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 .
Election/Restrictions
1. Applicant’s election without traverse of Group I, encompassing claims 1, 2, 9, 31-32 and 34, in the reply filed on August 28, 2025 is acknowledged. In response to the species election requirement, Applicant has elected SEQ ID NOs: 10, 11 and 12 for species A; SEQ ID NOs: 1, 2 and 3 for species B; SEQ ID NO: 22 for species C; and SEQ ID NO: 20 for species D. Applicant indicates that claims 1, 2, 9, 31-32 and 34 read upon the elected species.
Upon further consideration, the species of SEQ ID NO: 18 (in selection C, claim 2) and SEQ ID NO: 9 (in selection D, claim 9) will be rejoined.
2. Claims 16-17, 24, 33, 35, 50, 68-69, 78-80, 84 and 90-92 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 28, 2025.
3. Claims 1, 2, 9, 31-32 and 34 are under examination in the current office action.
Information Disclosure Statement
4. The information disclosure statements (IDSs) filed 09/06/2023 and 08/28/2025 have been considered and the references therein are of record.
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.
5. Claims 1-2, 9, 31-32 and 34 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and, (8) the breadth of the claims. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The claims are drawn to an isolated immune cell comprising an exogenous T cell receptor (TCR) having affinity for an Ataxia-Telangiesctasia Mutated (ATM) peptide, said exogenous TCR comprising an alpha chain and a beta chain, said alpha chain comprising (i) the amino acid sequences set forth in SEQ ID NOs: 10, 11 and 12, or (ii) the amino acid sequences set forth in SEQ ID NOs: 10 and 11 with no more than one amino acid modification and the amino acid sequence of SEQ ID NO: 12 with no more than two amino acid modifications, wherein said modifications can be substitutions, deletions or additions; and said beta chain comprising (i) the amino acid sequences set forth in SEQ ID NOs: 1, 2 and 3, or (ii) the amino acid sequences set forth in SEQ ID NOs: 1 and 2 with no more than one amino acid modification and the amino acid sequence of SEQ ID NO: 3 with no more than two amino acid modifications, wherein said modifications may be substitutions, deletions or additions. Dependent claims recite that: the alpha chain comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 18 or 20, and the beta claim comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 9 or 20; the immune cell is a T cell; the expression of the endogenous TCR alpha and beta chain coding sequences are downregulated in said T cell; and the ATM peptide comprises a valine, cysteine, or serine at the position corresponding to 2695 in the human ATM protein. Thus, the claims are broadly drawn to an immune cell comprising an exogenous TCR having affinity for an ATM peptide, wherein the CDR sequences of the alpha and beta chains of the TCR are not fully defined and may contain substantial variability.
The nature of the invention is the production of “[i]mmune cells (e.g., T cells) modified to include an exogenous TCR having affinity for an ATM peptide (e.g., a mutant ATM peptide)…[which] can be used to treat a mammal having cancer. Mutations in ATM…are commonly found, for example, in ovarian, endometrial, kidney, pancreas, gastric, bladder, lung, breast, brain, liver, cervical, uterine, prostate, or hematopoietic malignancies.” (p. 3 lines 12-20). In particular, the specification states at p. 3 lines 21-24, that the “document features an isolated immune cell (e.g., a T cell) comprising an exogenous TCR having affinity for an ATM peptide (e.g., a mutant ATM peptide comprising a valine, alanine, cysteine, or serine at the position corresponding to 2695 in the human ATM protein).”
The sole working example describes an experiment in which codon optimized nucleic acid molecules encoding a TCR against ATM were introduced into donor T cells, and the TCR-transfected T cells were co-cultured with dendritic cells expressing wildtype ATM or mutated forms of ATM (G2695V, G2695A, G2695C or G2695S). “After overnight incubation, the supernatant was assessed for production of interferon-gamma (IFN-g) using an ELISA. It was found that the introduced nucleic acids encoding TCRs conferred mutation reactivity without reactivity against the wild-type form of ATM” (p. 42 and Fig. 9A). Figure 9A shows that the highest IFN-g levels were produced by the TCR-transfected T cells cultured with ATM G2695V mutant-expressing dendritic cells, followed by G2695A, G2695C and G2695S mutants. There are no working examples demonstrating the use of such T cells for the treatment of cancer.
