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 .
Claims 1-4, 6, 8-10, 13-14, 22-24, 33-34, 37, and 40-43 are pending as amended 9/14/23, and are considered herein.
Formalities:
The drawings of 9/14/23 are accepted.
The specification of 9/14/23 is accepted.
The IDS filing of 5/10/24 and references therein have been considered and a signed copy of the same is supplied herewith.
Applicant’s priority is understood to be a CON to 16/721,156, now US PAT NO 11,771,719, filed 12/19/2019, which is a CON of 15/970,605, now US PAT NO 10,548,922, filed 5/3/2018, which is a CON of PCT/US2016/060273, filed 11/3/2016, which claims priority 62/250,561, filed 11/4/2015.
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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Claims 1-4, 6, 8-10, 13-14, 22-23, 24, 33-34, 37, and 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,771,719. Although the claims at issue are not identical, they are not patentably distinct from each other because
Claims 1 and 13: the patent teaches administering to an HSPC, a nucleic acid that downregulates expression of an endogenous gene/portion thereof, the nucleic acid being a CRISPR system (Claim 1). The downregulated gene necessarily comprises an antigen that is targeted by a CAR, and the claim itself teaches that one is doing to protect an HSPC from CAR-T cell therapy (Claim 1).
Claim 2: As shown in Claim 1, the HSPCs are protected from the CAR T cells, in a subject with myeloid disease, and thus, it is taught from this to administer the same CAR T cell therapy to the subject, as well as the HSPCs.
Claims 3-4: the nucleic acid capable of downregulating the endogenous gene is a CRISPR system, and may be a Cas expression vector and gRNA (e.g., Claims 2-3).
Claim 6: Claim 1 teaches an inducible promoter.
Claims 8 and 22: Claim 4 teaches a tumor antigen.
Claims 9 and 23: the gene is expressed on a tumor cell targeted by a CAR (Claim 5).
Claims 10 and 24: CD33 and CD123 are taught (Claim 6).
Claim 14: Claim 1 teaches the HSPC is autologous, and thus, is necessarily obtained from the subject in need of CAR T cell therapy.
Claim 33: the cells so-made are necessarily in a buffer with water, which is a pharmaceutically acceptable carrier.
Claim 40
Claim 41
Claims 34 and 37: as shown above, the method of protecting an HSPC from a CAR T cell therapy is claimed. Claim 1 also teaches that the HSPCs are protected from CAR T cells in a subject, where the subject has a myeloid disease. As such, it is inherent in the claim that the HSPCs and CAR T cell therapy are administered to the subject with myeloid disease.
Claims 42 and 43: The claims teach one disease which may be treated is acute myeloid leukemia (AML).
Thus, in light of the patent, Artisan would be motivated to make the invention, and administer to the same to a subject with myeloid disease. The Artisan would make it and expect success, as it is claimed subject matter and for the same purpose.
Claims 1-4, 8-10, 13-14, 22-24, 33-34, 37, and 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,548,922. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 1: Claim 14 teaches treating AML in a subject, comprising administering CAR-T cell therapy to the CD33 marker, and administering HSPCs resistant to CD33, which comprise and insertion/deletion in an endogenous CD33 coding sequence. Further, Claim 14 utilizes an introduction of an insertion/deletion in SEQ ID NO: 4, which results in a portion of CD33 to not be expressed as it is normally.
Claim 2: the CAR-T cell therapy is administered (e.g., Claim 14).
Claim 3: Claim 14 teaches CRISPR systems.
Claim 4: The essential written description for the CRISPR system is that such vector and guide are utilized (e.g., paragraph 6).
Claim 8: CD33 is a tumor antigen.
Claim 9: in AML the CD33 is the tumor antigen expressed on the tumor cell.
Claim 10: CD33 is taught.
Claim 13: As shown above, the HSPC is so-made (e.g., Claim 14). Claim 1 also teaches generating HSPCs by such method.
Claim 14: autologous HSPCs are taught (e.g., Claim 12).
Claim 22-24: CD33 is taught, which is such tumor antigen, and is targeted by the car (e.g., Claim 14).
Claim 33: the compositions are administered to the subject, and are required to be in an aqueous solution, and thus, it is with a pharmaceutically acceptable carrier.
Claims 34 and 37: as shown above, the modified HSPCs and CAR T cells are administered to treat AML.
