8-11, 25, 27, and 29 as being drawn to the elected invention, with claims 12-18, 20-21, 23-24, and 31-37 withdrawn for reading on the non-elected inventions. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1, 6, and 8-10 under 35 USC 103 over Ports et al
Applicant’s amendments to independent claim 1 requiring the small compound treatment to comprise dexamethasone obviates the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-6, 8-10, 25, 27, and 29 under 35 USC 103 over Ports et al in view of Valamehr et al
Applicant’s amendments to independent claims 1 and 25 requiring the small compound treatment to comprise dexamethasone obviates the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 6, and 8-11 under 35 USC 103 over Ports et al in view of Morgan et al
Applicant’s arguments in Pages 16-19 have been fully considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Therefore, the rejection is withdrawn.
It is of note that Applicant’s arguments in Pages 18-19 of the Remarks filed 29 June 2026 regarding the beneficial effects of treating immune cells with dexamethasone prior to cryopreservation are not commensurate in scope with the current claims, as the cited examples are directed to the culture of iNK or iT cells expressing a CAR. See Examples 2-3 of the instant disclosure. Furthermore, the ordinary artisan would have reasonably expected the immune cells cultured with dexamethasone prior to cryopreservation to exhibit an improved antigen specific recognition, increased cytotoxicity, and improved efficacy and persistence given the teachings of Rosen et al (WO 2019/018603 A2). See, for example, Figures 8A-C of Rosen et al and the 35 USC 103 rejection below.
RE: Rejection of claims 1-6, 8-11, 25, 27, and 29 on the grounds of nonstatutory double patenting over claims 1-2, 5-6, 17, 21-22, and 26 of US Patent 12,281,328 B2 in view of Ports et al and Morgan et al
Applicant’s amendments to independent claims 1 and 25 requiring the small compound
treatment to comprise dexamethasone obviates the rejection of record.
Therefore, the rejection is withdrawn.
New Grounds of Rejection
Claim Objections
Claim 6 is objected to because of the following informalities:
Regarding claim 6: The instant claim is objected to for reciting “immune cells” in Lines 1-2, but reciting “immune cell” within Line 2. It is of note that Applicant utilizes the singular “immune cell” throughout the claim language. Therefore, Applicant is required to select either the singular or plural recitation to consistently utilize throughout the claim language.
Appropriate correction is required.
Claim Interpretation
Under the broadest reasonable interpretation of instant claims 10 and 27, all of the “optional” limitations are not required.
Furthermore, Applicant has defined “substantially free” – as seen in instant claim 8 – as a composition that is free of a specified substance or its source thereof, such as, 95% free, 96% free, 97% free, 98% free, 99% free of the specified substance or its source thereof, or is undetectable as measured by conventional means. See Paragraph [00044] of the Specification filed 03 June 2022.
In regard to instant claims 3, 25, and 27, Applicant lists a representative number of species of “CD16 variants” within Paragraphs [000105]-[000106] of the instant Specification filed 03 June 2022, along with an associated structure-function relationship. More specifically, Applicant has listed different species of "high affinity CD16”, "non-cleavable CD16", or "high affinity non-cleavable CD16 (hnCD16)," CD16 variants, which refer to a natural or non-natural variants of CD16. With that, Applicant explains that the wildtype CD16 has low affinity and is subject to ectodomain shedding, a proteolytic cleavage process that regulates the cell's surface density of various cell surface molecules on leukocytes upon NK cell activation. F176V and F158V (without signal peptide) are exemplary natural CD16 polymorphic variants having high affinity. A CD16 variant having the cleavage site (position 195-198) in the membrane-proximal region 29 (position 189-212) altered or eliminated is not subject to shedding. Applicant notes that the cleavage site and the membrane-proximal region are described in detail in International Pub. No. WO 2015/148926, which is incorporated by reference. The CD16 S197P variant is an engineered non-cleavable version of CD16. A CD16 variant comprising both F158V and S197P has high affinity and is non-cleavable. Another exemplary high affinity and non-cleavable CD16 (hnCD16) variant is an engineered CD16 comprising an ectodomain originated from one or more of the 3 exons of the CD64 ectodomain.
Likewise, in regard to instant claims 3, 5, and 25, Applicant lists a representative number of species of “antibody fragments” within Paragraph [00132] of the instant Specification filed 03 June 2022, along with an associated structure-function relationship. More specifically, Applicant discloses that “[n]on-limiting examples of antibody fragments include Fab, Fab', F(ab)'2, F(ab)'3, Fv, antigen binding single chain variable fragment (scFv), (scFv)2, disulfide stabilized Fv (dsFv), minibody, diabody, triabody, tetrabody, single- domain antigen binding fragments (sdAb, Nanobody), recombinant heavy-chain-only antibody (VHH), and other antibody fragments that maintain the binding specificity of the whole antibody.”