Importantly, in order to be able to successfully use the claimed immune cells comprising the recited TCR, such as for the treatment of cancer in a mammal, the skilled artisan would need to know:
which MHC class I or class II MHC binding peptide epitopes are naturally produced from proteasomal cleavage of the ATM protein;
which of said naturally-occurring MHC class I or class II MHC binding peptide epitopes can in turn bind any given MHC class I allele or MHC class II allele with sufficient stability to be presented on the cell surface; and
for any such peptide:MHC complex that satisfies (i) and (ii) above, is such a hypothetical peptide:MHC complex expressed on the surface of a given cancer cell that also expresses ATM, and critically, is this particular peptide:MHC complex one that is recognized by the claimed TCR-expressing immune cells?
However, the instant specification does not provide sufficient direction or guidance for the skilled artisan to identify (i)-(iii) above, and given the complexity of the task, far more than routine experimentation would be required of the skilled artisan to discover the relevant peptide epitopes, if any, that could be used for the purpose of making and using the immune cells of the invention.
The prior art teaches that there are many different ATM mutations that can be found in various types of cancer, and that some types of cancer are due to germline mutations within the ATM gene while others are the result of somatic mutations (see Choi et al. Mol Cancer Ther. 2016, 15(8):1781-1791). The prior art recognizes only one example of a type of cancer in a patient, B-cell chronic lymphocytic leukemia (B-CLL), in which the patient’s B-CLL7 tumor expressed an ATM mutation of pre-germinal origin at position 2695 (G2695A) (see Table 1 at p. 301 of Stankovic et al. Blood, 2002, 99(1):300-309). Notably, this mutation resulted in a reduction in the ATM protein, and nearly two dozen different ATM mutations were found in the tumors of other patients. Accordingly, the prior art does not recognize an ATM mutation at position 2695 as being correlated to any particular type of cancer, or even with B-CLL, and is silent with respect to its presence in, or association with, any other type of cancer or lymphoma.
The prior art also recognizes that the repertoire of MHC class I and class II alleles is vast (see, e.g., Russell et al. US 2008/0219956; listed on 08/28/2025 IDS), wherein there are many hundreds of HLA-DR, -DQ and -DP MHC class II alleles expressed in the human population (see Figs. 4A-M of Russell), not to mention the many additional hundreds of predominantly 7-11 amino acid binding MHC class I alleles (see Figs. 3A-Z of Russell). Furthermore, while Table 1 of the instant specification provides four exemplary mutant ATM peptides, the specification does not disclose which of these peptides, if any, would be presented (naturally) on the cell surface in a peptide:MHC complex. Likewise, despite stating that “[a] mutant ATM peptide…can be, for example, from 8 to 30 amino acids in length” (p. 15), and providing various “exemplary” peptides of 9 amino acids in length in Table 1, the specification does not provide any direction or guidance as to any particular ATM peptide epitope that satisfies conditions (i)-(iii) as laid out above.
Furthermore, merely because any given mutant ATM peptide epitope may bind some particular MHC class I homomer+b or class II dimer with sufficient affinity and specificity to be presented and recognized on the surface, e.g., of dendritic cells, this does not necessarily mean that same mutant ATM-derived peptide will also be expressed on the surface of any given cancer cell in the context of some MHC class I homomer+b or class II dimer. Merely knowing the mutant ATM is expressed in a given cancer cell types does not provide the skilled artisan with any information about whether said cancer cell will also produce any given mutant ATM-derived peptide and then present said mutant ATM peptide in the context of some MHC class I homomer+b or class II dimer on the cancer cell surface such that immune cells. There is insufficient guidance to establish, for example, that CD8+ cytotoxic T-cells expressing a TCR comprising the alpha chain CDRs of SEQ ID NOs: 10-12 and the beta chain CDRs of SEQ ID NOs: 1-3, will bind an ATM peptide:MHC complexes on said cancer cells with sufficient affinity to be capable of recognizing and killing the cancerous cells and thereby treat cancer in a subject as disclosed.
