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 final rejection. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 20, 2026 has been entered.
2. Claim 1 has been amended. Claims 1-5 and 9 are pending and under consideration.
Priority
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Examiner has established a priority date of June 09, 2023 for the claims 1-5 and 9 because the claims as currently constituted recite “wherein each polynucleotide encoding each of the first, second, and third exogenous NeoTCRs comprises two P2A peptides that are codon diverged relative to the other,” and a review of the parent applications does not reveal the claimed limitation. Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
New 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.
4. Claims 1-5 and 9 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. This is new matter rejection.
Claim 1 has been amended to recite “wherein each polynucleotide encoding each of the first, second, and third exogenous NeoTCRs comprises two P2A peptides that are codon diverged relative to the other”.
Applicant argues that support for the amendment can be found at paragraphs [0581]-[0582]. A review of the cited support reveals support for “the NeoTCR sequences are unlinked from the endogenous, CRISPR-disrupted TCRα polypeptide by self-cleavage at a P2A peptide” [0581], a second self-cleaving P2A sequence motifs is included in the NeoTCR expression gene cassette to separate encoded NeoTCRα and NeoTCRβ polypeptides [0581], and the two P2A are codon diverged relative to each other [0582].
However, this does not provide support for the polynucleotides encoding the NeoTCRs comprising the two P2A peptides, i.e. the NeoTCR polynucleotides would contain the two P2A peptides, e.g. by fusion of the two P2A peptides with the NeoTCR polynucleotides or in a mixture, not just encode the two P2A peptides. Thus, the limitation is new matter.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
5. Claims 1-5 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 has been amended to recite “wherein each polynucleotide encoding each of the first, second, and third exogenous NeoTCRs comprises two P2A peptides that are codon diverged relative to the other”. It is unclear if this limitation is intended to simply encompass wherein the NeoTCR polynucleotides encode the two P2A peptides or wherein the NeoTCR polynucleotides contain the two P2A peptides, e.g., by fusion of the two P2A peptides with the NeoTCR polynucleotides or in a mixture. Thus, the scope of the claim 1 is unclear and indefinite.
Dependent claims 2-5 and 9 are also rejected because they incorporate by reference the limitations of claim 1.
Rejections Maintained
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.
6. Claims 1-5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/050994 A1 (Yelensky et al. March 14, 2019, IDS), “ Yelensky” in view of WO 2019/084552 (Roth et al. May 2, 2019, IDS), “Roth” for the reasons of record, set forth below.
Yelensky teaches a method for identifying T-cells that are antigen-specific for at least one neoantigen that is likely to be presented on surfaces of tumor cells of a subject. Peptide sequences of tumor neoantigens are obtained by sequencing the tumor cells of the subject. The peptide sequences are input into a machine-learned presentation model to generate presentation likelihoods for the tumor neoantigens, each presentation likelihood representing the likelihood that a neoantigen is presented by an MHC allele on the surfaces of the tumor cells of the subject. A subset of the neoantigens is selected based on the presentation likelihoods. T-cells that are antigen-specific for at least one of the neoantigens in the subset are identified. These T-cells can be expanded for use in T-cell therapy. TCRs of these identified T-cells can also be sequenced and cloned into new T-cells for use in T-cell therapy. See abstract.
Yelensky teaches identifying neoantigens and neoantigen specific T-cells. Yelensky teaches for T-cell therapy, the neoantigen-specific T-cells undergo expansion and/or new neoantigen-specific T-cells are genetically engineered. Yelensky teaches to genetically engineer new neoantigen-specific T-cells for T-cell therapy, the TCRs of the neoantigen-specific T-cells that were identified in vivo are sequenced. Next, these TCR sequences are cloned into an expression vector. The expression vector is then transfected into new T-cells. The transfected T-cells are expanded and the expanded T-cells are infused into the patient for T-cell tumor therapy. See Example 10, ¶¶ 0424-0429, 0534-0541, 0607-0611 and Figure 29.
