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 .
Claim Objections
Claim 76 objected to because of the following informalities: Claim 76 recites “[a] cell expressing a polypeptide encoding an antibody”. Polynucleotides can encode antibodies, not polypeptides. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 11, 12, 15, and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a GPC2-positive cancer comprising administering an anti-GPC2 antibody as a targeted therapy (e.g. as an antibody-drug conjugate, bispecific T cell engager, or CAR-T cell) or in combination with an anti-cancer agent, does not reasonably provide enablement for treating a GPC2-positive cancer using an anti-GPC2 as a standalone or unconjugated therapy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The nature of the invention relates to the fields of medicine, oncology, and immunotherapy; in particular, the development of agents useful for treating glypican 2 (GPC2)-positive cancers (see Field of Invention on Page 1 of Specification).
Claim 1 is broadly drawn to a method of treating a GPC2-positive cancer comprising administering an anti-GPC2 antibody.
The specification teaches that three antibodies – m201, m202, and m203 – specifically targeting GPC2 were isolated from a phage display antibody library and affinity matured. Further in vitro characterization demonstrated that these antibodies possess therapeutic activity for use in CAR-T, antibody drug conjugate (ADC) and bispecific antibody formats for cancer therapy as stated in Example 1. Indeed, recent studies establish that D3-GPC2-PBD, a GPC2-targeted ADC that links a human GPC2 antibody (D3) to DNA-damaging pyrrolobenzodiazepine (PBD) dimers induces durable neuroblastoma and SCLC tumor regression via induction of DNA damage, apoptosis, and bystander cell killing, notably with no signs of ADC-induced in vivo toxicity (Raman et al, see Abstract). In addition, a GPC2-specific CAR T cell exhibited potent and durable eradication of neuroblastomas expressing clinically relevant GPC2 antigen densities, without toxicity (Heitzeneder et al, Abstract). However, the specification does not appear to provide any evidence that the claimed anti-GPC2 antibodies as a standalone or unconjugated therapy can effectively treat a GPC2-positive cancer in a subject. Moreover, there is no guidance provided in the specification such as any particular dosage regimen or amount effective to achieve a therapeutic effect using an anti-GPC2-antibody as a standalone therapy, or any required functional characteristics of the antibody (e.g. Fc-mediated effector function such as antibody-dependent cellular cytotoxicity (ADCC), including isotype to elicit such activity).
The prior art teaches that unconjugated antibodies directed to tumor-associated antigens are not always effective as standalone therapies even when capable of engaging immune effector mechanisms. For example, it is reported that such antibodies produce insufficient levels of cytotoxicity in vivo and are not curative. As such, unconjugated antibodies specific for tumor associated antigens are more effective in combination therapies and/or repurposed as a targeted therapy such as conjugated/engineered formats (e.g. immunoconjugates which facilitate delivery of potent cytotoxic agents) (Wagoner et al, Abstract and Section 6: Strategies to Overcome ADCP Limitations; and Smaglo et al, Abstract). Thus, at the time of filing, it had not been established that merely targeting tumor-associated antigens with unconjugated antibodies predictably results in therapeutic benefit.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering and oncology. Even at this high level of skill, in the absence of further guidance, artisans would have to engage in undue trial-and-error experimentation (e.g. in vitro functional assays and animal tumor models) to determine whether the unconjugated antibodies encompassed by the claims can effectively treat a GPC2-specific cancer in a subject.
Claims 2-7, 11-12, 15, and 30 depend either directly or indirectly on claim 1 but do not cure the deficiencies of claim 1 and thus are also rejected. In particular, while claim 15 recites that the antibody is comprised in a chimeric antigen receptor or is a bispecific antibody, the claim also recites formats where the antibody remains unconjugated or is otherwise not in a format that facilitates targeted therapy.
Therefore, the specification is not enabling over the full scope of the claims.