Claims 42-43: AML, a leukemia, is taught.
Thus, in light of the patent, the Artisan would practice the invention. The Artisan would do so to treat AML. The Artisan would expect success, as it claimed subject matter and covered by essential written description for the claims.
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, 3-5, 8-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
As seen by non-rejected Claim 2, the rejected claims are generic for the simple protection of an HSPC from CAR T cell therapy, comprising administering the modified HSPC to the subject, without an administration of CAR T cell therapy, as emphasized by Claim 2.
The specification the process of providing HSPCs which do not an antigen which is an autoantigen, to thereby allow CAR T cell therapy against that autoantigen. E.g., p. 2, paragraph 4. Thereby, the HSPCs can regenerate cells without such antigen, to replace the cells lost that contain the autoantigen, allowing targeting of antigens which are normal, but would damage the body and cause aplasia. The sole example is the loss of CD33 in targeting an acute myeloid leukemia. E.g., Example 1.
With regard to the Art, the Examiner has found no prior, no any post-filing, Art where the modified cells, deleted for an auto-antigen, are administered without a concurrent CAR T cell therapy. With regard to the same, there is very little prior art even to providing the stem cells lacking the targeted antigen of the CAR-T cells. However, Bi, et al. (2022) “Chimeric Antigen Receptor T Cell Therapy for Acute Myeloid Leukemia”, Hematology/Oncology and Stem Cell Therapy, 15: 131-36 (admittedly post-filing, but demonstrating the lack of paucity of art to these methods), teaches that the Art, at least of 2018, recognized the use of CD33 KO bone marrow transplant in animal models being resistant to CD33 CAR-T cells, enabling anti-tumor activity in this instance, and recognizing that the CD33 deficient cells were fully functional suggesting CD33 may not be essential for normal cellular function and development, but hidden functional deficits may be present and as-yet unidentified (p. 135, col. 2, paragraph 2).
Thus, it is the Artisan recognized there is no such protection, without the concomitant CAR T cell therapy that attacks the same antigen missing.
Therefore, the Artisan would not have recognized Applicant to have been in possession of the invention as claimed.
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 1-4, 6, 8-10, 13-14, 22-24, 33-34, 37, and 40-43 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 treating AML with autologous or allogeneic CAR-T and HSPCs, wherein the CD33 gene is nonfunctional in the HSPC, does not reasonably provide enablement for any other form of therapy, xenogenic cells, or any modified gene which is expressed without the CAR-T recognizing antigen in it. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The claims are broad for the scope of diseases as emphasized by Claims 40-43, the use of xenogenic cells, the antigen-providing genes, and modified forms of the gene that do not express the antigenic region but express the gene.
The specification describes AML as cancers that do not have markers specific to them, i.e., all markers commonly found, and thus, are also present in normal cells of the subject. And, therefore, the use of CAR-T cell therapy to treat these cancers is difficult, because of the absence of a specific target. Therefore, targeting these tissues with CAR-T cell therapy necessarily would also destroy normal cells of the body. However, Applicant shows that CD33 can be targeted by the CAR-T cell therapy, along with administration of HSPCs that make up the hematopoietic lineages lost (i.e., the use of HSPCs modified to NOT express CD33). In the examples, human HSPCs modified by CRISPR to not express CD33 are administered NSG (i.e., severely immunocompromised) mice, along with the CAR-T cells targeting CD33. The Examples demonstrate knockout of the CD33 in the HSPCs did not lead to severely altered cell type differentiation, or inadequate cells once made. Thus, it is shown in the mouse model, the CAR-T cells could treat the AML, and replace the normal tissues list from off-target (non-cancer) cell destruction. In addition, a prophetic showing of TBI, and CD33-/- macaque HSPCs administered, to prophetically find an analysis of CD33 expression on the macaque cell populations. However, this contributes little to show therapy in macaques.