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.
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.
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 1-5, 8-11, 25, 27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable by Rosen et al (WO 2019/018603 A2, of record on IDS filed 05 December 2022).
Rosen et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). The applied
reference has a common Applicant with the instant application, and was published on 24 January 2019. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claim 1: Rosen et al disclose compositions and methods for modulating immune cells to improve their therapeutic potential for adoptive immunotherapies, wherein one or more compounds, either alone or in combination, are provided to the immune cells to improve their post-thaw cytotoxicity (Abstract; Paragraphs [00012], [00014], [00018], [00029], [00039], [00074], [000159], [000255]-[000256]; Figures 8A-C).
As such, Rosen et al disclose an embodiment of the invention wherein initially cryopreserved immune cells are thawed, treated with a glucocorticoid compound – specifically flunisolide – during culture and expansion in vitro, cryopreserved and thawed again, administered to a subject to assess the in vivo efficacy, and determined to have an increased post-thaw cytotoxicity (Paragraphs [000193], [000224], [000229], [000234], [000250]-[000262]; Figures 8A-C).
Rosen et al further disclose that other glucocorticoid compounds include dexamethasone acetate (Paragraphs [000127], [00134], [000234]; Table 1; Figures 2A-B).
Rosen et al do not exemplify or reduce to practice the treatment of the expanding immune cells with dexamethasone acetate prior to cryopreservation, as required by instant claim 1.
Therefore, it would have been prima facie obvious to have substituted the flunisolide within the exemplified method of Rosen et al with dexamethasone acetate, as doing so would have been a simple substitution of one glucocorticoid compound for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the two glucocorticoids are functionally comparable, as they are alternative glucocorticoid compounds that exhibit similar properties (Table 1; Figures 1A-D and 2A-B), and thereby would have been able to substitute the two glucocorticoid compounds with predictable results.
Consequently, Rosen et al render obvious a method wherein expanding immune cells are treated with dexamethasone acetate in vitro and subsequently cryopreserved, wherein the dexamethasone acetate treatment enhances the post-thaw cytotoxicity of the immune cells. This therefore renders obvious the method of the instant claim.
Regarding claims 2-4, 25, 27, and 29: Following the discussion of claim 1, Rosen et al further disclose that the immune cells are induced pluripotent stem cell (iPSC)-derived T cells (claims 2, 29) (Paragraphs [00024], [00032], [00044], [000185]-[000187]). Rosen et al further disclose that the iPSC-derived T cells comprise an exogenous nucleic acid encoding a chimeric antigen receptor (CAR) specific for a tumor antigen, specifically CD19, wherein the iPSCs are engineered to comprise the exogenous nucleic acid encoding the CAR (claims 3-4, 27) (Paragraphs [00023]-[00024], [00031]-[00032], [00035], [00043]-[00044], [00079], [000179], [000183], [000185]-[000188], [000198], [000250]). This therefore renders obvious the method of instant claim 25 for the same reasons as discussed in the rejection of instant claim 1.
Regarding claim 5: Following the discussion of claim 3, Rosen et al further disclose that the CAR can be an altered multispecific CAR comprising antigen binding domains for bispecific antibodies or multispecific single-chain antibodies (Paragraphs [00024], [000182], [000185], [000188]). As the polynucleotide encoding the CAR will co-express the multispecific single-chain antibody fragments, for example, this therefore reads on the method of the instant claim.
Regarding claim 8: Following the discussion of claim 1, Rosen et al further disclose that the glucocorticoid compound-treated immune cells can be washed to remove the glucocorticoid compound prior to being administered to a subject (Paragraphs [00027]-[00028], [000216]). Therefore, it would have been prima facie obvious to have modified the method of Rosen et al such that the glucocorticoid compound-treated immune cells are washed prior to being cryopreserved. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to ensure that the cryopreserved immune cells are free of the glucocorticoid compound, as the cryopreserved immune cells can be administered to a subject post-thaw without being expanded in vitro prior to administration (Paragraph [000216], [000250]), and would have had a reasonable expectation of success given that Rosen et al disclose the washing and cryopreservation of glucocorticoid compound-treated immune cells within separate embodiments of the invention. See MPEP § 2143(I)(G).
