DETAILED ACTION
Claims 1-2, 6-7, 10-11, 14, 16-18, 21, 26-30, and 34-40 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The Examiner notes a minor typo regarding the IDS submitted on 2/3/2025:
Regarding reference C31, “Levinger” should read “Leninger”.
Appropriate correction has been made by Examiner.
Drawings
The drawings are objected to because:
Instant Figure 2 is a grayscale drawing of isoplexis single cell secretome data showing polyfunctionality of CD5 CAR-NK cells with DAP10 costimulatory domain.
Instant Figure 2A describes a bar graph showing percent polyfunctionality of different CD5 CAR-NK cells compared to non-transduced NK cells, wherein the legend describes different number of proteins in different grayscale gradients. However, it is difficult to discern between “3 proteins” and “4 proteins” on the bar graph.
Instant Figure 2B describes a bar graph showing the polyfunctionality strength index among the different CD5 CAR-NK cells compared to non-transduced NK cells, wherein the legend describes functional properties in different grayscale gradients. However, it is difficult to discern among “Effector”, “Inflammatory” and “Stimulatory” on the bar graph.
Therefore, the figure is not able to be interpreted as currently drawn in grayscale.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112(a)
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.
Claim 37 is 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 killing cancer cells in an individual, comprising administering to the individual an effective amount of immune cells harboring the vector comprising the polynucleotide encoding the fusion protein comprising a CD28 transmembrane (TM) domain, DAP10 costimulatory (CS) domain and CD3ζ, does not reasonably provide enablement for the full scope of the claimed method of killing cancer cells in an individual comprising administering to the individual an effective amount of nonimmune cells harboring the vector comprising the polynucleotide encoding the said CAR. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation."' (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (A) The nature of the invention; (B) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Instant claim 37 recites a method of killing cancer cells in an individual, comprising administering an effective amount of any type of cells, including nonimmune cells, harboring the vector comprising the polynucleotide encoding the fusion protein comprising a CD28 TM domain, DAP10 CS domain, and CD3ζ. The instant claimed method encompasses administering any immunological and non-immunological cells, many of which do not have the ability to mount a cytotoxic response as required by the claim.
The breadth of the claims
Instant claim 37 places no limitation on the type of cell administered. The recited “cells harboring the vector” encompasses any cell capable of harboring a vector, including non-immune cells, such as fibroblasts, epithelial cells, and immortalized laboratory cell lines. Furthermore, instant claim 1 does not require an antigen binding domain. In fact, the limitation of adding “one or more antigen binding domains” is recited in instant claim 6, and the specification expressly describes the antigen binding domain as an optional further feature of the receptor (see page 2, ¶ [0009] of the specification).
The amount of direction provided by the inventor/the existence of working examples
The examples of the instant disclosure used constructs that are functionally characterized as a targeted CAR comprising an antigen binding domain, either CD5 scFv or a CD27 extracellular domain directed to CD70 (pages 62-63, §Example 1). Figures 1-5 and 7-14 disclose CD5-targeted CAR-NK cells, wherein Figure 6 discloses CD70-targeted CAR-NK cells. Additionally, all of the examples use NK cells derived from the cord blood. Furthermore, the in vivo anti-tumor data are limited to a PDX mantle cell lymphoma model using CD5 CAR-NK cells (Fig. 5), an NSG AML model using THP-1 and CD70 CAR-NK cells (Fig. 6), and a CCRF-CEM T lymphoblastoid model using CD5 CAR-NK cells (Figs. 8-10) (pages 63-64, ¶ [0255]-[0256]; page 64, ¶ [0259]-[0261]). However, there is no working example in which a construct lacking an antigen binding domain kills cancer cells, in vitro or in vivo. There is no guidance in the instant disclosure as to how such cells would be made to exert cytotoxic function against tumor cells.
The state of the art/the level of predictability in the art
At the time of filing, a chimeric antigen receptor (CAR) was defined as recombinant receptors providing both antigen-binding and T-cell-activating functions (page 388, Abstract; Sadelain et al, “The Basic Principles of Chimeric Antigen Receptor Design”, April 10 2013, Cancer Discov, 3(4):388-398; hereinafter Sadelain), and as receptors for antigen that, in a single molecule, redirect the specificity and function of T lymphocytes and other immune cells (page 388, §Introduction). Sadelain also teaches that effector capacity was expected to vary with the cell chosen, wherein various T cell subsets, T-cell progenitors, and other immune cells, such as natural killer cells can be targeted with a CAR (page 388, §Introduction), and that essential CAR-dependent functions cannot be investigated in leukemic or immortalized T-cell lines, but only in primary T cells (page 389, right column, §CAR Signaling, second paragraph). Sadelain further teaches that the antigen binding domain is not optional and is not merely a targeting convenience. Sadelain states that the antigen binding moiety of the CAR is not only a targeting device but also integral to CAR function, which is not solely defined by the signaling components incorporated into the cytoplasmic domain (page 389, left column, §CAR Targeting, third paragraph). Every construct catalogued across the dozens of targets surveyed comprises such a binding moiety, whether an scFv, Fab, or a natural ligand (page 389, left column, §CAR Targeting, second paragraph; Table 1).
