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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 11, 2026 has been entered.
Application Status
Applicant’s amendments filed February 11, 2026, amending claims 1, 5 and 9, canceling claim 24, and adding new claim 43 is acknowledged. Claims 1-2, 5-6, 8-10, 12-13, 18-19, 21-22, 28, 30-32, 35 and 42-43 are pending and under examination.
The amendment to claims 1 and 9 limiting the viral antigens to those from at least one of SARS-CoV-2, CMV, adenovirus or EBV overcomes the § 103 and nonstatutory double patenting rejections recited in the previous office action.
Any other rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Objections
Claim 43 is objected to because of the following informalities:
Claim 43 recites “wherein the viral antigen come from adenovirus…” which is grammatically incorrect. It is suggested that claim 43 either recite “wherein the viral antigens come from” or “wherein the viral antigen comes from”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – New Matter
Claims 1-2, 5-6, 8-10, 12-13, 18-19, 21-22, 28, 30-32, 35, 42-43 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 a NEW MATTER rejection.
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
In the instantly rejected claims, the combination of 1) Virus-specific antigens, and 2) the cytokine cocktail comprising IL-2, IL-4 and IL-7 in claims 1 and 9 appears to represent new matter. No specific basis for this limitation was identified in the specification, nor did a review of the specification by the examiner find any basis for the limitation.
The Specification generically recites cytokines for use in T cell expansion including IL-2, IL-4 and IL-7, including with other cytokine species. See e.g., [00202]. However, the generic disclosure is not in reference to specific viral antigens. The Specification only provides written support for the following virus and cytokine combinations: IL-4 and IL-7 with CMV ([0051], [0078]), IL-2 and IL-7 and IL-15 for JCV and BKC ([0051], [0079]), IL4 and IL-7 with adenovirus ([0051], [0080]); and IL-4 and IL-7 with EBV ([0051], [0081]). It does not appear that IL-2, IL-4 and IL-7 was ever a combination contemplated by Applicant for T cell expansion in the presence of viral-specific antigens since the three cytokines are never recited together without a generic recitation of many additional cytokines.
Additionally, there is no disclosure of which cytokine cocktail to be used specifically with SARS-CoV-2. SARS-CoV-2 is mentioned only three times in the Specification ([0011], [0077]) and none of the recitations indicate which cytokines to use with the coronaviral antigens.
Since no basis has been identified, the claims are rejected as incorporating new matter.
Response to Arguments – New Matter
Applicant argues that new claim 43 finds support throughout the Specification, at least in the Examples and in [0018], [0051], [0077]) (Remarks, page 7). Applicant argued in the Remarks filed in October 2025, that the combinations find support in [0051], [0053], [0055], and [0077]). These arguments have been fully considered but are not persuasive. Paragraph [0018] provides a description of FIG. 1 and recites “pepMixes from MCV, BKV and Ad in the presence of IL-7, IL-2 and IL-15”. As indicated in the rejection above paragraphs [0051] and [0077]-[0081] only provide for IL-4 and IL-7 with CMV; IL-2 and IL-7 and IL-15 for JCV and BKC; IL4 and IL-7 with adenovirus; and IL-4 and IL-7 with EBV. Paragraphs [0053] and [0055] recite transducing T cells to express cytokines and provides for means for genetic manipulation. A thorough review of “the examples” found no disclosure of using a combination of IL-2, IL-4 and IL-7. None of the cited portions of the Specification by Applicant appear to provide written support for the combination if IL-2, IL-4 and IL-7 while exposing T cells to viral antigens. Since no basis has been identified, the claims are rejected as incorporating new matter.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5-6, 8-10, 12-13, 18-19, 21-22, 28, 30-32 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Papadopoulou (Papadopoulou et al., Science Translational Medicine (2014), 6: 242ra83, pages 1-11 and Supplemental material) in view of Houghtelin (Houghtelin and Bollard, Frontiers in Immunology (2017), 8: 1272, pages 1-11, of record), Rezvani (US 20180333435 A1, published November 22, 2018, of record) and Gundry (Gundry et al., Cell Reports (2016), 17: 1453-1461, of record).
Claim 1 recites “comprising the steps of, in any order… (e) expanding the T cells in the presence of one or more viral antigens and optionally one of more cytokines to produce viral-specific T cells…” Thus, while the specific viral antigens are no longer optional, claim 1 does not require specific cytokines to be co-administered with them. Only claim 6 requires expansion in the presence of both the viral antigens and the cytokines.
