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 .
DETAILED ACTION
1. The Amendment filed October 01, 2025 in response to the Office Action of April 02, 2025 is acknowledged and has been entered. Claims 6-8 have been cancelled. Claims 1 has been amended.
2. Claims 1-5 and 9 are currently being examined.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
3. 37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings (Figure 4A and 8E) are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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.
4. Claims 1-5 and 9 is/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 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, 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 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.
5. Claims 1-5 and 9 is/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” for the reasons of record set forth below.
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.
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 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
6. Applicant argues that 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 vs. Clear-Vu Lighting LLC, 17 F.4th 155, 160 (Fed. Cir. 2021). Moreover, Applicant 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)). As outlined in detail below, Applicant respectfully submits: (1) that the Examiner has not established that one of ordinary skill would have been motivated to combine three or more NeoTCR populations targeting distinct neoantigens to arrive at the claimed subject matter with a reasonable expectation of success; and (2) that the unexpected results described in the instant application with respect to the claimed subject matter underscores the non-obviousness of the claimed subject matter.
Applicant argues that as conceded by the Examiner, neither Yelensky nor Bleakley teach compositions comprising three distinct NeoTCR cell populations. Instead, the Examiner argues that one of skill the art would have been motivated to combine multiple NeoTCR cell populations to arrive at the claimed subject matter as an “optimal treatment” or to reduce treatment steps. The Examiner, however, provides no evidence supporting this proposition. In fact, as of the earliest priority date available to the instant application, Oct. 8, 2019, one of skill would not have considered such a modification of the cited art (combining multiple NeoTCR cell populations into a single treatment) to be the optimal treatment or to reduce treatment steps with a reasonable expectation of success. As outlined in Yánez et al., Hemasphere. 2019 Mar 29; 3(2): e186. dot: 10.1097/HS9.0000000000000186 (attached as Exhibit A), T-cell therapies were considered to carry significant risk of Cytokine Response Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome, and such risks are considered to be cell-specific (e.g., see page 2, left column, “There are also differences between the CAR T cell products infused.”) Given the cell- specific risks recognized in the art, it is not simply a matter of combining multiple NeoTCR cell populations to arrive at an “optimal treatment” or to reduce treatment steps. As the Examiner has not offered any specific evidence that one of skill would have been motivated to alter the approaches described in Yelensky and Bleakley to arrive at the claimed subject matter with a reasonable expectation of success, and the art at the time of filing clearly provides evidence countering such modification for the proposed goal of optimized treatment or reducing treatment steps, Applicant respectfully submits that the Examiner has not established that art renders the instant claims obvious.
Applicant’s arguments have been considered, but have not been found persuasive. Although Yánez teaches that there are risks to T cell therapies, Yánez also provides ways to mediate those risks. See p. 5-Current Management of CNS toxicity and pp. 7-8. Yánez also does not teach that the risk of toxicities increases with the use of a combination of different types of T cells directed to different antigens. Additionally, cancer therapeutics routinely cause undesirable toxicities, but these toxicities are routinely managed by the treating physician so that the therapy can be performed. Thus, Applicant’s arguments are not found persuasive and the rejection is maintained.
Applicant also argues that the instant application demonstrates that the claimed compositions have unexpectedly superior properties (e.g., cytotoxicity) when compared to either single NeoTCR cell compositions or even what could reasonably be expected of combinations of individual NeoTCR cell compositions. Example 19, among other data, demonstrates the surprising synergistic results obtained when the claimed composition was evaluated for cytotoxic activity:
As shown in Figure 6A, the NeoTCR Products that comprise a single population of NeoTCR Cells have varying abilities to control the growth of the tumor cells. However, it was a surprise to find that NeoTCR Products that comprise three populations of NeoTCR Cells (i.e., the NeoTCR Product comprise three distinct populations of NeoTCR Cells, each population expressing a different NeoTCR) not only have an enhanced ability to control the growth of tumor cells but that the three different NeoTCR Cell populations in fact work together to elicit a synergistic effect to control the growth of the tumor cells (Figure 6B; the only cell growth seen in this figure is the growth of the tumor cells in the presence of media only without a NeoTCR Product).
See the instant application at page 108, lines 29-34, and page 109, lines 1-3 (emphasis added). Figure 6B, for example, shows that every combination had the ability to control the growth of the tumor cells well beyond that observed for a single NeoTCR cell population.
Applicant also argues that furthermore, the technical effect is demonstrated for multiple combinations of NeoTCRs which include at least 10 unique NeoTCR clonotypes between Figures 6 and 20 (e.g., TCR406, TCR408, TCR409, TCR412, TCR418, TCR421, TCR422, TCR426, TCR429, TCR433).
Applicant argues that in view of the foregoing, neither Yelensky nor Bleakley, alone or in combination, would have motivated one of ordinary skill in the art to arrive at the claimed subject matter. Applicant respectfully submits that Roth does not remedy the deficiencies of Yelensky or Bleakley as it is silent with respect the claimed combinations of NeoTCR cell populations. Accordingly, Applicant request withdrawal of the instant rejections.
Applicant’s arguments and evidence have been considered, but have not been found persuasive. 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.
MPEP 716.02 (d) teaches:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)
The cited evidence of combinations of 10-11 unique NeoTCRs cell populations in Figures 6 and 20 is not commensurate in scope with the claimed invention. Even with the disclosed 10-11 unique NeoTCRs there are 120-165 possible group of three NeoTCR combinations, e.g., for 10 NeoTCRs, C(n,r)=n!/r!(n−r)! or C(10,3)= 10!/3!(10−3)! = 10!/3! X 7!=120. However, the claims are not even limited to the disclosed cell populations with the disclosed NeoTCRs. Arstila et al. (Science 29 Oct. 1999 286: 958-961) 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 10-11 unique NeoTCRs 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, the disclosed data does not clearly show the amounts of each NeoTCRs in T cell population used in the experiments Figures 6 and 20. Thus, the observed combined effect could simply be an additive dose response of the combined three NeoTCRs in T cell population and thus not unexpected. Further, it is noted that to rebut a prima facie case of obviousness the claimed subject matter must be compared with the closest prior art, which has not explicitly been done. See MPEP 716.02(e). 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.
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.
7. 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” for the reasons of record.
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 one of the first, second, and third exogenous NeoTCRs are different, wherein each one of the first, second, and third exogenous NeoTCRs are derived from the same patient, and wherein the first, second, and third NeoTCR cell populations are capable of persisting in a tumor.
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 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 (e.g., Yánez et al.) Accordingly, Applicant requests withdrawal of the instant rejection.
Applicant’s arguments have been considered, but have not been found persuasive. Although Yánez teaches that there are risks to T cell therapies, Yánez also provides ways to mediate those risks. See p. 5-Current Management of CNS toxicity and pp. 7-8. Yánez does not teach that the risk of toxicities increases with the use of a combination of different types of T cells directed to different antigens. Additionally, cancer therapeutics routinely cause undesirable toxicities, but these toxicities are routinely managed by the treating physician so that the therapy can be performed. Thus, Applicant’s arguments are not found persuasive and the rejection is maintained for the reasons of record.
Conclusion
9. All other objections and rejections recited in the Office Action of April 02, 2025 are withdrawn in view of Applicant’s amendments and arguments.
10. No claims allowed.
11. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
12. 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 on M-F 8:30-5:30 Eastern Time
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/Peter J Reddig/
Primary Examiner, Art Unit 1642