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 .
DETAILED ACTION
The amendment filed April 14, 2026, is acknowledged and has been entered. Claims 1, 18, 58 and 66 have been amended. Claim 29 has been canceled.
Claims 1, 2, 4, 14, 15, 17-19, 27, 31, 55, 56, 58, 60, 61, 63, 65 and 66 are pending and under examination.
Grounds of Rejection Withdrawn
Unless specifically reiterated below, Applicant’s amendments have obviated or rendered moot the grounds of rejection set forth in the previous Office action mailed.
Applicant's amendment necessitated some amendments to the ground of rejections presented in this Office action.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 2, 4, 14, 18, 19, 27, 31 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Mougiakakos et al (N Engl J Med, 385(6), pages 1-3, 2021, IDS, see also Supplementary Appendix attached as Exhibit A), WO 2016/070061 A1 (Zhao et al) and US 2015/0017136 A1 (Galetto et al, IDS).
Mougiakakos et al disclose methods of treating systemic lupus erythematosus (SLE) by administering CD19 CAR T cells to a patient wherein the cells express an anti-CD19 CAR composed of the FMC63 scFv, a CD8-derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain (see page 1 and supplementary methods 2.1). Mougiakakos et al disclose assessing proteinuria and that the treatment alleviates proteinuria (see page 3). Mougiakakos et al disclose that the CAR is delivered to the immune cell via a viral vector that comprises a coding sequence for the anti-CD19 CAR (see page 1). Mougiakakos et al disclose that 46,000,000 CAR T cells were administered (comprises 10,000 and 40,000 cells, see supplementary methods 2.1). Mougiakakos et al disclose that the patient undergoes lymphodepletion with fludarabine at 25 mg/m2 for 3 days and cyclophosphamide at 1000 mg/m2 a day before CAR T cell treatment (see supplementary methods 2.3).
Mougiakakos et al does not disclose treating systemic lupus erythematosus (SLE) by administering allogeneic CD19 CAR T cells with a CD8 derived transmembrane domain or wherein the immune cells have been assessed for in vitro activity against B cells in co-culture with a B cell fraction by measuring a reduction in total IgG concentration characteristic of autoimmune disease or assessed for in vitro cytotoxicity in co-culture with B cells.
Zhao et al disclose that CAR T cells for use in treating systemic lupus erythematosus (SLE) can be allogenic or autologous and that the CAR can be a CD19 CAR that comprises a CD8 transmembrane domain (see pages 11, 26, 65, 95-96 and 139-141 and claims).
Galetto et al disclose inactivating PDCD1 (PD-1) and TRAC using TALE-nuclease methods in CAR T cells to have the advantage of making CAR T cells with increased activity and that are non-alloreactive (see abstract and pages 3 and 20).
Accordingly, it would have been prima facie obvious to administer allogeneic CD19 CAR T cells to a SLE patient by the methods of Mougiakakos et al wherein the cells express an anti-CD19 CAR composed of the FMC63 scFv, a CD8-derived hinge region, CD8-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain with inactivated PD-1 and TRAC because one of skill in the art would recognize that allogeneic or autologous CD19 CAR T cells could be used as the source of T cells and that the CD8 transmembrane domain could be predictably substituted for the TNFRSF19-derived transmembrane domain. Notably, one would see that such a method as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Then with respect inactivating PDCD1 (PD-1) and TRAC in the CAR T cells, Galetto evidences that such CAR T cells with inactivated PDCD1 (PD-1) and TRAC would be expected to have the advantage of having increased activity and being non-alloreactive so that the treatment would be expected to be more effective at targeting the B cells in SLE while not causing alloreactivity because they are allogenic T cells. Furthermore, one of ordinary skill in the art would have expected success in using such methods because allogeneic CD19 CAR T cells were known in the art to be effective and methods of making the modifications to CAR T cells were known in the art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
In the response, Applicant traverses the rejection and argues that “the T cells used in Mougiakakos are autologous T cells, where the polynucleotide encoding the CD19 CAR are delivered using lentiviral vectors. Effectiveness of autologous CAR-T cells developed from the patient does not predictably extrapolate to effectiveness of allogeneic CAR-T cells, which have different HLA types than the target cells on a recipient patient, and particularly to allogenic T cells having additional genome inactivation in PDCD1 or combination of TRAC and PDCD1 genes, against B cells in autoimmune patients.