Regarding claims 1, Papadopoulou teaches methods for producing and the adoptive transfer of virus specific cytotoxic T-cells to treat viral infections of immunocompromised patients (Abstract). Papadopoulou teaches producing multi-virus-specific T cells (mVSTs) (Methods, pages ¶2-3). Papadopoulou teaches (e) expanding T cells in the presence of a peptide mix including EBV-Lamp2 (i.e., for EBV), Adb-Penton (i.e., for adenovirus) and CMV-pp65 (i.e., for CMV) (Methods, ¶2). Papadopoulou teaches (b) expanding the T-cells with IL-4 and IL-7 (Methods, ¶3). Papadopoulou teaches that when the mVSTs were administered to patients they were able to expand in vivo and produce a response (page 7, ¶3). Papadopoulou teaches that patients are given immunosuppressive therapies to prevent graft versus host disease (GVHD) (Table 1; page 7, ¶3).
Papadopoulou does not teach modifying the T cells to express heterologous receptors or cytokines. Papadopoulou does not teach using Cas9 or Cpf1 and a guide RNAs to disrupt expression of one or more endogenous genes.
Houghtelin teaches hematopoietic stem cell transplants lead to higher risks for severe immunosuppression due to GVHD (Abstract). Houghtelin teaches that virus-specific T-cells are a targeted therapy that can be used to treat viral infections in immunocompromised patients (Abstract). Houghtelin teaches the virus-specific T cells (VSTs) that target multiple viruses have been produced using standard peptide mixes (page 4, ¶5). Houghtelin teaches that to produce a T-cell that can recognize a virus, the T-cell can be incubated in the presence of known viral peptide epitopes (Table 1), which are already known for CMV and EBV (Table 2). Houghtelin teaches that targeting of multiple viruses in a single product is a logical extension given the success of treating individual viral infections with virus-specific T cells (page 4, ¶5). Houghtelin teaches that “steroid treatment, often used in high doses to treat GVHD, can… render VST infusion futile through inactivation of the product. To this end, VST have been gene manipulated to inactivate the glucocorticoid receptor, allowing them to maintain cytotoxicity in the presence of steroids (page 7, ¶7).
Rezvani teaches methods of producing BK Virus-specific T-cells by stimulating expanded T-cells with viral specific antigens (Abstract, [0194]). Rezvani teaches that recipients of VSTs are immunocompromised due to therapies to suppress lethal GVHD ([0003]). Rezvani teaches stimulating mononuclear cells (i.e., includes T cells) with IL-2, IL-7 and IL-15 ([0194]). Regarding step (c), Rezvani also teaches VSTs can be engineered to have no expression of the glucocorticoid receptor (GR) using Cas9 and guide RNAs ([0013]). Rezvani teaches exemplary gRNA sequences for CRISPR-Cas mediated knockout of the GR encoding NR3CP1 gene ([0132]). Rezvani teaches the reason for knocking out GR is to make the VSTs resistant to glucocorticoids ([0029]). Regarding (d), Rezvani teaches the VSTs can be engineered to express a chimeric antigen receptor (CAR) and/or a T cell receptor (TCR) (i.e., modifying the T cells to express one or more heterologous antigen receptors) ([0013]). Rezvani teaches examples of CARs ([0101]-[0115] and TCRs ([0116]-[0124]) and methods of introducing the genes for expressing the CARs or TCRs in T cells ([0095]-[0098]).
Gundry teaches methods of modifying the genome of hematopoietic cells (i.e., blood cells) (Abstract). Gundry teaches delivering Cas9 and NR3C1-specific guide RNAs (i.e., guide RNAs that target the glucocorticoid receptor gene) to primary cord blood cells for the purpose of knocking out NR3C1 (page 1459, ¶5; Supp Materials, page 12, ¶3; Table S1; Figure S4).