Yelensky teaches isolating the neoantigen specific TCRs from the same patient. See Fig. 29.
Yelensky teaches where the alpha and beta chains are expressed from a single construct or open reading frame, or cases wherein a marker gene is included in the construct, the construct may comprise a ribosomal skip sequence. The ribosomal skip sequence may be a 2A peptide, e.g., a P2A or T2A peptide. See ¶¶ 0593 or 0598 and Fig. 25.
Yelensky teaches that the codon usage may be optimized, such as for use in humans and increased translation efficiency. See ¶¶ 0229 and 0590.
Yelensky teaches patients can present at least three neoantigens. See Example 7B and Fig. 13B.
Yelensky teaches that the T cell therapy followed by vaccine therapy promotes persistence of the therapeutic T cells. See p. 135-[00613].
Yelensky teaches isolation and sequencing of TCRs of neoantigen specific T-cells. See pp. 116-117, Example 11, Figures 21 and 24 and Supplementary Table 6.
Yelensky teaches identification neoantigens from different genes to various MHC alleles. See ¶¶ 0179-0186, Example 10 and Tables, 2, 3 and 5. Yelensky teaches
Yelensky teaches multiple neoantigens that are expressed by the same gene, like HSPA8. See Table 3-p141.
Yelensky teaches multiple neoantigens that bind to the same that bind to the same or different MHC. See Table 3.
Yelensky teaches that the T cells may be modified to promote cytokine, like IL-15, secretion to allow long term persistence. See ¶ 0584.
Yelensky teaches carrier for the composition comprising serum albumins and DMSO in PBS (a crystalloid solution) as cryopreserving agents. See ¶¶ 00208 and 0565.
Yelensky teaches carriers for pharmaceutical compositions, including sodium chloride and potassium chloride solutions, which are crystalloid solutions. See ¶¶ 0223.
Although Yelensky does not explicitly teach combining a first NeoTCR cell population comprising a first patient-derived exogenous NeoTCR that binds a first neoantigen, and a second NeoTCR cell population comprising a second patient-derived NeoTCR that binds a second neoantigen; wherein the first and second NeoTCR are different or combining this with a different third NeoTCR cell population with codon optimized P2A peptide sequences separating the alpha chain, beta chain and marker to allow for the separate expression of the genes, it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Yelensky to identify thee or more NeoTCR cell populations to different neoantigens comprising exogenous NeoTCRs, such as those described by Yelensky, and combine the three or more NeoTCR cell populations to the different neoantigens identified in a patient so all of the neoantigens could have been targeted during treatment and to provide the optimal treatment. The combination of the three or more NeoTCR cell populations to the different neoantigens would have reduced the number of treatment steps, thus providing additional motivation for the combined treatment.
Additionally, one would have been motivated to express a cytokine, like IL-15, in the NeoTCR cell populations to allow long term persistence of the cells at the treated tumor .
Yelensky teaches as set forth above, but does not teach wherein the NeoTCRs are integrated into an endogenous TRAC or TRBC locus.
Roth teaches that development of entirely new types of receptors is time consuming, expensive, and fails to take advantage of the fact that, through development of the endogenous T cell repertoire, the body naturally produces TCRs that bind almost any possible antigenic target. The ability to obtain human T cells and replace their endogenous TCR with a TCR having a desired antigen specificity could be transformative in the development and application of adoptive T cell therapies. See ¶ 0002.
Roth teaches methods of inserting heterologous TCRs into an endogenous TRAC or TRBC locus. See abstract, Figures 1-3, and claims 1-74.
Roth teaches expressing the P2A peptides between the TCR- and TCR-β chains. See ¶¶ 0028-0030, 0084 and 0150 and Figs. 1 and 2. .
Roth teaches inserting a heterologous NeoTCR specific for a NY-ESO-1 melanoma neoantigen into the endogenous TRAC or TRBC locus. See Examples-pp. 36-44.
