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
1. 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 allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). 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, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on May 5, 2026 has been entered.
Claims 1-17 are pending and being examined.
Claim Objections
2. Claims 2, 3, 9 are free of the art but are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
New Rejection
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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3. Claims 1, 4-8, and 10-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 10,457,961 in view of Zhang et al (Molecular Therapy vol. 19 no. 4, 751–759; April 2011).
The US Patent claims:
1. A system for regulating expression of a target polynucleotide in a lymphocyte, the system comprising:
(a) a chimeric receptor polypeptide (receptor) comprising a transmembrane receptor or a fragment thereof, that undergoes a receptor modification including a conformational change or chemical modification upon binding to its ligand, wherein the receptor comprises a cleavage moiety that cleaves a cleavage recognition site; and
(b) a chimeric adaptor polypeptide (adaptor) that binds the receptor in response to the receptor modification, wherein the adaptor comprises a gene modulating polypeptide (GMP) comprising an actuator moiety linked to the cleavage recognition site, and wherein the adaptor does not bind any extracellular ligand,
wherein the target polynucleotide encodes for a protein involved in immune cell regulation, and
wherein the receptor is activatable upon binding of the receptor to the ligand to recruit the adaptor to the receptor, and wherein the receptor releases the actuator moiety from the GMP of the recruited adaptor by action of the cleavage moiety at the cleavage recognition site, to effect regulating expression of the target polynucleotide in the lymphocyte.
2. The system of claim 1, wherein the receptor modification is phosphorylation.
3. The system of claim 1, wherein the actuator moiety is an RNA-guided actuator moiety, and wherein the system further comprises a guide RNA that complexes with the actuator moiety.
4. The system of claim 3, wherein the RNA-guided actuator moiety substantially lacks DNA cleavage activity.
5. The system of claim 1, wherein cleavage of the cleavage recognition site is effective to release the adaptor from the receptor that has undergone the receptor modification, rendering the receptor available for binding with another adaptor comprising a GMP.
6. The system of claim 4, wherein the RNA-guided actuator moiety is Cas9 or fragment thereof that substantially lacks DNA cleavage activity.
7. The system of claim 1, wherein the transmembrane receptor comprises a G-protein coupled receptor or fragment thereof.
8. The system of claim 1, wherein the adaptor is linked to at least one targeting sequence which directs transport of the adaptor to a specific region of the lymphocyte.
9. The system of claim 1, wherein the receptor is linked to at least one targeting sequence which directs transport of the receptor to a cellular membrane.
10. The system of claim 1, wherein the receptor or the adaptor is linked to a polypeptide folding domain.
11. The system of claim 1, wherein the actuator moiety comprises a repressor effective to decrease expression of the target polynucleotide.
12. The system of claim 1, wherein the protein involved in immune cell regulation is PD-1 and/or CTLA-4.
13. The system of claim 1, wherein the target polynucleotide comprises genomic DNA or RNA.
14. The system of claim 1, wherein the adaptor binds to an intracellular domain of the receptor upon the receptor modification.
15. The system of claim 1, wherein the actuator moiety is a DNA-guided actuator moiety and the system further comprises a guide DNA that complexes with the actuator moiety.
16. The system of claim 1, wherein the lymphocyte is a T cell.
17. The system of claim 1, wherein the lymphocyte is a B cell.
18. The system of claim 1, wherein the lymphocyte is a natural killer (NK) cell.
19. A method of regulating expression of a target polynucleotide in a lymphocyte, the method comprising:
(a) contacting a ligand to a chimeric transmembrane receptor polypeptide (receptor) comprising a cleavage moiety, wherein the receptor is modified upon contacting to the ligand, and wherein the receptor modification comprises a conformational change or a chemical modification;
(b) binding a chimeric adaptor polypeptide (adaptor) comprising a gene modulating polypeptide (GMP) to the receptor in response to the receptor modification, wherein the GMP comprises an actuator moiety linked to a cleavage recognition site, wherein the receptor is activatable upon binding of the receptor to the ligand to recruit the adaptor to the receptor, and wherein the adaptor does not bind any extracellular ligand; and
(c) releasing the actuator moiety from the GMP of the recruited adaptor by action of the cleavage moiety at the cleavage recognition site, to effect regulating expression of the target polynucleotide in the lymphocyte, wherein the target polynucleotide encodes for a protein involved in immune cell regulation.
