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 .
Applicant’s amendment filed on 11/13/2025 has been entered.
Claims 1-16 and new claims 30-32 are pending in the present application.
Applicant elected previously without traverse the following species: (i) at least 5/10, 6/10, 7/10, 8/10, or 9/10 match at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci to each other; (ii) modified CD4+ T cells expressing CD49b; and (iii) CD4+ T cells are in a frozen suspension.
Claims 15-16 were withdrawn previously from further consideration because they are directed to a non-elected species.
Accordingly, claims 1-14 and new claims 30-32 are examined on the merits herein with the above elected species.
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.
Claims 1-4, 6-14 and new claims 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Gregori et al (WO 2016/146542) in view of Yee et al (WO 2021/231661 with an effective filing date of 05/13/2020). This is a slightly modified rejection necessitated by Applicant’s amendment, particularly for new claims 30-32.
The instant claims encompass a population of CD4+ T cells that have been genetically modified to comprise an exogenous polynucleotide encoding IL-10, wherein: (a) the CD4+ T cells were obtained from at least three different T cell donors; and (b) the exogenous polynucleotide is integrated into the T cell nuclear genome.
With respect to the elected species, Gregori et al already disclosed a homogenous IL-10-engineered CD4+ T (CD4IL-10) cell population that was generated by transducing human CD4+ T cells with a bidirectional lentiviral vector (LV) encoding for human IL-10 and ∆NGFR, as clinical grade marker gene, leading to a constitutive over-expression of IL-10 (Abstract; Summary of the Invention; and Fig. 1). As a result of transducing human CD4+ T cells with the bidirectional lentiviral vector (LV) encoding for human IL-10 and ∆NGFR, the exogenous polynucleotide encoding IL-10 is integrated into the T cell nuclear genome. Gregori et al also stated “Surprisingly, the CD4IL-10 cell population of the present invention was able to eliminate tumor, but maintained the intrinsic characteristic, Tr1-like, to prevent xeno-GVHD” (page 2, lines 23-25); “The ability of CD4IL-10 cells to eliminate myeloid leukemia in an alloAg-independent but HLA class I-dependent manner renders them an interesting tool to limit, and possibly to overcome, leukemia relapse caused by the loss of shared LA alleles after haploidentical-HSCT, or matched unrelated HSCT” (page 26, lines 17-20); and taught that CD4IL-10 cells homogenously express GzB, are CD18+, which in association with CD11a forms LFA-1, CD2+, and CD226+ (page 2, lines 34-35). Gregori et al also noted that Tr1 cells are induced in the periphery upon chronic antigen stimulation in the presence of IL-10, and are characterized by the co-expression of CD49b and LAG-3, and at least the ability to secrete IL-10 (page 1, lines 13-16). Gregori et al also disclosed that the CD4IL-10 cell secretes at least 1ng/ml of IL-10 (page 6, likes 10-17); and Fig. 1B showed that CD4IL-10 cells after stimulation with immobilized anti-CD3 and soluble anti-CD28 mAbs for 48 hours produced about 3.75 ng/mL IL-10 in culture supernatant using 2x105 cells/well (page 18, lines 11-15). Gregori et al also taught that CD4+ T cells were purified by negative selection with the CD4 T cell isolation kit with a resulting purity of >95% (page 17, lines 6-8); and transduced CD4+∆NGFR+ T cells were purified 14 days after transduction by FACS-sorting or using CD271+ Microbeads (page 17, lines 24-26).
Gregori et al did not teach explicitly at least a IL-10-engineered CD4+ T (CD4IL-10) cell population that was obtained from at least three different T cell donors; the CD4+ T cells in the population collectively have six, seven, eight, nine, ten, eleven, twelve, or more different HLA haplotypes (claim 3); or wherein all the CD4+ T cells in the population have at least 5/10, 6/10, 7/10, 8/10, or 9/10 match at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci to each other (claim 4); or wherein the CD4+ T cells in the population are present in a therapeutically effective amount and/or wherein at least 95% of the CD4+ T cells in the population are viable (new claims 30-32).