Roth teaches that both the TCR- and TCR-β chains can be knocked in simultaneously in a single multiplexed round of editing (Figure 2). This is similar to the targeting strategy in Figure la and Figure 1b, except that at both the TCR- and TCR-β constant loci, only the variable regions of the desired antigen specific TCR are inserted. This has the benefit of both reducing the total size of the insertions (from one 1.5 kbp insertion to two 500 bp insertions), but also means that any T cell expressing both chains of the desired antigen specific TCR will have both its previously recombined endogenous TCR- and TCR-β chains knocked out, preventing the potentially undesirable pairing of an inserted antigen specific TCR- chain with an endogenous TCR-β chain for example. See ¶ 0002.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Yelensky and Roth and use the methods of Roth to integrate NeoTCR of Yelensky and Roth into an endogenous TRAC or TRBC locus to make T-cells that are specific for the targeted neoantigens because Roth teaches the advantages of inserting the Neo-TCR into an endogenous TRAC or TRBC locus. One of skill in the art would have been motivated to insert the Neo-TCR into an endogenous TRAC or TRBC locus because, as taught by Roth, it is more efficient than engineering completely novel neoantigen receptors and eliminates the endogenous TCRs that may interfere with the activity and function of the inserted Neo-TCR.
7. Claims 1-5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/140278 A1 (Bleakley et al. July 18, 2019, filed Jan. 11, 2019), “Bleakley”, in view of WO 2019/084552 (Roth et al. May 2, 2019, IDS), “Roth”.
Bleakley teaches patient T cell receptors for targeting the neoantigen fusion protein Core Binding Factor, -subunit: Myosin Heavy Chain 11(CBF:MYH11) antigen for the treatment of acute myeloid leukemia (AML). Bleakley teaches transducing T-cells with the T-cell receptors. See abstract, p. 26-4th paragraph to p. 58, Examples 5-8, and claims 1-110.
Bleakley teaches six T cell clones that recognize the HLA-B*40:01 specific epitope REEMEVEHEL (SEQ ID NO: 2). See Example 7 and Table 5.
Bleakley teaches isolating T cell receptors expressed by T-cells from patients that recognize the HLA-B*40:01 specific epitope REEMEVEHEL (SEQ ID NO: 2) that recognize and kill acute myeloid leukemia (AML) cells. See Examples 1-7 and Tables 3-5.
Bleakley teaches generating T-cells expressing the exogenous TCRs specific to SEQ ID NO: 2. See Example 7 and Figure 9.
Bleakley teaches four T cell clones that recognize the HLA-A*02:01 specific epitope (Q)LLAVTVHEL (SEQ ID NO: 1). See Example 8, Table 9, and Figure 10.
Bleakley teaches a third epitope EEMEVEHEL (SEQ ID NO: 3) was recognized by clone D7.C24, which also recognizes SEQ ID NO: 2. See p. 94-2nd paragraph and Figure 10C.
Bleakley teaches neoTCRs can bind a CBF:MYH11-HLA complex wherein the HLA comprises HLA-A*02:0l; HLA-A*03:0l; HLA-A*11:0l; HLA-B*40:0l; HLA-B*44:02; HLA-B*40:02; or HLA-B*44:03. See p. 27-2nd paragraph and claims 34, 35, 95 and 96.
Bleakley teaches that the cells of the invention may be combined together for therapeutic treatments. See p. 59-last paragraph and p. 45-2nd paragraph.
Bleakley teaches using the P2A peptide for expression of separate proteins for the same polynucleotide vector, between TCR- and TCR-β chains and/or separating a tag/marker sequence. See p. 3-last paragraph, p. 35-3rd full paragraph, p. 36- 2nd and 3rd full paragraphs through p. 37 and p.82-3rd full paragraph, Example 8 and Figure 5A.
Bleakley teaches that that the 2A elements are codon-diversified and optimized to enhance expression. See p. 92-2nd paragraph.