Regarding claim 1, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have 1) knocked out the NR3C1 gene using the method of Gundry and 2) expressed a heterologous CAR and in the mVSTs of Papadopoulou. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that Papadopoulou’s mVSTs could be modified by expressing a heterologous CAR and knocking out the NR3C1 gene because Rezvani teaches that other VSTs can be modified as such and provides methods of introducing the genes for expressing the CARs or TCRs in T cells. The skilled artisan would have been motivated to do so because 1) Rezvani teaches embodiments of different VSTs with those modifications and 2) Houghtelin teaches that knockout of GR can help maintain VST efficacy when given to GVHD patients treated with glucocorticoid. The skilled artisan would have been motivated to use Gundry's RNP Cas9-guideRNA delivery method to knockout the GR-encoding NR3C1 gene because Gundry teaches the RNP method is effective at knocking out GR expression.
Regarding claim 2, Houghtelin also teaches T cells can also be genetically manipulated to be resistant to calcineurin inhibitors (page 7, ¶7). Rezvani also teaches that multiple genes can be modified via CRISPR/Cas in the VSTs including genes encoding CISH and the TGFb receptor ([0130]), and provides exemplary guide RNAs sequences for their modification ([0132]).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have further modified the NR3C1-KO mVSTs rendered obvious above by knocking an additional gene such as CISH or TGFb receptor using the RNP method of Gundry with the guide RNA sequences in Rezvani. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have predicted that the obvious NR3C1-KO mVSTs could be additionally modified by knocking out expression of a second gene, and been motivated to do so, because Rezvani suggests that more than one gene in VSTs cells can be modified for altered expression.
Regarding claim 5, Rezvani also teaches the VSTs (i.e., expanded T cells) can be engineered to express multiple CARs and TCRs so that the T cells can recognize additional antigens ([0095]).
It would have been obvious to one skilled in the art to have modified the NR3C1-KO, CAR-expressing mVST cells rendered obvious above a second time to express an additional CAR or T cell receptor (TCR) gene. It would have amounted to the duplication of steps by known means to yield predictable results. The skilled artisan would have predicted that two different CARs could be expressed in the NR3C1-KO mVSTs because Rezvani teaches such a feature of the virus specific cells. "[M]ere duplication of parts has no patentable significance unless a new and unexpected result is produced." MPEP 2144.04.VI.B. In this case modifying the cells by transfecting them with another vector that encodes a different CAR would result in the expected product of a mVST cell expressing two different CARs or a CAR and a TCR.
Regarding claims 6, Papadopoulou teaches replenishing media and cytokines a second time (Methods, ¶3). Rezvani teaches the cytokines can be provided to the T-cells simultaneously in the prescience of the viral antigens ([0194]) instead of sequentially as in Papadopoulou.
It would have been obvious to one skilled in the art to have modified the methods rendered obvious above to provide the cytokines and viral antigens simultaneously followed by expansion with fresh media and cytokines. It would have amounted to a combination of known steps by known means to yield predictable results. The skilled artisan would have predicted that IL-4 and IL-7 could be provided to the PBMCs simultaneously, and been motivated to have done so, because Rezvani teaches simultaneous administration for a different set of viral antigens and cytokines resulted in the production of sufficient numbers of VSTs. Additionally, simultaneous administration should save time and eliminate the need for sequential administration.
Regarding claim 8, Rezvani teaches the cytokines for T-cell expansion may include IL-21 ([0085]). It would have been obvious to one skilled in the art to have modified the method rendered obvious above to initially provide IL-21 to the PMBCs either before or after viral antigen exposure and IL-4/IL-7 treatment. It would have amounted to a combination of known steps by known means to yield predictable results. The skilled artisan would have predicted that IL-12 could be used to initially or subsequently expand T cell populations, and been motivated to have done so because Rezvani indicates that IL-12 can be used for such a purpose.
Regarding claim 9, the teachings of Papadopoulou, Houghtelin, Rezvani and Gundry are recited above as for claim 1. Briefly, Papadopoulou teaches (a) exposing T cells to a peptide mix including EBV-Lamp2 (i.e., for EBV), Adb-Penton (i.e., for adenovirus) and CMV-pp65 (i.e., for CMV), and (b) stimulating the virus-exposed T-cells with IL-4 and IL-7 (Methods, ¶2-3). As indicated above for claim 1, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have knocked out the NR3C1 gene using the method of Gundry and in the mVSTs of Papadopoulou. It would have amounted to the simple combination of elements by known means to yield predictable results and been motivated by the need to make the mVSTs glucocorticoid resistant.