While Zhao discloses use of CD8 transmembrane domain in T cell activating receptor constructs, and Galetto discloses generation of T cells having inactivated immune checkpoint genes, such as PDCD1 and CTLA4, both Zhao and Galetto examine its constructs effectiveness against cancer cells but do not provide any reasonable expectation that they are effective in killing B cells from autoimmune patients. Neither Mougiakakos, Zhao, and Galetto demonstrate the construction of a CD19 CAR-T cell with an inactivated PDCD1 gene and its effectiveness against B cells from autoimmune patients. The description in Zhao and Galetto for autologous, allogeneic, and xenogeneic T cells, along with its numerous different CAR-T constructs for treatment of autoimmune disease, without any objective evidence of effectiveness, amounts to mere speculation, a wish or plan, essentially an invitation to experiment.”
These arguments are not found persuasive because the prior art establishes that either autologous or allogenic T cells can be used and Applicant has not established that allogenic T cells would not be expected to treat SLE by targeting CD19 expressing B cells. Furthermore, it is noted that allogenic stem cell transplantation occurs in patients for a variety of diseases including blood cancers and SLE patients (see Lionberger et al (Biol. Blood. Marrow Transplant, 21:S127, poster 136, abstract only) and Gladstone et al (Lupus 26(7):773-776, 2017)) and SLE has developed in patients after allogenic stem cell transplantation (see Lionberger et al, Biol. Blood. Marrow Transplant, 21(S127, poster 136, abstract only)) such that the genus of SLE patients includes those that would necessarily include those that would be treated with allogenic T cells. Furthermore, with respect to using allogeneic T cells, it is noted that HLA-matched T cells can be used, HLA-deleted T cells can be used or HLA downregulated T cells can be used (see Jin et al (Leukemia, 34:909-913, 2019), Li et al (US 2022/0313736 A1) and Wang et al (Mol. Ther., 29(2):718-733, 2021). Notably, generating non-alloreactive allogenic T cells is an objective of Galetto et al (see abstract) and one of ordinary skill in the art would reasonably expect such allogeneic T cells comprising an anti-CD19 CAR, wherein the anti-CD19 CAR comprises FMC63, a CD8 hinge, a CD8 transmembrane domain, a 4-1BB co-stimulatory domain, and a CD3 zeta and wherein the engineered allogeneic CAR-T further comprises an inactivated PDCD1 gene to be able to treat SLE because those allogeneic T cells would target CD19 on B cells and kill the B cells and CD19 on B cells is a target in SLE therapies.
Claims 15, 17 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Mougiakakos et al (N Engl J Med, 385(6), pages 1-3, 2021, IDS, see also Supplementary Appendix attached as Exhibit A), WO 2016/070061 A1 (Zhao et al) and US 2015/0017136 A1 (Galetto et al, IDS) as applied to claims 1, 2, 4, 14, 18, 19, 27, 31 and 66 above, and further in view of US 2020/0149009 A1 (Regev et al).
Claims 15, 17 and 65 are further drawn to the nucleic acid encoding the CD19 CAR is integrated into the genome via a CRISPR nuclease and an nucleic acid-targeting nucleic acid, wherein prior to the integration, the nucleic acid coding for the anti-CD 19 CAR is delivered into the immune cell via a viral vector and wherein the nucleic acid comprising a coding sequence for the anti-CD 19 CAR is integrated into the gene for TRAC.