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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Claim 76 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11814440B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite an isolated engineered cell comprising an antibody or antibody derivative that binds to a cancer cell-associated Glypican 2 on a Glypican-2 positive cancer cell, wherein the antibody or antibody derivative comprises the heavy chain CDRs of SEQ ID NOs: 5, 6, and 7 (corresponding to SEQ ID NOs: 5, 6, and 7 of the instant claims) and the light chain CDRs of SEQ ID NOs: 7, 8, and 9 (corresponding to SEQ ID NOs: 7, 8, and 9 of the instant claims); or a VH and VL chain pair of SEQ ID NOs: 2 and 4, respectively (corresponding to SEQ ID NOs: 2 and 4 of the instant claims) (issued claim 2).
Thus, the issued claim anticipates instant claim 76.
Note: While the instant application is filed as a divisional of the parent application, the restriction requirement between the inventions of Group II (drawn to a chimeric antigen receptor comprising an anti-GPC2 antibody) and Group III (drawn to a hybridoma or engineered cell that encodes an anti-GPC2 antibody) was withdrawn in the parent application in the Non-Final Rejection dated 05/05/2022 in the parent case 15/773,256. Therefore, instant claim 76, which is directed to the invention of Group II, is not entitled to the safe harbor protection of 35 USC 121.
Claims 1-5, 12, 15, 30, and 76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 8-61 of copending Application No. 17/597,580 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a method of treating a human subject having a GPC2-expressing cancer comprising administering to the human subject a population of human T cells comprising a nucleic acid encoding a CAR that selectively binds to GPC2 (co-pending claims 1, 16, and 20). The GPC2-specific CAR comprises an antigen binding domain having
the VH chain of SEQ ID NO: 30 (corresponding to SEQ ID NO: 2 and fully comprising the CDRs of SEQ ID NOs: 5, 6, and 7 of the instant claims) and the VL chain of SEQ ID NO: 32 (corresponding to SEQ ID NO: 4 and fully comprising the CDRs of SEQ ID NOs: 8, 9, and 10 of the instant claims) (see Sequence Alignments_054 vs 580, OA.Appendix).;
the VH chain of SEQ ID NO: 34 (corresponding to SEQ ID NO: 12 and fully comprising the CDRs of SEQ ID NOs: 15, 16, and 17 of the instant claims) and the VL chain of SEQ IDNO: 36 (corresponding to SEQ ID NO: 14 and fully comprising the CDRs of SEQ ID NOs: 18, 19, and 20 of the instant claims) (see Sequence Alignments_054 vs 580, OA.Appendix).; or
the VH chain of SEQ ID NO: 38 (corresponding to SEQ ID NO: 22 and fully comprising SEQ ID NOs: 25, 26, and 27 of the instant claims) and the VL chain of SEQ ID NO: 40 (corresponding to SEQ ID NO: 24 and fully comprising the CDRs of SEQ ID NOs: 28, 29, and 30 of the instant claims) (co-pending claims 1 and 4) (see Sequence Alignments_054 vs 580, OA.Appendix).
wherein the antigen binding domain is a Fab or single-chain variable fragment (scFv) (co-pending claim 3). Thus, the human T cells comprising a CAR having a GPC2-specific antigen binding domain read on the cells expressing polypeptides encoding the same anti-GPC2 antibody as recited in instant claim 76. The GPC2-expressing cancer is a solid tumor cell selected from the group consisting of sarcoma, neuroblastoma, rhabdoid cancer, neuroblastoma, retinoblastoma, medulloblastoma, small cell lung cancer, uterine carcinosarcoma, glioma, thymoma, a testicular germ cell tumor, glioblastoma multiforme, melanoma, hepatocellular carcinoma, thyroid cancer, renal clear cell carcinoma, renal papillary cell carcinoma, stomach adenocarcinoma, cholangiocarcinoma, adenoid cystic carcinoma, prostate adenocarcinoma, lung adenocarcinoma, head-neck squamous carcinoma, pancreatic adenocarcinoma, breast cancer, mesothelioma, colon and rectal adenocarcinoma, an esophageal carcinoma, ovarian cancer, lung squamous cell carcinoma, and bladder urothelial carcinoma. (co-pending claims 22-24). Of note, the GPC2-specific CAR is an obvious variant of the anti-GPC2 specific antibody with both reading on identical antigen-binding domain sequences.
Thus, the co-pending claims meet the limitations of instant claims 1-5, 12, 15, 30, and 76.