As described by Bossi et al. (OncoImmunology, 2013, 2:11, e26840; listed on 08/28/2025 IDS), T-cell mediated cytolytic killing of cancer cells depends on, inter alia, the affinity of T-cells for the cognate antigen and on the extent of cancer cell induced down-regulation of MHC class I (see p. e26840-4, col. bridging paragraph). Thus, there are a number of different factors which could have major effects on the ability of the skilled artisan to treat any given cancer by administering, for example, an immune cell comprising an exogenous TCR having affinity for a particular mutant ATM peptide sequence, which mutant ATM peptide may or may not even be present within cancer cells/tissues of a subject having cancer.
Similarly, Nakatsugawa et al. (Int J Oncology, 2011, 39:1041-1049; cited on 08/28/2025 IDS) teaches the production and screening of cytotoxic T lymphocyte (CTL) clones reactive to specific HLA-A*0201-restricted epitope peptides of a carcinoma antigen (Lengsin protein) for the induction of tumor-reactivity, wherein the peptide epitopes were selected by computerized algorithm based on a permissive HLA-A*0201 binding motif (see abstract). Nakatsugawa found that one of the peptide-specific CTL clones failed to recognize tumor cells expressing Lengsin, even though this same clone showed efficient recognition against HLA-A*0201+ target cells in the presence of exogenously added peptide. The authors concluded that “CTLs induced by reverse immunology approaches often fail to recognize HLA-matched tumor targets expressing specific genes” (p. 1048, top of left column). Possible explanations for this failure were stated to include (p. 1048): (1) induced CTLs might not have sufficient avidity to recognize a limited number of naturally presented peptides on the surface of tumor cells; and (2) the predicted candidate peptides might not be processed and presented on the surface of the targeted tumor cells. Thus, as can be seen, the prior art acknowledges unpredictability when it comes to the production and therapeutic use of peptide antigen-specific immune cells for the treatment of cancer.
Furthermore, even if the instant specification taught (i)-(ii) as laid out above, the prior art recognizes that, in general, alpha and beta chains comprising six CDRs are required to create the TCR peptide-MHC binding site (see Janeway et al. Immunobiology, 5th Ed., Garland Science (2001) pp. 106-108, 117-118 and 260-263; cited on 08/28/2025 IDS), whereas the instant claims encompass TCRs in which the CDRs may contain one or more modifications to their amino acid sequences. In particular, the art teaches that there is a bias where the TCR CDR3 regions are predominantly involved in peptide binding, and the TCR CDR1 and CDR2 regions are predominantly involved in MHC binding, although this bias is not absolute (see Janeway at pp. 118 and 262, as well as the Discussion section of Goyarts et al. Mol. Immunol. 1998, 35(10):593-607; cited on 08/28/2025 IDS). This canonical diagonal interaction of the TCR with peptide-bound MHC is recognized, for instance, in Garcia et al. (Cell, 2005, 122:333-336; cited on 08/28/2025 IDS). Garcia theorizes that the CDR1 and CDR2 interactions with MHC are dependent on the CDR3 interactions with the peptide bound to the MHC, and therefore “there may be as many TCR/pMHC orientations as CDR3 sequences” (see Garcia, p. 336, col. bridging paragraph).
Because the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a polypeptide’s amino acid sequence while still retaining similar structure and/or function requires detailed knowledge and guidance with regard to the ways in which amino acid residues within the sequence relate to the structure and function of the polypeptide. In the instant case, a detailed disclosure of which amino acid residues within the TCR sequence, and in particular its alpha and beta CDR regions, are tolerant of modification and which must be conserved (i.e., expectedly intolerant to modification) is lacking within the instant application and in the prior art generally. Thus, again even if the present specification provided direction on factors (i)-(iii) as discussed above, given the lack of guidance on modifying amino acid residues within the CDRs of the TCR, undue experimentation would be required of the skilled artisan to determine which amino acid residues or CDR sequences were tolerant of modification such that the resultant variant TCRs not only would retain sufficient binding affinity for their cognate ATM peptide:MHC complex but also would be capable of inducing an appropriate immune response to facilitate the treatment of cancer.
The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In view of the breadth of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability as evidenced by the prior art, and the amount of required experimentation, it is the examiner’s position that undue experimentation would be necessary for a skilled artisan to make and use the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to practice the claimed invention in a manner reasonably correlated with the scope of the claims. Without sufficient guidance, determination of which immune cells comprising exogenous TCRs having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir., 1988).
Conclusion
6. No claims are allowed.
Advisory Information
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675