Regarding claim 10, as indicated above for claim 2, it would have been obvious to have further modified the obvious NR3C1-KO mVSTs by knocking an additional gene such as CISH or TGFb receptor using the RNP method of Gundry with the guide RNA sequences in Rezvani. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have predicted that the obvious NR3C1-KO mVSTs could be additionally modified by knocking out expression of a second gene, and been motivated to do so, because Rezvani suggests that more than one gene in VSTs cells can be modified for altered expression.
Regarding claim 12, as indicated above for claim 9, Papadopoulou teaches (a) exposing T cells to a peptide mix including EBV-Lamp2, Adb-Penton, and CMV-pp65 (i.e., a first, second and third virus-specific mixture of peptide antigens (Methods, ¶2).
Regarding claim 13, the teachings of Papadopoulou, Houghtelin, Rezvani and Gundry are recited above as for claims 1 and 9. As indicated above for claim 1, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have both 1) knocked out the NR3C1 gene using the method of Gundry and 2) expressed a heterologous CAR and in the mVSTs of Papadopoulou. It would have amounted to the simple combination of elements by known means to yield predictable results and been motivated by the need to make the mVSTs glucocorticoid resistant and engineer the T-cells to recognize additional antigens.
Regarding claims 18-19, 28, 32 and 35, Papadopoulou teaches providing the mVSTs to individuals that were candidates for stem cell transplant (Methods, ¶1) and had various diseases including ALL (i.e., individuals in need there or that have an immune-related disorder or cancer) in a single dose (i.e., administered to the individual once) (Table 1).
Regarding claims 21-22 and 30, Rezvani and Gundry teach guide RNAs for modifying NR3C1, the gene encoding a glucocorticoid receptor, as indicated above for claim 1.
Regarding claim 31, Houghtelin teaches that glucocorticoid treatment is often used in high doses to treat GVHD (page 7, 17). Houghtelin teaches that for this reason virus-specific T cells have been edited to inactivate the glucocorticoid receptor, which allows the virus-specific T cells to maintain their cytotoxicity function in the presence of steroids (page 7, 17).
It would have also been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered glucocorticoids to an individual with GVHD that is being treated with the NR3C1-KO, mVSTs to treat a viral infection in the method of treatment rendered obvious above. The skilled artisan would have been motivated to use the NR3C1-KO mVSTs along with glucocorticoids to treat GVHD because Houghtelin teaches using NR3C1-KO virus-specific T-cells is useful when treating GVHD with high doses of glucocorticoids.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Papadopoulou (Papadopoulou et al., Science Translational Medicine (2014), 6: 242ra83, pages 1-11 and Supplemental material), Houghtelin (Houghtelin and Bollard, Frontiers in Immunology (2017), 8: 1272, pages 1-11, of record), Rezvani (US 20180333435 A1, published November 22, 2018, of record) and Gundry (Gundry et al., Cell Reports (2016), 17: 1453-1461, of record) as applied to claims 1-2, 5-6, 8-10, 12-13, 18-19, 21-22, 28, 30-32 and 35 above, and further in view of Beane (Beane et al., Molecular Therapy (2015), 23: 1380-1390, of record).
The teachings of Papadopoulou, Houghtelin, Rezvani and Gundry are recited and applied above as for claims 1-2, 5-6, 8-10, 12-13, 18-19, 21-22, 28, 30-32 and 35. Papadopoulou teaches that between 106 and 107 cells were administered to patients (Table 1). Rezvani also teaches that a therapeutic effectively amount of VSTs for administration to a subject is between 105 and 109 cells per kilogram of the subject ([0146]).
Papadopoulou, Houghtelin, Rezvani and Gundry do not teach the number of cells needed for transduction of the Cas9 and guide RNA for genetic modification of an endogenous gene.