Benmebarek (Benmebarek et al, “Killing Mechanisms of Chimeric Antigen Receptor (CAR) T cells”, Int. J. Mol. Sci., March 14, 2019, 20(1283):1-21; hereinafter Benmebarek) teaches that the machinery for destroying a target cell, e.g. killing a cancer cell, depends on the host cell and is lineage-restricted. Benmebarek explains that killing a cell follows formation of a stable immune synapse, which is the prerequisite for inducing target cell death after which lysis proceeds by pathways the effector cell itself possesses (pages 3-4, §Non-Classical Immune Synapse Formation; Fig. 3). Benmebarek further teaches that cells bearing the same receptor do not kill equally, disclosing that CD4+ T cells carry substantially less intracellular perforin and granzyme than CD8+ T cells so that killing a diseased cell by CD4+ CAR-T cells is delayed or requires more effector cells to reach comparable lysis (page 5, third paragraph). MacDonald (MacDonald et al, “Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor”, J Clin Invest., 2016, 126(4):1413-1424; hereinafter MacDonald) expressed an HLA-A2-specific second generation CAR comprising a scFv, CD28 and CD3ζ in both human regulatory T cells and conventional T cells. Conventional T cells comprising the said CAR robustly induced caspase 3 activation, while regulatory T cells comprising the identical CAR killed substantially less at every ratio tested and produced negligible caspase 3 activation against HLA-A2+ PBMC targets (page 1417, §CAR-stimulated Tregs have minimal cytotoxic activity; Fig 6). MacDonald further teaches that specificity of the binding domain, not mere presence of a CAR, governs function, wherein MacDonald discloses that regulatory T cells comprising an irrelevant CAR, e.g. a HER2-CAR, failed to suppress proliferation in the presence of HLA-A2. Only the A2-CAR Tregs, in the presence of HLA-A2, suppressed proliferation (page 1416, right column, first paragraph).
Accordingly, one of ordinary skill in the art would not have expected that any type of cell expressing a CAR without an antigen binding domain would kill cancer cells.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
To practice the full claimed scope, the skilled artisan must determine, for each untargeted construct and for each of the cell types, whether the administered cells kill cancer cells in a subject, and if not, what further modifications would be needed to perform the required function. Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict which combination of construct(s) and cell(s) would have predictably killed cancer cells when administered to an individual by using the instant claimed methods. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to develop a method which accurately predicts the specific combination of constructs and cells that performs the required function of killing cancer cells. Applicant is enabled for method of killing cancer cells in an individual, comprising administering to the individual an effective amount of immune cells harboring the vector comprising the polynucleotide that encodes the said CAR.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. Instant claim 37 recites administering any type of cells harboring the polynucleotide encoding the said CAR without limitation as to cell type, encompassing cell types, such as fibroblasts or epithelial cells, that do not possess the cytolytic mechanism to kill diseased cells. Therefore, a skilled artisan would be left to determine by trial and error which of the many cell types encompassed by the instant claim can perform the recited method of killing cancer cells. As such, instant claim 37 is determined to not meet the scope of enablement requirement of 35 USC § 112(a).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 6-7, 10-11, 14, 16-17, 21, 26-30, and 36-40 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Whitfield et al (WO2019036724A2, Priority to 8/18/2017, IDS entered on 11/21/2024), hereinafter Whitfield.
Regarding instant claims 1-2 and 10-11, Whitfield teaches nucleic acid sequences encoding chimeric antigen receptors (CARs) comprising a CD28 transmembrane (TM) domain, one or more costimulatory (CS) domain, e.g. DAP10, 4-1BB, NKG2D, and a CD3ζ intracellular signaling (ICS) domain (page 1, Abstract; page 13, ¶ [35]-[38]; page 14, ¶ [40]).
Regarding instant claims 6-7 and 37, Whitfield teaches that the CARs comprise an antigen binding (AB) domain that binds to a target molecule expressed in diseases-associated macrophages (DAMs) and can be used for treating diseases associated such as cancer (page 41, ¶ [172]). Accordingly, Whitfield also teaches that the CAR-expressing immune cells may also be used in a method of treating various cancers (pages 100-101, §Therapeutic applications; page 104, ¶ [442]).
Regarding instant claims 14-17, Whitfield teaches that the CARs may co-express homing molecules, e.g. CCR4, to increase trafficking to the disease site (page 80-81, [344]).
Regarding instant claims 21 and 26, Whitfield teaches vectors comprising the
nucleic acid sequence encoding the CAR, and cells expressing the CARs (page 1, Abstract; pages 84-87, §Vectors; pages 88-99, §Cells).