Claims 6 and 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 8-61 of copending Application No. 17/597,580, as applied to claims 1-5, 12, 15, 30, and 76 above, in view of Enblad et al (Enblad, Gunilla, Hannah Karlsson, and Angelica SI Loskog. "CAR T-cell therapy: the role of physical barriers and immunosuppression in lymphoma." Human gene therapy 26.8 (2015): 498-505.), hereinafter Englad.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the GPC2-expressing cancers are metastatic cancers.
However, Enblad teaches that combining CAR T-cells with other immune therapeutics such as checkpoint blockade antibodies or oncolytic viruses can increase their survival in the tumor lesions and support efficacy. For example, the checkpoint blockade antibodies targeting the CTLA-4 and PDL1/PD1 pathways may prevent CAR T-cell exhaustion. The combination immunotherapy also broadens the immune activity against the tumor since both checkpoint blockade antibodies and oncolytic viruses will activate not only the CAR T-cells but also the naturally occurring tumor-recognizing T-cells, thus preventing escape mutant tumor cells that are not positive for the CAR target (“Conditioning of Patients Receiving Car T-cell Therapy” and “Future Considerations” section).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that the GPC2-specific CAR is administered in combination with a immunotherapeutic agent such as a checkpoint blockade antibody. One of ordinary skill in the art would have been motivated to do so since combining CAR T-cells with other immune therapeutics such as checkpoint blockade antibodies or oncolytic viruses can increase their survival in the tumor lesions and support efficacy. Therefore, one of ordinary skill in the art would have expect that combining the GPC2-specific CAR of the co-pending claims with an immunotherapeutic agent such as a checkpoint blockade antibody can more effectively treat a GPC2-expressing cancer in a subject.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 8-61 of copending Application No. 17/597,580, as applied to claims 1-5, 12, 15, 30, and 76 above, in view of DeNardo et al (DeNardo, David G et al. “Immune cells as mediators of solid tumor metastasis.” Cancer metastasis reviews vol. 27,1 (2008): 11-8. doi:10.1007/s10555-007-9100-0), hereinafter DeNardo.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the GPC2-expressing cancers are metastatic cancers.
However, DeNardo teaches that metastatic tumors represent the greatest threat to cancer patient mortality. For example, when breast cancer is diagnosed early and metastases are not present, 5-year survival is >88%; however, if metastases are also present, long-term survival is significantly diminished (~10%) (first paragraph under “The Problem of Metastasis”). Thus, subjects having metastatic cancers represent a patient population that would benefit from anti-cancer treatment.
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that the GPC2-expressing cancer to be treated is a metastatic cancer. One of ordinary skill in the art would have been motivated to do so since metastatic tumors increase cancer patient mortality; thus, subjects having metastatic cancers represent a patient population in need of anti-cancer treatment such as with the GPC2-specific CAR T cells of the co-pending claims. Therefore, one of ordinary skill in the art would have expect that the method of the co-pending claims can be used to effectively treat a GPC2-expressing cancer that is metastatic.
Claims 1-5, 12, 15, 30, and 76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 9, 11, 15-23, 30, 33, 38, and 40 of copending Application No. 18716387 (reference application) in view of Orentas et al (Orentas, Rimas J et al. “Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers.” Frontiers in oncology vol. 2 194. 17 Dec. 2012, doi:10.3389/fonc.2012.00194), hereinafter Orentas.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method of treating cancer in a patient comprising administering a cell comprising a polynucleotide encoding a CAR having a GPC2-specific single chain antibody variable region (co-pending claims 1, 33, and 40). The GPC2 single chain antibody comprises the VH chain of SEQ ID NO: 1 (corresponding to SEQ ID NO: 2 and thus fully comprising the CDRs of SEQ ID NOs: 5, 6, and 7 of the instant claims) and the VL chain of SEQ ID NO: 2 (corresponding to SEQ ID NO: 4 and thus fully comprising SEQ ID NOs: 8, 9, and 10 of the instant claims) (co-pending claim 15) (see Sequence Alignments_054 vs 387, OA.Appendix). Further recited in the co-pending claims is a cell comprising the polynucleotide encoding the GPC2-speicfic CAR (co-pending claim 33). Of note, the GPC2-specific CAR is an obvious variant of the anti-GPC2 specific antibody with both reading on identical antigen-binding domain sequences.