Consequently, Rosen et al render obvious a method wherein the glucocorticoid compound-treated immune cells are washed prior to being cryopreserved to remove the glucocorticoid compound. This therefore renders obvious the method of the instant claim.
Regarding claim 9: Following the discussion of claim 1, Rosen et al further disclose that the dexamethasone acetate-treated CAR-T cells have an enhanced post-thaw in vivo efficacy, including increased ability in tumor clearance, improved cell persistence in vivo post-transfer, and increased ability to reduce tumor burden (Paragraphs [000223], [000227], [000229], [000250]-[000262]; Figure 8C). This therefore reads on the method of the instant claim.
Regarding claim 10: Following the discussion of claim 1, Rosen et al further disclose that the glucocorticoid compound treatment lasts for 6 days (Paragraphs [000194], [000250]). See MPEP § 2131.03. This therefore reads on the method of the instant claim.
Regarding claim 11: Following the discussion of claim 1, Rosen et al further disclose that the compound is present at a concentration in the range of 10 nM to 10μΜ (Paragraphs [000193], [000224]). See MPEP § 2131.03. This therefore reads on the method of the instant claim.
Claims 1-6, 8-11, 25, 27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable by Rosen et al (WO 2019/018603 A2, of record on IDS filed 05 December 2022) in view of Albertson et al (US 2021/0198372 A1).
The discussion of Rosen et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Rosen et al render obvious claims 1-5, 8-11, 25, 27, and 29. Albertson et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 01 December 2017.
Regarding claim 6: As aforementioned in the discussion of claim 1 above, Rosen et al render obvious a method wherein expanding in vitro immune cells are treated with dexamethasone acetate and subsequently cryopreserved.
Rosen et al further disclose that the immune cells are T cells that comprise an exogenous nucleic acid encoding a chimeric antigen receptor (CAR) specific for a tumor antigen, specifically CD19 (Paragraphs [00023]-[00024], [00031]-[00032], [00035], [00043]-[00044], [00079], [000179], [000183], [000185]-[000188], [000198], [000250]).
Rosen et al further disclose that the cryopreserved anti-CD19 CAR-T cells are thawed and administered to a subject to assess in vivo tumor killing ability and persistence (Paragraphs [000250]-[000262]).
Rosen et al do not disclose that the cryopreserved CAR-T cells are treated with dexamethasone subsequent to cryopreservation, as required by instant claim 6.
Albertson, et al, however, disclose methods involving the administering and/or determining the dosing of CAR-T cell therapies (Abstract).
As such, Albertson et al disclose the administration of anti-CD19 CAR-T cells to a subject, assessing the in vivo expansion and persistence of the anti-CD19 CAR-T cells, and then administering dexamethasone acetate at a therapeutically effective concentration in order to dampen the anti-CD19 CAR-T cell expansion and/or proliferation to maintain the amount of anti-CD19 CAR-T cells within the therapeutic range (Paragraphs [0020], [0025]-[0026], [0033], [0064], [0067]-[0071], [0073], [0089], [0097], [0146], [0250]-[0251], [0253]-[0259], [0492], [0541], [0545]-[0550], [0648]-[0654]; Figure 31). Albertson et al further disclose that the subject suffers from cancer and the therapeutic range of anti-CD19 CAR-T cells is in regard to tumor killing ability or reducing tumor burden (Paragraphs [0025]-[0026], [0068], [0097], [0160]-[0161], [0163], [0197], [0206], [0246]-[0248]).
Therefore, it would have been prima facie obvious to have modified the method of Rosen et al such that the cryopreserved anti-CD19 CAR-T cells are thawed, administered to a subject, and then contacted with dexamethasone acetate in vivo to maintain the amount of anti-CD19 CAR-T cells within the therapeutic range, as detailed in Albertson et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to ensure that the amount of anti-CD19 CAR-T cells does not surpass the peak therapeutic range, and would have had a reasonable expectation of success given that the disclosures of both Rosen et al and Albertson et al teach the administration of anti-CD19 CAR-T cells to a subject suffering from cancer, assessing the in vivo persistence and tumor killing ability, and contacting the anti-CD19 CAR-T cells with dexamethasone acetate. See MPEP § 2143(I)(G).
Consequently, Rosen et al as modified by Albertson et al render obvious a method wherein expanding anti-CD19 CAR-T cells are treated with dexamethasone acetate in vitro, cryopreserved, thawed, administered to a subject suffering from cancer, assessed for in vivo persistence and tumor killing ability, and administered a second treatment of dexamethasone acetate in order to contact the anti-CD19 CAR-T cells in vivo. This therefore renders obvious the method of the instant claim.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
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