Before the effective filing date of the present application (6/28/2021), Yee et al already disclosed an engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells derived from a plurality of donors (e.g., at least about two different donors, about 5 different donors, at least about 10 different donors, or at least about 25 different donors or more), including the plurality of different donors in which two or more donors that are less than 100% human leukocyte antigen (HLA) matched, less than about 90%, less than about 80% or less than about 70% HLA matched; wherein the engineered T cell composition is used for adoptive therapy such as cancer immunotherapy and/or allogeneic therapies (see at least Abstract; Summary; particularly paragraphs [0003], [0005]-[0008], [0010], [0017], [0020], [0054], [0070]-[0071], [0122]-[0129], [0150]-[0151] and [0189]-[0191]). Yee et al taught that the engineered T cell composition contains CD4+ and CD8+ T cells (paragraph [0020]), and the engineered T cell composition is formulated, cryopreserved, and then stored for an amount of time (e.g., 1 day to six months) (paragraph [0858]). With respect to existing engineered T cells (e.g., engineered T cells expressing CARs), Yee et al noted that populations or composition from particular donors may not display any proliferation or expansion, or in some cases, may expand more slowly than those derived from another donor, and thus require extra days to complete the engineering process; and in some aspects compositions of engineered T cells that exhibit substantial variability among different individual donor subjects from which they are produced. Accordingly, the enriched CD57-T cell compositions used to produce the engineered T cell compositions of the present invention exhibit more consistent features among different T cell compositions, including a more consistent ability to undergo proliferation and expansion, such as during processes for stimulating or engineering T cells (paragraphs [0125] and [0127]). Yee et al stated clearly “[o]ne or more donors is evaluated for human leukocyte antigen (HLA) matching. HLA matching depends on the level of resolution and which HLA loci (e.g. “markers”) are assessed. In some cases, between about 6 markers and about 12 markers are assessed to determine HLA match. For example, 10 HLA markers that may be assessed are the HLA-A, -B, -C, -DRB1, and -DQB1 loci. In such cases, two individuals would be 100% HLA matched if they share all loci (e.g., 10/10) (paragraph [0190]); and “In some embodiments, a donor is evaluated for at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 HLA markers. In some embodiments, one or more donors is evaluated for HLA matching to one or more other donors, where a 100% HLA match indicates that the donors being evaluated for matching match for each HLA marker being evaluated (e.g., 6/6/, 8/8, 10/10, or 12/12 markers). In some embodiments, the plurality of different donors comprises two or more donors that are less than 100% human leukocyte antigen (HLA) matched, less than about 90% HLA matched, less than about 80% HLA matched, less than about 70% HLA matched, less than about 60% HLA matched, or less than about 50% HLA matched” (paragraph [0191]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Gregori et al by also preparing at least a IL-10-engineered CD4+ T (CD4IL-10) cell population that was obtained from at least three different T cell donors, including such engineered CD4+ T cell population is also enriched for CD57 negative and/or CD27 positive CD4+ T cells; as well as the CD4+ T cells in that population collectively have six, seven, eight, nine, ten, eleven, twelve, or more different HLA haplotypes, wherein all the CD4+ T cells in the population have at least 5/10, 6/10, 7/10, 8/10, or 9/10 match at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci to each other, in light of the teachings of Yee et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Yee et al already taught successfully preparation of an engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells derived from a plurality of donors (e.g., at least about two different donors, about 5 different donors, at least about 10 different donors, or at least about 25 different donors or more), including the plurality of different donors in which two or more donors that are less than 100% human leukocyte antigen (HLA) matched, less than about 90%, less than about 80% or less than about 70% HLA matched; and in some cases between about 6 markers and about 12 markers are assessed to determine HLA match, for example 10 HLA markers that may be assessed are the HLA-A, -B, -C, -DRB1, and -DQB1 loci. Moreover, Yee et al also taught that the enriched CD57-T cell compositions used to produce their engineered T cell compositions exhibit more consistent features among different T cell compositions, including a more consistent ability to undergo proliferation and expansion, such as during processes for stimulating or engineering T cells, in comparison with prior art engineered T-cell compositions.