Bleakley teaches the polynucleotide sequences can be codon optimized for expression in a particular cell, like a human T cell. See p. 33-1st full paragraph and p.82-3rd full paragraph. .
Regarding wherein the NeoTCRs are derived from the same patient, product claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I). The source of the broadly claimed NeoTCRs, i.e. from the same patient, does not limit the structure of the NeoTCRs.
Bleakley teaches that inclusion of CD4+ T cells in an immunotherapy cell product can augment persistence of cytotoxic CD8+ T cells. See p. 39-2nd paragraph.
Bleakley teaches a T-cell clone specific for the RUNX1:RUNX1T1 neoantigen peptide. See p. 7-3rd paragraph, p. 8-2nd paragraph, Example 8, Figure 1 and Figure 10B.
Bleakley teaches that the pharmaceutical compositions can comprise saline or dextrose (crystalloid solutions) or serum albumin. See p. 62-4th paragraph.
Bleakley teaches cryopreserving PBMCs in RPMI 1640, a crystalloid solution with salts and glucose, with human serum and DMSO, a cryopreservation agent. See p.75-first paragraph.
Bleakley teaches that the compositions of the invention can be administered in a manner and dose appropriate to the patient’s condition and health. See p. 62-last paragraph.
Bleakley teaches that eliminating endogenous checkpoint genes like PD-1 or LAG-3 can be used to improve the persistence of the T cells. See paragraph bridging pp. 51-52 and first paragraph on p. 52.
Although Bleakley does not explicitly teach combining a first NeoTCR cell population comprising a first patient-derived exogenous NeoTCR that binds a first neoantigen, and a second NeoTCR cell population comprising a second patient-derived NeoTCR that binds a second neoantigen; wherein the first and second NeoTCR are different or combining this with a different third NeoTCR cell population, it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Bleakley and administer combinations of transgenic T-cells expressing the various TCRs to the various CBF:MYH11 neoantigen epitopes and/or RUNX1:RUNX1T1 neoantigen peptide taught by Bleakley with diversified and codon optimized P2A peptide sequences separating the alpha chain, beta chain and tag/marker to allow for the separate expression of the genes because Bleakley teaches combinations for treatment and that the compositions of the invention can be administered in a manner and dose appropriate to the patient’s condition and health. One would have been motivated to target the different CBF:MYH11 and/or RUNX1:RUNX1T1 neoantigens identified in a patient so all of the neoantigens could have been targeted during treatment and to provide the optimal treatment. The combination of the three or more NeoTCR cell populations to the different neoantigens would have reduced the number of treatment steps, thus providing additional motivation for the combined treatment.
Additionally, one would have been motivated to eliminating endogenous checkpoint genes like PD-1 or LAG-3 in the NeoTCR cell populations to allow long term persistence of the cells at the treated tumor.
Bleakley teaches as set forth above, but does not teach wherein the NeoTCRs are integrated into an endogenous TRAC or TRBC locus.
Roth teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Bleakley and Roth and use the methods of Roth to integrate NeoTCR of Bleakley and Roth into an endogenous TRAC or TRBC locus to make T-cells that are specific for the targeted neoantigens because Roth teaches the advantages of inserting the Neo-TCR into an endogenous TRAC or TRBC locus. One of skill in the art would have been motivated to insert the Neo-TCR into an endogenous TRAC or TRBC locus because, as taught by Roth, it is more efficient than engineering completely novel neoantigen receptors and eliminates the endogenous TCRs that may interfere with the activity and function of the inserted Neo-TCR.
Response to Arguments
8. Applicant argues that solely to expedite prosecution and without acquiescing to the Examiner's positions, claim 1 has been amended to specify that each polynucleotide encoding each of the first, second, and third exogenous NeoTCRs comprises two P2A peptides that are codon diverged relative to the other. As the Examiner is no doubt aware, "[a]n obviousness determination generally requires a finding that all claimed limitations are disclosed in the prior art and that a person of ordinary skill in the art would have been motivated to combine or modify the teachings in the prior art and would have had a reasonable expectation of success in doing so." Univ. of Strathclyde v. Clear-Vu Lighting LLC, 17 F.4th 155, 160 (Fed. Cir. 2021). None of Yelensky, Bleakley, or Roth disclose this feature. In view of the foregoing, the cited art, alone or in any combination, would not have motivated one of ordinary skill in the art to arrive at the currently claimed subject matter. Accordingly, the cite art provides an insufficient basis for the instant rejection and its withdrawal is requested.
