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 .
Application Status
Applicant’s amendments filed June 23, 2026, amending claims 1, 9 and 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 claim 1 requiring a specific order of steps, the amendment to claim 9 requiring step (d), and both claims requiring the viral antigens to be present with the specific combination of cytokines overcomes the § 103 and nonstatutory double patenting rejections recited in the previous office action.
Applicant’s arguments regarding the new matter rejection are persuasive. The 112(a) rejection of the claims is withdrawn.
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.
Priority
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, 365(c), or 386(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) 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 35 U.S.C. 112(a) or the first paragraph of 35 U.S.C. 112 (pre-AlA). See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No 62/941638 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application. The applications fail to provide support for the claims under examination, since there is no disclosure therein of providing SARS-CoV2 antigens. The first evidence of support for expanding T cells in the presence of SARS-CoV2 antigens is the provisional application 63/022828 (filed May 11, 2020). As such, the effective filing date for all pending claims except claim 43 is May 11, 2020. Because claim 43 is limited to adenovirus, the effective filing date for claim 43 is November 27, 2019.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection necessitated by amendment to claim 1.
Claim 6 depends from claims 2 and 1 and recites “wherein at any time during the method the cells are expanded in the presence of one or more viral antigens and one or more cytokines to produce viral-specific T-cells. However, claim 1 already requires expanding the cells in the presence of viral antigens together with cytokines (step b), and the method would necessarily produce viral-specific T-cells. Therefore, claim 6 does not further limit the subject matter of the claims from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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). This is a new rejection necessitated by amendment.
Regarding claims 1 and 6, 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). Regarding step (b), Papadopoulou teaches incubating 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 also teaches expanding the T-cells with IL-4 and IL-7 immediately following exposure to the viral antigens (Methods, ¶3). Regarding step (e), Papadopoulou expanding the cells a second time with the cytokines (i.e., IL-4 and IL-7) (Methods, ¶3). Papadopoulou teaches that when the VSTs 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. Papadopoulou does not teach providing the IL-4 and IL-7 simultaneously with the viral antigens.
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 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 (b), Rezvani teaches the cytokines can be provided to the T-cells simultaneously in the prescience of the viral antigens ([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 step (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 claims 1 and 6, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have 1) initially expanded the T-cells using simultaneous cytokine and viral antigen incubation, 2) knocked out the NR3C1 gene using the method of Gundry and 3) expressed a heterologous CAR and in the VSTs of Papadopoulou. It would have amounted to the simple combination of elements by known means to yield predictable results. Regarding the simultaneous cytokine and viral antigen stimulation, 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. The skilled artisan would have predicted that Papadopoulou’s VSTs 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 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 provide IL-21 to the PMBCs for further expansion after genetic manipulation. 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 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, “viral-specific T cells” and “virus-specific mixture of peptide antigens” is interpreted broadly, but reasonably to include T-cells that are specific for more than one virus and peptide mixes that have peptides from more than one virus, respectively. Thus, the peptide mix of Papadopoulou encompasses “a first virus-specific mixture of peptide antigens”.
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 arguments are directed to the withdrawn rejections. However, to the extent they apply to the current §103 rejection they are addressed here.
Applicant argues that Papadopoulou generates virus-specific T cells (VSTs) using a peptide mix for three different viruses, but does not use them individually (Remarks, page 11, ¶3-4). This argument has been fully considered but is not persuasive because the claims are not limited to using antigens individually. In fact, claim 1 recites “expanding the T cells in the presence of one or more viral antigens”, but does not recite that the antigens come from a single virus and does not include viral antigens from an additional virus. Claim 9 recites a method for producing viral-specific T-cells also does not exclude T-cells that are specific for more than one virus. For instance, Papadopoulou characterizes T cells that recognize 12 antigens from 5 viruses as VSTs, which is an acronym for virus-specific T cells (Abstract). Finally, the claims use only open language through the limitations of steps and compositions, and thus encompasses combinations of antigens for more than one virus.
Applicant argues that Papadopoulou’s data wherein only 30% of engineered T cells showed activity against the viral antigens used, which would suggest to the skilled artisan that the relationship between cytokine combinations and viral antigen targets is highly variable and context-dependent (¶ spanning pages 11-12). This argument has been fully considered but is not persuasive as it does not address the merits of the rejection. Papadopoulou already teaches the combination of CMV peptides and IL-4 and IL-7. There the combination of cytokine/antigen does not require predictability in the art. Additionally, Papadopoulou notes that “failure rate” was likely due to the donors age and previous exposure to viruses. Papadopoulou concludes “our manufacturing protocol supports the generation of broad-spectrum VSTs, whose range is currently only limited by the previous viral exposure of the VST donor.” (¶ spanning pages 8-9). As such, the skilled artisan would be motivated to use, as a starting point, the manufacturing protocol in Papadopoulou.
