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 election without traverse filed December 2, 2025, is acknowledged and has been entered. Applicant has elected Group I.
The amendment filed December 2, 2025, is acknowledged and has been entered. Claims 1, 4 and 14 have been amended. Claims 65 and 66 have been newly added. Claims 36-37, 46 and 52 have been canceled.
Claims 1, 2, 4, 14, 15, 17, 19, 27, 29, 31, 55, 56, 60, 61, 63, 65 and 66 are pending and under examination.
Information Disclosure Statement
The information disclosure statements have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18 and 58 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 is indefinite in the recitation of the limitation “the dose used to treat B cell malignancies with the CD19-targeting engineered immune cells”. This recitation renders the claim indefinite because this claim depends from claim 1, and claim 1 does not recite “a dose used to treat B cell malignancies with the CD 19-targeting engineered immune cells”, so this term lacks antecedent basis. Furthermore, the specification does not identify a dose used to treat B cell malignancies with CD19-targeting engineered immune cells and any dose used treat B cell malignancies with CD19-targeting engineered immune cells can vary significantly such that it is unclear what 1/1000 of such a dose might be. Therefore, this claim fails to delineate the metes and bounds of the subject matter that Applicant regards as the invention with the requisite particularity and clarity, so as to permit the skilled artisan to know or determine infringing subject matter and thereby satisfy the requirement set forth under 35 U.S.C. § 112, second paragraph.
Claim 58 is indefinite in the recitation of the limitation “the co-culture has an effector cell:target cell ratio between 1:10 and 10:1”. This recitation renders the claim indefinite because this claim depends from claim 55, and claim 55 does not recite “a co-culture that has an effector cell and target cell”, so this term lacks antecedent basis. Therefore, it cannot be determined which (if any) co-culture is being referred to. Therefore, this claim fails to delineate the metes and bounds of the subject matter that Applicant regards as the invention with the requisite particularity and clarity, so as to permit the skilled artisan to know or determine infringing subject matter and thereby satisfy the requirement set forth under 35 U.S.C. § 112, second paragraph.
Accordingly, these claims are indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
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, 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 (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 and 96).
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.
Claim 29 is 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, 19, 27, 31 and 66 above, and further in view of US 2013/0302300 A1 (Radvanyi et al).
Claim 29 is further drawn to lymphodepletion with fludarabine at 25 mg/m2 for up to 5 days and cyclophosphamide at 60 mg/kg up to 2 days before treatment.
Radvanyi et al disclose lymphodepletion in patients with fludarabine at 25 mg/m2 for up to 5 days and cyclophosphamide at 60 mg/kg up to 2 days before treatment (see ¶ 74)..
Accordingly, it would have been obvious to one of ordinary skill in the art to substitute the lymphodepletion of Radvanyi et al for the lymphodepletion in Mougiakakos et al suggested above because the lymphodepletion of Radvanyi et al was another known method of lymphodepletion that could be used before administering the allogeneic CAR T cells suggested by the prior art.
Therefore, using the lymphodepletion of Radvanyi 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, one of ordinary skill in the art would have expected success in using the lymphodepletion of Radvanyi et al because using the Radvanyi et al disclose it as an effective method of lymphodepletion.
Therefore, 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.
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, 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.
Therefore, 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.
Claims 55-56, 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 in vitro cytotoxicity CD19-CAR T cells in co-culture with B cells (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 such assays such that one would have been motivated to test the allogeneic CD19 CAR T cells 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.
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, 29, 31, 55, 56, 60, 61, 63, 65 and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 9, 10, 14, 15, 17, 19, 27, 29, 31, 55, 56, 60, 61 and 63 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 instant claims 1, 2, 4, 9, 10, 14, 15, 17, 19, 27, 29, 31, 55, 56, 60, 61 and 63 anticipate instant claims 1, 2, 4, 14, 15, 17, 19, 27, 29, 31, 55, 56, 60, 61 and 63 as the copending claims recite similar limitations (see claims 1 and 9-10 that correspond to instant claim 1 and then the other claims correspond numerically).
Finally, with respect to instant claims 65 and 66, 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.
Therefore, claims 65 and 66 are not patentably distinct from the copending claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
December 31, 2025