Applicant’s arguments have been considered, but have not been found persuasive. Yelensky teaches where the alpha and beta chains are expressed from a single construct or open reading frame, or cases wherein a marker gene is included in the construct, the construct may comprise a ribosomal skip sequence. The ribosomal skip sequence may be a 2A peptide, e.g., a P2A or T2A peptide. See ¶¶ 0593 or 0598 and Fig. 25. Yelensky also teaches that the codon usage may be optimized, such as for use in humans and increased translation efficiency. See ¶¶ 0229 and 0590.
Similarly Bleakley teaches using the P2A peptide for expression of separate proteins for the same polynucleotide vector, between TCR- and TCR-β chains and/or separating a tag/marker sequence. See p. 3-last paragraph, p. 35-3rd full paragraph, p. 36- 2nd and 3rd full paragraphs through p. 37 and p.82-3rd full paragraph, Example 8 and Figure 5A. Bleakley teaches that that the 2A elements are codon-diversified and optimize to enhance expression. See p. 92-2nd paragraph. Bleakley teaches the polynucleotide sequences can be codon optimized for expression in a particular cell, like a human T cell. See p. 33-1st full paragraph and p.82-3rd full paragraph.
Additionally, Roth teaches expressing the P2A peptides between the TCR- and TCR-β chains. See ¶¶ 0028-0030, 0084 and 0150 and Figs. 1 and 2.
Thus it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high in view of the teachings of the art to use diversified and codon optimized P2A peptide sequences separating the alpha chain, beta chain and tag/marker to allow for the separate and optimized expression of the genes.
Applicant argues that notwithstanding the foregoing, Applicant also notes that results of an unexpected nature are considered particularly relevant to the obviousness inquiry as "[u]nexpected results are useful to show the improved properties provided by the claimed compositions are much greater than would have been predicted." Id. (quoting Leo Pharm. Prods., Ltd., 726 F.3d 1346, 1358 (Fed. Circ. 2013)). To this end, Applicant respectfully traverses the Examiner's contentions that the cited evidence is not commensurate to the scope of the claimed invention, and that the combined effect could simply be an additive dose response. Applicant notes that "[t]he NeoTCR Cells were tested as single NeoTCR Product or as a 3 NeoTCR Product composed ¹/₃ of each one of the 3 NeoTCRs" and that every combination comprising three distinct populations of NeoTCR cells outperformed the NeoTCR Product comprising a single population of NeoTCR cells. See Published specification at paragraph [0562]-[0563]. Moreover, "the combination of three populations of NeoTCR Cells (i.e., the NeoTCR Product comprise three distinct populations of NeoTCR Cells, each population expressing a different NeoTCR) results in greater efficacy than two populations of NeoTCR Cells, experiments were performed on every combination of NeoTCRs 408, 409, and 429 (FIGS. 7A- 7D)". Therefore, the synergistic effect is not simply additive as suggested by the Examiner and not limited to any particular NeoTCR. As the unexpected results are not only more than merely additive, and the data presented is consistent with the results being entirely generalizable across different NeoTCRs, Applicant submits that the results are indeed commensurate in scope with the pending claims.