Applicant argues that the sequence of steps is not taught, suggested or obvious and the order of steps can have significant consequences on the steps (page 13, ¶1-2). This argument has been fully considered but is moot. The current rejection addresses the order of steps. Additionally, it is noted that Applicant’s working examples and the evidence provided in the Declaration filed October 13, 2025, does not demonstrate modifying T cells to express a heterologous antigen receptor or heterologous cytokine after Cas9-mediated genome editing. If Applicant believes that the order of two genetic manipulations, viral antigen activation, and cytokine treatment is not enabled in view of the prior art, Applicant should provide evidence how Applicant’s own claimed invention is enabled.
Applicant argues that the combination of IL-4 and IL-7 provided unexpected results for expanding adenoviral-specific VSTs as discussed in the Declaration filed October 13, 2025 (¶ spanning pages 13-14). This argument has been fully considered but is not persuasive since the proffered evidence is not commiserate in scope with the claims, except for claim 43, which is indicated as allowable (see discussion below). The proffered evidence only demonstrates increased expansion numbers using AdV antigens in combination with IL-2, IL-4, IL-7, whereas the claimed combinations in claims 1 and 9 are much broader encompassing 1) combinations of viral antigens and 2) IL-4 and IL-7 with CMV and EBV, and IL-2, IL-4 and IL-7 with SARS-CoV-2 antigens.
Applicant argues that Beane does not cure the deficiencies of Papadopoulou in view of Houghtelin, Rezvani and Gundry (page 15, ¶2). Applicant also argues that Beane does not provide the motivation to combine Beane with a CRISPR platform because Beane acknowledged that only ZFNs have been used to treat patients in a clinical trial and the office has failed to articulate how the clinical-scale parameters validated for ZFN/CCR5/HIV would translated to the claimed invention (page 15, ¶3-4). These arguments have been fully considered but are not persuasive. First, a prima facie case of obviousness is established for the independent claims for the reasons set for in the §103 rejections of record and the response to Applicant' s arguments above and so Beane is not needed to cure any deficiencies. Second, in response to applicant's argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, in the art CRISPR/Cas9 methods are considered as the next generation after ZFN and TALEN-mediated methods for genetic manipulation. Beane was published in 2015, when CRISPR/Cas9-editing was in its infancy. However, by 2019, CRISPR/Cas9-mediated gene editing was well established as indicated in both Resvani and Gundry. Thus, any discoveries/advancements regarding the manufacturing of genetically modified cells by ZFNs are applicable to CRISPR/Cas9-mediated genetic modification and the skilled artisan would have been motivated to have applied them. Third, Beane’s disclosure is used as evidence to demonstrate that T cell transformation and genetic editing has a low efficiency thus requiring large numbers of starting cells. The skilled artisan would have been motivated to apply this finding to determine how many cells are needed for the related CRISPR/Cas9 editing since both technologies require delivery of nucleic acids encoding the genetic-editing machinery and selection/screening for cells having the desired edits. It was well known in the art, as evidenced by the earliest CRISPR/Cas9 references that gene editing technologies suffer from low gene-editing rates (e.g., see Mali et al., Science (2013), 339: 823-826; FIG S10). As such, the skilled artisan would have been motivated to increase the cell numbers reported in Beane for CRISPR/Cas9-mediated gene knockout.
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, 35 and 42 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 20 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 16, 30, 32, and 37 and are incorporated here. The teachings of Houghtelin are recited above in paragraph 18, 22, 34 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 39 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 16-17). 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.
Allowable Subject Matter
Claim 43 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closest prior art is Papadopoulou and Rezvani whose teachings are recited above. Papadopoulou does not teach using a combination of IL-2, IL-4 and IL-7 for expansion of T cells in combination with the adenoviral (Adv) antigens. Although IL-2, IL-4 and IL-7 are well known cytokines that have been used individually or in combination with additional cytokines for T cell expansion (e.g. see Rezvani), the specific combination of AdV antigens with IL-2, IL-4 and IL-7 has surprising efficacy on AdV-specific T cell expansion according to the proffered evidence in the Declaration filed October 13, 2025 (Fig A and B). As such it would not have been obvious to modify the methods of making Adv-specific T-cells by using the combination of IL-2, IL-4 and IL-7 for expansion.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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