Beane teaches methods for clinical scale editing of T cells using zinc finger nucleases (ZFN) (Abstract). Beane teaches T-cells cultured with IL-2 and then transduced with mRNA encoding a ZFN engineered to target the PD-1 gene (page 1388, 18- page 1389, ¶1; Fig 1). Beane teaches the T-cells were expanded to a total of 109 T cells (page 1382, ¶3; Fig 1). Beane teaches electroporating cells at a concentration of 108/ml with ZFN mRNA at 120 μg/ml (page 1382, ¶3). Beane teaches the efficiency of PD-1 gene editing was between 37-46% (Fig 2).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have transduced at least 108, 109 or 1010 T cells with the Cas9 and guide RNA of Gundry to produce the NR3C1-KO mVSTs rendered obvious above. It would have amounted to a simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that at least 108, 109 or 1010 T cells could be transduced because Beane teaches methods for expanding T cells to reach quantity needed for clinical scale. The skilled artisan would have been motivated to transduce 108, 109 or 1010 T cells because 1) Rezvani teaches that 109 cells can be a therapeutic dose, and 2) Beane teaches that gene editing is less than 50% efficient. The skilled artisan would have recognized that at least twice as many T-cells than the dosage amount would need to be transduced since gene editing is only 50% efficient.
Response to Arguments - §103
Applicant argues that Rezvani only teaches BKV-specific T-cells and does not support the use of IL-4 + IL-7 in the expansion of T-cells because they teach IL7 + IL-15 is superior (Remarks, pages 8-9). This argument has been fully considered and is persuasive in view of the amendments to claim 1 and 9. The §103 rejection over Rezvani and Gundry is withdrawn. However, Papadopoulou teaches the claimed combination of cytokines with CMV, EBV, and adenoviral antigens.
Applicant argues that the combination of IL-4 and IL-7 provided unexpected results for expanding adenoviral-specific VSTs (¶ spanning pages 9-10). This argument has been fully considered but is not persuasive in view of the current rejection over Papadopoulou who demonstrates expanding multi-virus specific T-cells, including for adenovirus using IL-4 and IL-7, in sufficient numbers for administration to patients.
Applicant also argues that the combination of IL-2, IL-4 and IL-7 resulted in a surprising increase in expansion and expression of activation genes in response to adenoviral antigens (page 10, ¶1). This argument has been fully considered but is not persuasive because there is no support in the Specification as filed for using the combination of IL-2, IL-4 and IL-7 for adenovirus-specific T-cells. Thus, although it might have been surprising, as of November 27, 2019, the effective filing date of the claimed invention, or October 26, 2022, the filing date of the present Application, Applicant does not appear to have contemplated the IL-2, IL-4 and IL-7 combination for any specific viral antigens.
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, 5-6, 8-10, 12-13, 18-19, 21-22, 28, 30-32 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6, 8-11, 14-16, 18-19, 21, 23 and 50 of copending Application No. 17/997148 in view of Gundry (Gundry et al., Cell Reports (2016), 17: 1453-1461, of record). Claims 12, 18-19, 28, 30-32, 35 and 42 are rejected further in view of Papadopoulou (Papadopoulou et al., Science Translational Medicine (2014), 6: 242ra83, pages 1-11 and Supplemental material) and Houghtelin (Houghtelin and Bollard, Frontiers in Immunology (2017), 8: 1272, pages 1-11, of record). Claim 42 is rejected further in view of Beane (Beane et al., Molecular Therapy (2015), 23: 1380-1390, of record).
Copending claim 1 recites an ex vivo method of preparing SARS-CoV-2-specific T cells, comprising the step of culturing a starting population of cells in the presence of a mixture of peptides and one or more of IL-2, IL-4, IL-7, IL-15, and IL-21, wherein the mixture of peptides comprises overlapping peptides spanning at least one protein from SARS-CoV-2, thereby producing SARS-CoV-2- specific T cells. Copending claim 3 recites wherein the starting population of cells comprises peripheral blood mononuclear cells (PBMCs), lymphocytes, or a mixture thereof. Copending claim 18 recites further comprising the step of genetically modifying the starting population of cells or the SARS-CoV-2- specific T cells to (a) disrupt expression of one or more endogenous genes in the cells; and/or (b) express one or more chimeric antigen receptors (CAR) and/or one or more T cell receptors (TCR). Copending claim 19 recites wherein the endogenous gene is one or more (i.e., a second gene) of NR3C1. Copending claim 21 recites wherein the T cell is genetically modified to express a CAR and/or a TCR (i.e., modified twice to express a heterologous antigen receptor). Copending claim 50 recites, wherein the mixture comprises IL-2, IL-4 and IL-7.
The copending claims do not recite using Cas9 of Cpf1 and a guide RNA for disrupting the endogenous gene. The copending claims do not recite using additional peptides that are derived from additional viruses (claim 12). The copending claims do not recite administering the cells to an individual in need thereof or methods of treating an individual (claims 18-19, 28, 30-32, 35). The copending claims do not recite specific numbers of T-cells used for gene disruption (claim 42).