Applicant’s arguments have been considered, but have not been found persuasive. The cited Example is drawn to a combination of three NeoTCRs 408, 409, and 429. However, The claims encompass three large genera of different NeoTCRs cell populations which are not limited any particular NeoTCR that are integrated into TRAC or TRBC locus or any particular cell types. As previously set forth MPEP 716.02 (d) teaches: the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”
However, the claims are not even limited to NeoTCRs 408, 409, and 429 or any of the disclosed cell populations with the disclosed NeoTCRs. Arstila et al. (Science 29 Oct. 1999 286: 958-961, of record) teach that the number of distinct T cell receptors expressed by the 1012 T-cells is not known. Arstila teaches that in the blood there are 106 different chains pairing on average with at least 25 different chains. See abstract. Thus, the claims encompass three very large genera of different NeoTCR cell populations and nearly unlimited combinations of the NeoTCR cell populations of any cell type. Thus the disclosed data with NeoTCRs 408, 409, and 429 in T cell populations, in which the NeoTCRs do not appear to be integrated into a TRAC or TRBC locus, is not sufficient to support Applicant’s assertion of non-obviousness of the claimed invention.
Additionally, in the cited Fig. 7, Fig. 7A compares the cytotoxic activity NeoTCRs 408, 409, and 429 individually and collectively. Each of the NeoTCRs 408, 409, and 429 individually show significant cytotoxic activity and the TCR 409 close to the cytotoxic activity of the combined NeoTCRs 408, 409, and 429. The values of the control Neo12 at the end time point is approximately 35. From Fig. 7A, the value of NeoTCR 429 is ~ 30 (~ 14% growth inhibition), the value of NeoTCR 408 is ~25 (~ 29% growth inhibition), the value of NeoTCR 409 is ~10 (~ 71% growth inhibition), and the combined value From Fig. 7A of NeoTCRs 408, 409, and 429 is ~5 (~ 86% growth inhibition). Thus, the observed combined effect appears be an additive response to the combined three NeoTCRs in T cell population and thus is not unexpected.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. Thus, the rejections are maintained for the reasons of record.
New Claim Rejections - 35 USC § 102
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.
9. Claim(s) 1, 3, 5, and 9 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2021/0106621 A1 (Sennino et al. Apr. 15, 2021), “Sennino”.
Sennino teaches methods of treating cancer in Non-Responder Patients with an engineered NeoTCR Product. See abstract.
Sennino teaches a method of killing cancer cells from a Non-Responder Patient with a NeoTCR Product designed and made for such patient. See ¶¶ 0008-0009.
Sennino teaches the NeoTCR Product comprises CD8+ and/or CD4+ T cells from the Non-Responder Patient, wherein the T cells have been engineered to express one, two, or three, neoTCRs. See ¶¶ 0024-0025..
Sennino teaches the T cells in the NeoTCR Product have been engineered to express a first neoTCR, a second neoTCR, and a third neoTCR, wherein each T cell expresses one neoTCR selected from the first neoTCR, the second neoTCR, and the third neoTCR, wherein each neoTCR binds a neoepitope comprising an amino acid mutation resulting from a somatic coding mutation present in the patient's cancer.. See ¶¶ 0028-0029.
Sennino teaches the neoTCR in the NeoTCR Product is present in the T cell genome at the endogenous TCR locus, i.t. the TCR-alpha or TCR-beta loci. See ¶¶ 0030, 0056-0063 and 0191-0192.
Sennino teaches the first, second, and third NeoTCR Products are different NeoTCR Products. See ¶¶ 00216 and 0218.
Sennino teaches the polynucleotide encoding the NeoTCR Products comprises: a TCR gene sequence positioned between the first and second homology arms; a first P2A-coding sequence positioned upstream of the TCR gene sequence and a second P2A-coding sequence positioned downstream of the TCR gene sequence, wherein the first and second P2A-coding sequences code for the same amino acid sequence that are codon-diverged relative to each other. See ¶¶ 0035-0038.
Sennino teaches neoantigens expressed by 3 or more different genes that bind different MHC. See Fig. 2B, 2D, 3A, and 3D.
Sennino teaches the TCR Products are cryopreserved in freezing media in CryoMACS Freezing Bags or formulated with serum albumin. See ¶¶ 0235, 0236 and 0252.