The co-pending claims do not specifically recite that the cancer treated is a GPC2-expressing cancer.
However, Orentas teaches that glypican-2 (GPC2) is a tumor associated antigen expressed in several pediatric solid tumors, such as Ewing’s sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, osteosarcoma, and neuroblastoma; and thus represents GPC2-expressing tumors can be the target of CAR or antibody-based therapies (see Abstract, “Tumors Analyzed” section under Results, and Figure 2).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that the cancer treated is a GPC2-expressing solid tumor such as embryonal rhabdomyosarcoma or neuroblastoma. One of ordinary skill in the art would have been motivated to do so since GPC2 is expressed in several pediatric tumors such as embryonal rhabdomyosarcoma or neuroblastoma and can thus be targeted and treated by the GPC2-specific CAR of the co-pending claims. Therefore, one of ordinary skill in the art would reasonably expect the GPC2-specific CAR of the co-pending claims to effectively treat GPC2-expressing tumors in a subject.
Claims 6 and 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 9, 11, 15-23, 30, 33, 38, and 40 of copending Application No. 18716387, as applied to claims 1-5, 12, 15, 30, and 76 above, in view of Enblad et al (Enblad, Gunilla, Hannah Karlsson, and Angelica SI Loskog. "CAR T-cell therapy: the role of physical barriers and immunosuppression in lymphoma." Human gene therapy 26.8 (2015): 498-505.), hereinafter Enblad.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the GPC2-expressing cancers are metastatic cancers.
However, Enblad teaches that combining CAR T-cells with other immune therapeutics such as checkpoint blockade antibodies or oncolytic viruses can increase their survival in the tumor lesions and support efficacy. For example, the checkpoint blockade antibodies targeting the CTLA-4 and PDL1/PD1 pathways may prevent CAR T-cell exhaustion. The combination immunotherapy also broadens the immune activity against the tumor since both checkpoint blockade antibodies and oncolytic viruses will activate not only the CAR T-cells but also the naturally occurring tumor-recognizing T-cells, thus preventing escape mutant tumor cells that are not positive for the CAR target (“Conditioning of Patients Receiving Car T-cell Therapy” and “Future Considerations” section).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that the GPC2-specific CAR is administered in combination with a immunotherapeutic agent such as a checkpoint blockade antibody. One of ordinary skill in the art would have been motivated to do so since combining CAR T-cells with other immune therapeutics such as checkpoint blockade antibodies or oncolytic viruses can increase their survival in the tumor lesions and support efficacy. Therefore, one of ordinary skill in the art would have expect that combining the GPC2-specific CAR of the co-pending claims with an immunotherapeutic agent such as a checkpoint blockade antibody can more effectively treat a GPC2-expressing cancer in a subject.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 9, 11, 15-23, 30, 33, 38, and 40 of copending Application No. 18716387, as applied to claims 1-5, 12, 15, 30, and 76 above, in view of DeNardo et al (DeNardo, David G et al. “Immune cells as mediators of solid tumor metastasis.” Cancer metastasis reviews vol. 27,1 (2008): 11-8. doi:10.1007/s10555-007-9100-0), hereinafter DeNardo.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the GPC2-expressing cancers are metastatic cancers.
However, DeNardo teaches that metastatic tumors represent the greatest threat to cancer patient mortality. For example, when breast cancer is diagnosed early and metastases are not present, 5-year survival is >88%; however, if metastases are also present, long-term survival is significantly diminished (~10%) (first paragraph under “The Problem of Metastasis”). Thus, subjects having metastatic cancers represent a patient population that would benefit from anti-cancer treatment.
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that the GPC2-expressing cancer to be treated is a metastatic cancer. One of ordinary skill in the art would have been motivated to do so since metastatic tumors increase cancer patient mortality; thus, subjects having metastatic cancers represent a patient population in need of anti-cancer treatment such as with the GPC2-specific CAR T cells of the co-pending claims. Therefore, one of ordinary skill in the art would have expect that the method of the co-pending claims can be used to effectively treat a GPC2-expressing cancer that is metastatic.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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