Regarding all examined claims, the teachings of Gundry are recited above in paragraph 24 and are incorporated here. Briefly, Gundry teaches using Cas9 and a guide RNA targeted to NR3C1 to knockout expression of NR3C1. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used a Cas9/gRNA to knock out NR3C1 in the copending method. It would have amounted to using known means for gene knockout in the same cell types. The skilled artisan would have predicted that Cas9/gRNA could be used and been motivated to use the nuclease because Gundry demonstrates its effectiveness.
Regarding claims 12, 18-19, 28, 30-32, 35 and 42, the teachings of Papadopoulou are recite above in paragraphs 20, 30, 35, 37, and 42 and are incorporated here. The teachings of Houghtelin are recited above in paragraph 22, 26, 39 and incorporated here. Briefly, Papadopoulou teaches producing multi-virus-specific T cells (mVSTs) by expanding T cells in the presence of a peptide mix including antigens from EBV, adenovirus, and CMV. Papadopoulou teaches that patients are given immunosuppressive therapies to prevent graft versus host disease (GVHD). Papadopoulou teaches providing the mVSTs to individuals that were candidates for stem cell transplant and had various diseases including cancer patients in a single dose. Houghtelin teaches hematopoietic stem cell transplants lead to higher risks for severe immunosuppression due to GVHD. Houghtelin teaches the virus-specific T cells (VSTs) that target multiple viruses have been produced using standard peptide mixes (page 4, ¶5). Houghtelin teaches that targeting of multiple viruses in a single product is a logical extension given the success of treating individual viral infections with virus-specific T cells (page 4, ¶5). Houghtelin teaches that “steroid treatment, often used in high doses to treat GVHD, can… render VST infusion futile through inactivation of the product. To this end, VST have been gene manipulated to inactivate the glucocorticoid receptor, allowing them to maintain cytotoxicity in the presence of steroids (page 7, ¶7).
Regarding claim 12, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have stimulated the mononuclear cells with peptide mixtures containing peptides of CMV or EBV along with the Sars-CoV-2 peptides in the copending method. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that CMV and EBV peptides could be added to the Sars-CoV-2 peptides because Houghtelin and Papadopoulou teaches that multi-virus-specific T-cells have been generated using peptide mixes previously, and CMV and EBV peptide mixes are known in the art. The skilled artisan would have been motivated to have also included CMV antigen peptides and EBV antigen peptides because Houghtelin teaches that making multi-virus-specific T cells was a next logical step.
Regarding claims 18-19, 28, 30-32 and 35, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have further administered the copending SARS-CoV-2-specific T-cells to immunocompromised patients because Houghtelin and Papadopoulou suggest and/or demonstrate that VSTs can be used to treat viral infections in those patient populations.
Regarding claim 42, the teachings of Beane are recited above in paragraph 44 and incorporated here. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have transduced at least 108, 109 or 1010 of the copending SARS2-CoV-2-specific T cells with the Cas9 and guide RNA of Gundry to produce NR3C1-KO T cells. It would have amounted to a simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that at least 108, 109 or 1010 T cells could be transduced because Beane teaches methods for expanding T cells to reach quantity needed for clinical scale. The skilled artisan would have been motivated to transduce 108, 109 or 1010 T cells because Papadopoulou teaches between 106-108 cells are used as a therapeutic dose, and 2) Beane teaches that gene editing is less than 50% efficient. The skilled artisan would have recognized that at least twice as many of the copending T-cells than the dosage amount would need to be transduced since gene editing is only 50% efficient.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments - NSDP
Applicant argues that the copending application has a later patent term filing date than the present application, and thus the provisional nonstatutory double patenting (NSDP) rejection should be withdrawn (¶ spanning pages 13-14). Examiner agrees that the co-pending application has a later US filing date. However, MPEP 804.1.B.1.(b).(i) makes clear that a provisional NSDP rejection should be made and maintained by the examiner until the rejection has been overcome by amendment or the rejection is the only rejection remaining in an application having the earlier patent term filing date. Because the claims are still rejected under §112(a) and §103, the provisional rejection for nonstatutory double patenting is maintained.
Conclusion
No claims are allowable.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635