20. The method of claim 19, wherein the receptor modification is phosphorylation.
21. The method of claim 19, wherein the actuator moiety is an RNA-guided actuator moiety that forms a complex with the target polynucleotide.
22. The method of claim 19, wherein the RNA-guided actuator moiety substantially lacks DNA cleavage activity.
23. The method of claim 19, further comprising (i) binding another adaptor to the receptor that has undergone the receptor modification, wherein the another adaptor comprises a GMP comprising an actuator moiety linked to a cleavage recognition site, and (ii) cleaving the cleavage recognition site of the another adaptor to release its actuator moiety.
24. The method of claim 19, wherein receptor modification comprises modification at multiple modification sites, and each modification site is effective to bind an adaptor.
25. The method of claim 19, wherein the actuator moiety is a Cas9 or a fragment thereof that substantially lacks DNA cleavage activity.
26. The method of claim 19, wherein the receptor comprises a G-protein coupled receptor or fragment thereof.
27. The method of claim 19, wherein the actuator moiety comprises a repressor effective to decrease expression of the target polynucleotide.
28. The method of claim 19, wherein the protein involved in immune cell regulation is PD-1 and/or CTLA-4.
29. The method of claim 19, wherein the adaptor binds to an intracellular domain of the receptor upon the receptor modification.
30. The method of claim 19, wherein the lymphocyte is a T cell.
31. The method of claim 19, wherein the lymphocyte is a B cell.
32. The method of claim 19, wherein the lymphocyte is a natural killer (NK) cell.
The US Patent does not claim that the target polynucleotide encoding for a protein involved in immune cell regulation is IL-12.
Zhang teaches an inducible system in a T cell for regulating the expression of IL-12, wherein the expression of IL-12 is enhanced upon T-cell receptor (TCR) binding to a tumor antigen. Zhang teaches IL-12 is an immunostimulatory cytokine. IL-12 is recognized as an important regulator of cell-mediated immunity, beneficial for the treatment of infectious and malignant diseases by enhancing the cytotoxic activity of NK cells and cytotoxic T lymphocytes (abstract; Introduction). Zhang utilized the immunostimulatory properties of IL-12 to enhance the antitumor activity of tumor-infiltrating lymphocytes or specific TCR-engineered PBLs. Zhang demonstrated that primary human T lymphocytes engineered to express IL-12 and TCR could enhance TCR recognition of tumor targets through stimulating higher amounts of interferon-γ (IFN-γ) in vitro (Introduction). Zhang demonstrated that antigen-specific T cells engineered with the inducible IL-12 vector-enhanced therapeutic effect in an established murine tumor model (Introduction).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to utilize IL-12 as the target polynucleotide in the system of the US Patent. One would have been motivated to and have a reasonable expectation of success to, because: (1) the US Patent claims the system’s target polynucleotide encodes for a protein involved in immune cell regulation, and claims the system is expressed by a T cell; (2) Zhang teaches IL-12 is a target polynucleotide encoding for a protein involved in immune cell regulation; (3) Zhang teaches inducing IL-12 expression in T cells through a system triggered by receptor ligand binding; and (4) Zhang demonstrates that the system successfully enhances IL-12 expression upon TCR-antigen binding and the system enhanced tumor immunotherapy.
4. Conclusion: Claims 1, 4-8, and 10-17 are rejected. Claims 2, 3, 9 are objected to. See the office action mailed February 6, 2026 for the closest prior art cited on record.
5. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/ Primary Examiner, Art Unit 1642
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