Regarding instant claims 27-30, 36, 38-40, Whitfield teaches that cells expressing the CARs are NK cells derived from the bone marrow or blood (page 30, ¶ [130]; page 89-92, ¶ [378]-[389]).
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 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.
Claims 18 and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Whitfield et al (WO2019036724A2, Priority to 8/18/2017, IDS entered on 11/21/2024), hereinafter Whitfield.
The teachings of Whitfield are discussed above in the 102 rejection.
However, Whitfield does not explicitly teach that the polynucleotide further encodes a cytokine, e.g. IL-15 as recited in instant claims 18 and 34-35.
Whitfield, however, teaches that persistence may be facilitated by the administration of cytokines, e.g. IL-15, to the cells comprising the nucleic acid encoding the CARs (page, ¶ [356]). Furthermore, Whitfield discloses that cells comprising the nucleic acid encoding the CARs are incubated in the presence of stimulating conditions or agents, such as cytokines, for activation and expansion (page, ¶ [414]-[417]).
Regarding instant claims 18 and 34-35, it would have been obvious for a person of ordinary skill in the art at the time of filing to modify the CAR comprising a CD28 TM domain, DAP10 CS domain, CD3ζ ICS domain to include further comprising a sequence encoding IL-15 to enhance cellular activity, expansion and persistence as disclosed by Whitfield. This is obvious, because Whitfield teaches that persistence, activation, and expansion may be enhanced by the administration of cytokines, e.g. IL-15, to the cells comprising the nucleic acid encoding the CARs. Thus, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant polynucleotide or cells comprising the instant polynucleotide encoding a CAR comprising a CD28 TM domain, DAP10 CS domain, CD3ζ, and the cytokine IL-15.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 6-7, and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,310,988B2 (Rezvani et al; hereinafter ‘988). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1-2 and 6-7, claim 1 of ‘988 teaches a chimeric antigen receptor (CAR) comprising an anti-B-cell maturation antigen (BCMA) antibody or antigen binding fragment thereof, a hinge domain, a transmembrane domain, a DAP10 costimulatory domain, and at least one intracellular signaling domain, wherein the CAR comprises a specific amino acid sequence. Claims 2 and 3 teach a polynucleotide encoding the said CAR comprising a specific nucleic acid sequence.
Therefore, the claims of ‘988 render the instant claims obvious.
Claims 1-2, 6-7, 10-11, 14, 16-18, 21, 26-30 and 34-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 12, 14-26, 30-38, 40-60, 64, 97-98, 112-115, 117-129, 133-141, and 143-150 of copending Application No. 18/700,483 (Daher et al, US20250074950A1; hereinafter ‘483);
claims 1, 17, 20, 24-25, 27-31, 39, 43-47, 49-50, 83-97, and 100-105 of copending Application No. 18/574,539 (Rezvani et al, US20240325444A1, hereinafter ‘539);
claims 1, 8, 15-16, 22-23, 28, 31-33, 40, 45-49, 60-74, and 77-82 of copending Application No. 18/560,791 (Rezvani et al, US20240252539A1, hereinafter ‘791); and
claims 1-3, 19, 28, 33-36, 39-51, and 65-69 of copending Application No. 18/552,727 (Rezvani et al, US20240189357A1, hereinafter ‘727).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1-2 and 6-7, the claims of the copending applications are directed to a polynucleotide that encodes a chimeric antigen receptor (CAR) comprising (i) an antigen binding domain that targets a tumor antigen; (ii) a CD28 transmembrane domain; (iii) a CD3ζ intracellular domain; (iv) a DAP10 intracellular domain. Regarding instant claims 10-11, the claims of the copending applications teach that the polynucleotide encoding the said CAR comprises two or more intracellular domains, e.g. 2B4, DAP12, 4-1BB, NKG2D, DAP10, and CD28. Regarding instant claims 14-18, the claims of the copending applications teach that the polynucleotide encoding the said CAR further encodes an additional polypeptide of interest, wherein the polypeptide of interest is IL-15, a cytokine that enhances proliferation and expansion. Regarding instant claims 21 and 26-30, the claims of the copending applications teach a vector comprising the polynucleotide encoding the said CAR, and an immune cell comprising the polynucleotide comprising the said CAR, wherein the immune cell is a NK cell derived from cord blood, peripheral blood, cell line, etc. Regarding instant claims 34-36, the claims of the copending applications teach a population of NK cells comprising the polynucleotide encoding the said CAR and expressing a recombinant cytokine, e.g. IL-15. Regarding instant claims 37-40, the claims of the copending claims further teach a method of killing cancer cells in an individual, comprising administering to the individual an effective amount of cells comprising the polynucleotide encoding the said CAR.
Therefore, the claims of the copending applications render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Friday 7-2.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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