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Gregori et al and Yee et al as set forth above; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified population of CD4+ T cells resulting from the combined teachings of Gregori et al and Yee et al is indistinguishable and encompassed by the presently claimed invention. With respect to dependent claims 8 and 10 reciting “wherein at least 90%, at least 95%, or at least 98% of the CD4+ T cells within the population express the selection marker from the exogenous polynucleotide” and “wherein at least 90% of the CD4+ T cells within the population express IL-10”, respectively; it is noted that since the primary Gregori reference already used the same bidirectional lentiviral vector (LV) encoding for human IL-10 and ∆NGFR as that of the present application; and purifying transduced CD4+∆NGFR+ T cells by the same FACS-sorting or using CD271+ Microbeads, the modified population of CD4+ T cells would also possess the recited characteristics. Similarly, with respect to dependent claim 13 reciting that the genetically modified CD4+ T cells express CD49b, since the CD4IL-10 cell population of the Gregori et al is already Tr1-like and expresses GzB, and CD18+, which in association with CD11a forms LFA-1, CD2+, and CD226+, the modified population of CD4+ T cells would also express CD49b. With respect to new claims 30-32, due to the intrinsic characteristics of a homologous IL-10 engineered CD4+ T cell population obtained from an individual donor ( >95% purity; Gregory reference at page 17, lines 6-8 and 24-26) in the primary Gregori reference possesses which are: Tr1-like cells that suppress T-cell responses primarily via the secretion of IL-10 and TGF-beta (Gregori reference at page 6, lines 33-34), the anergic phenotype, the ability to suppress in a cell-to-cell contact independent manner in vitro (Gregori reference at page 2, lines 10-13), and prevent xeno-GVHD/suppressive function in vivo (section titled “Adoptive transfer of CD4IL-10 cells prevents xeno-GvHD while spearing the GvL of allogeneic T cells” at pages 23-24 in Gregory reference); an ordinary skill in the art would reasonably expect that in the pooled population of CD4IL-10 cells obtained from at least three different T cell donors at least 95% of the CD4IL-10 cells are viable and in a therapeutically effective amount. It is also noted that term “therapeutically effective amount” is defined by the present application to be any amount that is effective to treat, and thus ameliorate a symptom of a disease (paragraph [0104]).
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above 103 rejection in the Amendment filed on 11/13/2025 (pages 6-7) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued basically that Gregori’s disclosure is limited to CD4IL-10 cells from a single donor, and an ordinary skill in the art reading Gregori would not have been motivated to pool CD4IL-10 cells from at least 3 different donors as claimed. This is because it was well known that pooling T cells of multiple allogeneic donors (e.g., in a 2-way mixed lymphocyte culture (MLC) resulted in “fratricide”, both in mice (Exhibit A) and humans (Exhibit B) adversely affecting viability and expansion of T cells in the pooled population. With respect to the Yee reference, Applicant argued that this reference addresses an immune cell population with significantly different properties than those presently claimed, which are “engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells”. Accordingly, a person of ordinary skill would not have turned to Yee and would have no reason to expect that the CD4IL-10 cells disclosed in Gregori would not be fratricidal and in fact could be therapeutically effective when pooled from at least three donors. Additionally, Applicant argued that a person of ordinary skill would not have placed significant weight on the disclosure of Yee because the reference fails to provide experimental data demonstrating functional properties or viability of the T cells when pooled from at least three different donors (basically Yee describes multi-donor pooling prophetically, without experimental data). Applicant also argued that although Yee further suggests that deletion of beta2 microglobulin (and class I HLA molecules), endogenous TCRs, or TCR/CD3 complexes from T cells would make them less immunogenic and potentially reduce immune recognition and GvHD in the host; but none of these strategies involve IL-10. Accordingly, Yee fails to provide reasonable expectation that CD57 negative and/or CD27 positive T cells would be viable when pooled from at least three donors, let alone that claimed CD4IL-10 cells would be viable when pooled from at least three donors. In contrast, the present application provides data demonstrating that CD4IL-10 cells can be pooled without negative consequences on their viability, and the pooled CD4IL-10 cell population provides preferred biological properties such as: (i) suppression of proliferative responses of both allogeneic CD4+ and CD8+ T cells upon in vitro co-culture in MLCs; (ii) suppression of the NLRP3 inflammasome in allogeneic monocytes in vitro, resulting inhibition of the pro-inflammatory cytokines IL-1 beta and IL-18, indicating that the CD4IL-10 cells have anti-inflammatory properties; and (iii) reduction of xeno-GvHD in a standard humanized mouse model and downregulation of severe xGvHD induced by control (CD4+ T cells without IL-10 transduction). Neither Gregori nor Yee provides any teaching or suggestion that the pooled CD4IL-10 cell population would be viable and have the desired properties, which was unexpected from Greogri and Yee, alone or in combination; and no reasonable expectation of success in so doing.