Regev et al disclose insertion of CAR transgenes, such as a CD19 CAR into the TRAC locus which inactivates TRAC via a CRISPR nuclease and a nucleic acid-targeting nucleic acid, wherein prior to the integration, the nucleic acid coding for CAR is delivered into the immune cell via a viral vector (see ¶¶ 265, 346 and 352). Regev et al disclose that CD19 CAR T cells obtained by CRISPR were significantly superior (see ¶ 265).
Accordingly, it would have been obvious to one of ordinary skill in the art to substitute CRISPR CD19 CAR integration into the TRAC locus of Regev et al for the TALE nuclease of Galetto because the CRISPR CD19 CAR integration into the TRAC locus was another known method of genomic integration that could be used in the allogeneic CAR T cells suggested by the prior art.
Therefore, using the CRISPR CD19 CAR integration into the TRAC locus of Regev et al would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, as Regev et al disclose that CD19 CAR T cells obtained by CRISPR were significantly superior there would also be a motivation to use this superior method that has a significant advantage. Finally, one of ordinary skill in the art would have expected success in using the CRISPR CD19 CAR integration into the TRAC locus of Regev et al because Regev et al disclose it as an effective method of genomic integration.
Accordingly, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection and argues that “Regev do not provide any objective evidence that the anti-CD19 CAR-T cells would predictably kill B cells obtained from autoimmune patients”.
In response, this argument is not found persuasive because B cells are known to express CD19 which would be targeted by the CD19 CAR-T cells to predictably kill B cells. Applicant has not supplied any evidence that CD19 expressing B cells from autoimmune patients would not be expected to be killed by anti-CD19 CAR-T cells.
Claims 55-56, 58, 60-61 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Mougiakakos et al (N Engl J Med, 385(6), pages 1-3, 2021, IDS, see also Supplementary Appendix attached as Exhibit A), WO 2016/070061 A1 (Zhao et al) and Imura et al (JCI Insight, 2020, pages 1-25,
https://doi.org/10.1172/jci.insight.136185).
Mougiakakos et al disclose methods of treating systemic lupus erythematosus (SLE) by administering CD19 CAR T cells to a patient wherein the cells express an anti-CD19 CAR composed of the FMC63 scFv, a CD8-derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain (see page 1 and supplementary methods 2.1).
Mougiakakos et al does not disclose treating systemic lupus erythematosus (SLE) by administering allogeneic CD19 CAR T cells with a CD8 derived transmembrane domain or wherein the immune cells have been assessed for in vitro activity against B cells in co-culture with a B cell fraction by measuring a reduction in total IgG concentration characteristic of autoimmune disease or assessed for in vitro cytotoxicity in co-culture with B cells.
Zhao et al disclose that CAR T cells for use in treating systemic lupus erythematosus (SLE) can be allogenic or autologous and that the CAR can be a CD19 CAR that comprises a CD8 transmembrane domain (see pages 11, 26, 65 and 96).
Imura et al disclose assessing total IgG antibody levels produced by primary human B after co-culture with CD19-CAR T cells and assessing T cells in co-culture with B cells at ratios of 10:1 and 1:1 (see pages 17-18 and Figs. 2, 4 and 5).