Double Patenting-Maintained
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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8. Claims 1-5 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,304,978 B2 (Sennino et al. Apr. 19, 2022) in view of WO 2019/050994 A1 (Yelensky et al. March 14, 2019, IDS), “Yelensky”
The ‘978 claims are drawn to:
1. A composition comprising a peripheral T cell comprising: a. an exogenous T cell receptor (TCR) recognizing a neoantigen; and b. an exogenous CD8 comprising: i. a CD8α signal peptide, a CD8α extracellular domain, a CD8α transmembrane domain, and a CD8β intracellular domain; or ii. a CD8α signal peptide, a CD8α extracellular domain, a CD8α transmembrane domain, and a CD4 intracellular domain.
5. The composition of claim 1, wherein the exogenous TCR is a patient derived TCR.
11. The composition of claim 1, further comprising a cryopreservation agent, serum album, and a crystalloid solution.
12. A composition comprising a peripheral T cell comprising: a. an exogenous T cell receptor (TCR) recognizes a neoantigen; and b. an exogenous CD8 comprising: i. a CD8α signal peptide, a CD8α extracellular domain, a CD8α transmembrane domain, and a CD8β intracellular domain; or ii. a CD8α signal peptide, a CD8α extracellular domain, a CD8α transmembrane domain, and a CD4 intracellular domain; wherein the exogenous TCR is encoded by a polynucleotide integrated into a TRAC and/or TRBC locus of the cell.
17. The composition of claim 12, wherein the exogenous TCR is a patient derived TCR.
23. The composition of claim 12, further comprising a cryopreservation agent, serum album, and a crystalloid solution.
24. The composition of claim 12, wherein the polynucleotide is non-virally integrated into the TRAC or TRBC locus.
The ‘978 claims teach as set forth above, but do not teach a composition comprising: (a) a first NeoTCR cell population comprising a first patient-derived exogenous NeoTCR that binds a first neoantigen; (b) a second NeoTCR cell population comprising a second patient-derived exogenous NeoTCR that binds a second neoantigen; and (c) a third NeoTCR cell population comprising a third patient-derived exogenous NeoTCR that binds a third neoantigen; wherein each polynucleotide encoding each of the first, second, and third exogenous NeoTCRs comprises two P2A peptides that are codon diverged relative to the other wherein each one of the first, second, and third exogenous NeoTCRs are different, and wherein each one of the first, second, and third exogenous NeoTCRs are derived from the same patient.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘978 claims and Yelensky to identify thee or more NeoTCR cell populations to different neoantigens comprising exogenous NeoTCRs, such as those described by Yelensky, and express the three or more NeoTCRs to the different neoantigens identified in a patient in the three or more cell populations of the ‘978 claims with codon optimized P2A peptide sequences separating the alpha chain, beta chain and marker to optimize the treatment by targeting multiple neoantigens and so that all of the neoantigens could have been targeted during treatment and to provide the optimal treatment. The combination of the three or more NeoTCR cell populations to the different neoantigens in three or more cell populations of the ‘978 claims would have reduced the number of treatment steps, thus providing additional motivation for the combined treatment.
Additionally, one would have been motivated to express a cytokine, like IL-15, in the NeoTCR cell populations to allow long term persistence of the cells at the treated tumor .
Response to Arguments
8. Applicant argues that for the reasons outlined above, that Yelensky is insufficient to support the instant rejection as it would not motivate one of skill in the art to modify the compositions disclosed in the ‘978 patent to arrive at the claimed subject matter in view of the knowledge in the art at the time. Accordingly, Applicant requests withdrawal of the instant rejection.
Applicant’s arguments have been considered, but have not been found persuasive. Applicant is reiterating the arguments set forth above with respect to Yelensky. Thus, for the reasons set forth above Applicant’s arguments are not found persuasive and the rejection is maintained.
Conclusion
9. No claims allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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/PETER J REDDIG/ Primary Examiner, Art Unit 1646
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