First, since the above rejection was made under 35 U.S.C. 103 each of the cited references does not have to teach every element of the claims. For example, the primary Gregori reference does not have to teach or suggest pooling CD4IL-10 cells obtained from at least three different T cell donors. Nor does the Yee reference have to teach or suggest CD4IL-10 cells. It also appears Applicant considered each of the cited references in total isolation one from the other, without taking into consideration the teachings of the specific combination of Gregori et al and Yee et al.
Second, both Exhibits A and B relate to cytotoxic T lymphocytes that mediate cytotoxic response in mixed leukocyte cultures (MLC) containing alloimmune peripheral blood or spleen cells as responding cells (fully HLA-mismatched cells). Unlike cytotoxic T lymphocytes, a homologous IL-10 engineered CD4+ T cell population obtained from an individual donor ( >95% purity; Gregory reference at page 17, lines 6-8 and 24-26) in the primary Gregori reference possesses the following characteristics: Tr1-like cells that suppress T-cell responses primarily via the secretion of IL-10 and TGF-beta (Gregori reference at page 6, lines 33-34), the anergic phenotype, the ability to suppress in a cell-to-cell contact independent manner in vitro (Gregori reference at page 2, lines 10-13), and prevent xeno-GVHD/suppressive function in vivo (section titled “Adoptive transfer of CD4IL-10 cells prevents xeno-GvHD while spearing the GvL of allogeneic T cells” at pages 23-24 in Gregory reference). These immunosuppressive characteristics of CD4IL-10 cells are well known in the prior art as evidenced at least by the teachings of Andolfi et al (Molecular Therapy 20:1778-1790, 2012) and Gregori et al (Frontiers in Immunology 9; doi: 10.3389/fimmu.2018.0023; 8 pages; 2018). Due to the intrinsic immunosuppressive characteristics of these CD4IL-10 cells, an ordinary skill in the art would reasonably expect that in the pooled population of CD4IL-10 cells obtained from at least three different T cell donors there would not be any significant adverse immune response or “fratricidal” activity among the pooled CD4IL-10 cells; and at least 95% of cells in the pooled CD4IL-10 cell population are viable and in a therapeutically effective amount; let alone CD4IL-10 cells obtained from at least 3 T cell donors who are fully HLA matched (encompassed by the claims). Please also note that the standard under 35 U.S.C. is a “reasonable” expectation of success and not certainty.
Third, the Yee reference was cited to supplement the primary Gregori reference because the Yee reference already disclosed an engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells derived from a plurality of donors (e.g., at least about two different donors, about 5 different donors, at least about 10 different donors, or at least about 25 different donors or more), including the plurality of different donors in which two or more donors that are less than 100% human leukocyte antigen (HLA) matched, less than about 90%, less than about 80% or less than about 70% HLA matched; wherein the engineered T cell composition is used for adoptive therapy such as cancer immunotherapy and/or allogeneic therapies. Additionally, the teachings of Yee et al are not necessarily limited only to working examples. It is noted that CD4IL-10 cells of the primary Gregori reference are also “engineered” T cells. Additionally, similar to the teachings of Yee et al the prior art in the form of Sourdive et al (WO 2015/075175; IDS) also taught a method of pooling lymphocytes from different donors (e.g., from at least three donors, more preferably between 3 and 10 donors) to avoid NK alloreactivity and anti-HLA immune response, wherein lymphocytes from each donor are inactivated for at least a gene encoding a TCR component (see at least Abstract; Summary of the Invention; page 5, lines 15-23). Sourdive et al stated clearly “Lymphocytes of these batches are characterized in that they do not express TCR at the surface of the cell to avoid GVHD and are originated from different donors to minimize effect of anti-HLA immunoreactivity in patients and reduces NK alloreactivity” (page 3, lines 21-23); and “Thus, the pooling strategy ideally focuses on maintaining sufficient HLA diversity to avoid NK alloreactivity and anti-HLA antibodies depletion of the major population of transplanted cells” (page 5, lines 12-14). Accordingly, before the effective filing date of the present application (6/28/2021) the concept of pooling lymphocytes (e.g., engineered T cells) from at least three different donors was neither novel nor non-obvious.