Accordingly, it would have been prima facie obvious to administer allogeneic CD19 CAR T cells to a SLE patient wherein the cells express an anti-CD19 CAR composed of the FMC63 scFv, a CD8-derived hinge region, CD8-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain because one of skill in the art would recognize that allogeneic or autologous CD19 CAR T cells could be used as the source of T cells and that the CD8 transmembrane domain could be predictably substituted for the TNFRSF19-derived transmembrane domain. Notably, one would see that such a method as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Then with respect to assessing the cytotoxicity of the CAR T cells and the ability of the CAR T cells to reduce total IgG concentrations characteristic of autoimmune disease in co-cultures with B cells, Imura et al evidence that CAR T cells are routinely tested for in vitro activity in assays such that one would be motivated to assess in vitro cytotoxicity CD19-CAR T cells in co-culture with B cells at ratios of 10:1 and 1:1 such that one would have been motivated to test the allogeneic CD19 CAR T cells to confirm their cytotoxicity wherein the cells express an anti-CD19 CAR is composed of the FMC63 scFv, a CD8-derived hinge region, CD8-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain because this assessment would provide evidence that the CAR T cells would be expected to be effective in vivo. In developing therapies for treatment for any disease with any therapy, the therapy is routinely tested in vitro such that these wherein clauses do not distinguish from the methods suggested by the prior art because such in vitro tests are suggested in the prior art to test CAR T cells for in vitro activity against B cells as part of developing the therapy. Furthermore, one of ordinary skill in the art would have expected success in using such methods because allogeneic CD19 CAR T cells were known in the art to be effective and methods of assessing CAR T cells for cytotoxicity and the ability of the CAR T cells to reduce total IgG concentrations were known in the art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
In the response, Applicant traverses the rejection and argues that “Imura actually describe testing of CD19 Treg cells with primary human B cells not for cytotoxic activity but for suppression of B-cell activity”.
In response, this argument is not found persuasive because Imura evidence that co-culture assays can be used to assess the result of T cells on B cells. One of skill in the art would recognize that B-cell activity can be assessed or cytotoxicity of the T cells towards the B cells could be assessed and as the method is drawn to treating an autoimmune disease by administering cytotoxic T cells one would be motivated to assess the cytotoxicity of the T cells towards the B cells. Notably, in producing cytotoxic CAR T cells in vitro cytotoxicity tests are routinely preformed to determine that the CAR T cells are functioning correctly using cells that express the antigen (such as in this case B cells expressing CD19) and the instant claims just recite that the test has been performed and do not require actively performing any specific test.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
Claims 1, 2, 4, 14, 15, 17-19, 27, 31, 55, 56, 58, 60, 61, 63, 65 and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 15, 17, 19 and 31 of copending Application No. 18/965,147 in view of US 2020/0149009 A1 (Regev et al).
In this case, Application No. 18/965,147 and the instant application both have PCT/US23/067936 as a parent application and the ccopending claims generally anticipate the instant as the copending claims recite similar limitations (see claim 1).
Finally, with respect to the other claims, these claims are not patentably distinct as they are obvious over the copending claims in view of Regev et al.
Regev et al disclose insertion of CAR transgenes, such as a CD19 CAR into the TRAC locus which inactivates TRAC via a CRISPR nuclease and a nucleic acid-targeting nucleic acid, wherein prior to the integration, the nucleic acid coding for CAR is delivered into the immune cell via a viral vector (see ¶¶ 265, 346 and 352). Regev et al disclose that CD19 CAR T cells obtained by CRISPR were significantly superior (see ¶ 265).
Accordingly, it would have been obvious to one of ordinary skill in the art to integrate CD19 CAR into the TRAC locus to inactivate TRAC because CRISPR CD19 CAR integration into the TRAC locus was another known method of genomic integration that could be used in the allogeneic CAR T cells of the copending claims while any other difference would be seen as obvious variations of the copending claims because the copending claims recite treating lupus with the same CAR T cells where PDCD1 has been inactivated.
This is a provisional nonstatutory double patenting rejection.
In the response, Applicant traverses the rejection and argues that “it is submitted that the procedure provided in MPEP § 804 (I)(B)(1)(b)(i) should also be applied in the case of a provisional double patenting rejection between two copending applications with the same effective filing date. In other words, if the only remaining rejection in a first filed application is a nonstatutory double patenting rejection, the examiner should withdraw the rejection in that application and permit the application to issue, and the double patenting rejection be applied to the later filed pending application upon issuance of the patent from the first filed application.”
In response, this argument in not found persuasive because copending Application No. 18/965,147 and the instant application appear to have the same patent term filing date of June 5, 2023 and when both the application under examination and the reference application have the same patent filing date, the provisional nonstatutory double patenting rejection made in each application should be maintained until it is overcome (see MPEP 1490).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the amended 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner works a flexible schedule.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
July 6, 2026
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