With regard to the breadth of diseases, the specification teaches a wide range of cancers and autoimmune diseases (e.g., p. 4, last paragraph). There is no discussion as to which markers may be targeted and provided as antigen-absent HSPCs to also develop into the cell lineages required in the proper amounts to replace the lost tissues to each of the diseases being attacked, and no discussion of whether the absence of the marker would be detrimental to the reconstitution of the lineages. With even the scope of cancers, no other cancers are taught as being CD33+, and thus, a marker must be determined in each case. The same target needs to be determined as to which ones may be deleted and/or which antigenic regions of the target marker may be removed and yet still replace the cells lost. Further, the Art recognized that immune suppressor cells are often present in the milieu of cancers (e.g., Albeituni, et al. (2013) “Hampering the immune Suppressors: Therapeutic Targeting of Myeloid-Derived Suppressor Cells (MDSC) in Cancer”, Cancer Journal, 19(6): 490-501, abstract). Albeituni explores the art, and finds that MDSCs have no universal marker for immunosuppression (Conclusion), and that even those in cells with CD33+ markers, those cells are only a subset of the immunosuppressor cells present (e.g., Introduction). The Artisan would not reasonably predict if removing only a subset of immunosuppressor cells would even have a measurable effect on the cancer, particularly given that the cancer itself may not CD33+ cells. Still further, even post-filing, the Artisan recognizes that while in the instance of CD33, CAR-T cells may be used in treating AML with administration of replacement CD33-deficient myeloid cells are fully functional, suggesting that CD33 may not be essential for normal cell function and development, however, hidden deficits in CD33 KO cells cannot be excluded (e.g., Bi, et al. (2022) “Chimeric Antigen Receptor T-cell Therapy for Acute Myeloid Leukemia”, Hematology/Oncology and Stem Cell Therapy, 15(3): 131-136, p. 135, col. 2, section 3.5). The same is backed up by the fact that Applicant’s own experiments were required to prove that CD33 knockout did not alter the differentiation of the HSPCs or cause them to be non-functional (e.g., pp. 47-48) Thus, the Artisan would not predict that any HSPC could be administered with any particular knock-out/knockdown of the antigenic region of the CAR-T targeting protein, as the breadth of markers on the cells would be detrimental to the development and replacement of somatic tissues. Lastly, xenogenic cells are known to be attacked with the powerful immune response of the innate and elicited immune system (e.g., Cascalho, et al. (2009) “Challenges and potentials of xenotransplantation”, Clinical Immunology, 15: 1215-22, e.g., 1216, col. 2, paragraph 1).
Thus, The Artisan would have to experiment to determine if, in any instance, for any marker/CAR-T target, any particular immunosuppressor cell is affected, if the cells would be replaced by functional stem cells so-differentiating, and even to find the markers to attack in each case. Further experimentation is required to determine which xenogenic cells would work with which subjects.
Such is considered undue experimentation, as it is required in order to determine the vast majority of working embodiments.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-4, 9, 13, 22-23, and 33 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mandal, et al. (2014) “Efficient Ablation of Genes in Human Hematopoietic Stem and Effector Cells using CRISPR/Cas9”, Cell Stem Cell, 15: 643-52 (cited by Applicant in IDS of 5/10/24, NPL reference No. 14).
Claim 1: Mandal teaches transplanting human CD4+ T cells and CD34+ HSPCs into recipients (p. 650, col. 2, paragraph 3), where the CCR5 and B2M genes have been ablated by plasmids administered that encode human CD4+ T cells and CD34+ HSPCs. A CAR may be designed which targets these genes, and thus, the claimed antigen domain targeted by a CAR is taught.
Claim 3: plasmids encoding the human CD4+ T cells and CD34+ HSPCs are taught (e.g., p. 650, col. 2, paragraph 2).
Claim 4: the system may be found in the cell, as when expressed the gRNAs and present and the expression vector expressing the Cas9.
Claims 8-9: B2M is known to be associated with several cancer types, e.g., multiple myeloma, chronic lymphocytic leukemia, and lymphomas (Official Notice).
Claim 13: Mandal teaches targeting B2M and CCR5 in human CD4+ T cells and CD34+ HSPCs, which lead to ablation of the genes (e.g., ABSTRACT), and it is taught that the cells are transfected with plasmids encoding Cas9-2A-GFP and gRNA targeting the genes (e.g., p. 650, col. 2, paragraph 2). Each of these proteins may be an antigen target for a CAR, and as such, the claim is anticipated.
Claim 14:
Claims 22-23: B2M is known to be associated with several cancer types, e.g., multiple myeloma, chronic lymphocytic leukemia, and lymphomas (Official Notice).
Claim 33: the composition is necessarily present in water and buffer, otherwise, it could not be transplanted into recipients (e.g., pp. 647-48, paragraph bridging).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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