Fourth, an ordinary skill in the art would reasonably expect that CD57 negative and/or CD27 positive CD4IL-10 T cells would be viable when pooled from at least three different T cell donors (including fully HLA-matched donors) on the basis of the immunosuppressive characteristics possessed by CD4IL-10 T cells as discussed in the preceding paragraphs. Once again, the standard under 35 U.S.C. is a “reasonable” expectation of success and not certainty.
Fifth, there is nothing that is unexpected regarding to the characteristics exhibited by the pooled CD4IL-10 T cell population of the present application since a homologous IL-10 engineered CD4+ T cell population obtained from an individual donor ( >95% purity; Gregory reference at page 17, lines 6-8 and 24-26) in the primary Gregori reference already possesses the following characteristics: Tr1-like cells that suppress T-cell responses primarily via the secretion of IL-10 and TGF-beta (Gregori reference at page 6, lines 33-34), the anergic phenotype, the ability to suppress in a cell-to-cell contact independent manner in vitro (Gregori reference at page 2, lines 10-13), and prevent xeno-GVHD/suppressive function in vivo (section titled “Adoptive transfer of CD4IL-10 cells prevents xeno-GvHD while spearing the GvL of allogeneic T cells” at pages 23-24 in Gregory reference).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Gregori et al (WO 2016/146542) in view of Yee et al (WO 2021/231661 with an effective filing date of 05/13/2020) as applied to claims 1-4, 6-14 and 30-32 above, and further in view of Hamburger et al (US 2022/0315931 with the effective filing date of 03/26/2021).
The combined teachings of Gregori et al and Yee et al were presented above. However, none of the cited references teach or suggest that all the CD4+ T cells in the population have an A*02 allele.
Before the effective filing date of the present application (6/28/2021), Hamburger et al already disclosed immune cells (e.g., T cells, B cells, or NK cells) expressing engineered receptors for use in adoptive cell therapy, wherein the immune cells comprising an inhibitory receptor comprising a ligand binding domain specific to a class I major histocompatibility complex (MHC-I) molecule, or a peptide-MHC complex thereof; and particularly the HLA class I allele comprises HLA-A*02, and wherein expression and/or function of beta-2-microglobulin (B2M) in the immune cells has been reduced or eliminated (see at least Summary; particularly paragraphs [0007]-[0010], [0014] and [0049]). Hamburger et al also taught that the immune cells use a two- receptor system, in which activator and inhibitory signals are integrated at the cellular level within the immune cells, by which selective targeting of tumor but not non-tumor cells based on loss of heterozygosity is achieved (paragraph [0038]; and Figs. 2A, 2B, 3A and 3B); and the two receptor system can be expressed in allogeneic immune cells specifically engineered to decrease complications such as graft versus host disease (GvHD) and host versus graft disease (HvG) (paragraph [0039]). Hamburger et al stated “In some embodiments, the allogeneic immune cells comprise an activator receptor, an inhibitory receptor, and an endogenous TCR (i.e., the allogeneic immune cells have not been modified to reduce or eliminate expression of one or more TCR subunits). In some embodiments, expression of the inhibitory receptor by the allogeneic immune cells, for example an inhibitory receptor that targets HLA-A*02, reduces or eliminates GvHD” (paragraph [0115]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to further modify the combined teachings of Gregori et al and Yee et al by also preparing the CD4IL-10 cell population obtained from at least three different T cell donors, in which cell population all the CD4+ T cells have an “A*02 allele, in light of the teachings of Hamburger et al as presented above.
An ordinary skilled artisan would have been motivated to further carry out the above modification to take advantage of the use of a two-receptor system comprising an inhibitory receptor that targets HLA-A*02 in allogeneic immune cells as described by Hamburger et al to reduce or eliminate GvHD.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Gregori et al, Yee et al and Hamburger et al as set forth above; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified population of CD4+ T cells resulting from the combined teachings of Gregori et al, Yee et al and Hamburger et al is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above 103 rejection in the Amendment filed on 11/13/2025 (pages 7-8) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued basically that Hamburger does not cure the deficiencies of Gregori and Yee since it also fails to disclose a population of CD4IL-10 cells generated from CD4+ T cells obtained from at least three different T cell donors. Even if Hamburger disclosed “HLA-A*02” recited in dependent claim 5, the reference does not render the claims obvious because it does not address the limitation that “the CD4+ T cells were obtained from at least three different T cell donors” which is missing from Gregori and Yee along with the arguments set forth above for the rejection of claims 1-4, 6-14 and 30-32 above.
Please refer to the examiner’s same responses to Applicant’s arguments on the deficiency of Gregori and Yee for the rejection of claims 1-4, 6-14 and 30-32 above. Additionally, since the rejection was made under 35 U.S.C. 103, each of the cited references does not have to teach every limitation of the instant claim. In this instance, the Hamburger reference does not have to teach a population of CD4IL-10 cells generated from CD4+ T cells obtained from at least three different T cell donors.
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 1-14 and new claims 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 16, 26-27, 34, 37, 39, 41, 46, 48 and 61-63 of copending Application No. 18/725,659 (reference application). This is a slightly modified rejection necessitated by Applicant’s amendment, particularly new claims 30-32.
Although the claims at issue are not identical, they are not patentably distinct from each other because a population of CD4+ T cells that have been genetically modified to comprise an exogenous polynucleotide encoding IL-10, wherein (a) the CD4+ T cells were obtained from at least two different T cell donors; and (b) the exogenous polynucleotide is integrated into the T cell nuclear genome, including the population in which at least 90% of the CD4+ T cells within the population express IL-10 (the CD4+ T cells must be viable and in a therapeutically effective amount, dependent claim 37), the population in which at least 95%, or at least 98% of the CD4+ T cells within the population express the selection marker from the exogenous polynucleotide (the CD4+ T cells must be viable and in a therapeutically effective amount; dependent claim 46), in claims 1-4, 16, 26-27, 34, 37, 39, 41, 46, 48 and 61-63 of copending Application No. 18/725,659 anticipates the population of CD4+ T cells that have been genetically modified to comprise an exogenous polynucleotide encoding IL-10 in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. It is noted that term “therapeutically effective amount” is defined by the present application to be any amount that is effective to treat, and thus ameliorate a symptom of a disease (paragraph [0104]).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 6-8, 10-13 and new claims 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 (reference application). This is a slightly modified rejection necessitated by Applicant’s amendment, particularly new claims 30-32.
Although the claims at issue are not identical, they are not patentably distinct from each other because a population of CD4+ T cells that have been genetically modified to comprise an exogenous polynucleotide encoding IL-10, wherein the CD4+ T cells were obtained from at least three different T cell donors (poly-donor CD4IL-10 cells), including wherein the exogenous polynucleotide is integrated into the T cell nuclear genome (dependent claim 24), wherein at least 90% of the CD4+ T cells within the population express IL-10 (dependent claim 28), wherein at least at least 90% of the CD4+ T cells within the population express the selection marker from the exogenous polynucleotide (dependent claim 37), and a pharmaceutical composition comprising the same population in claims 1, 3-4, 14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 anticipate/encompass the population of CD4+ T cells that have been genetically modified to comprise an exogenous polynucleotide encoding IL-10 in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. It is noted that term “therapeutically effective amount” is defined by the present application to be any amount that is effective to treat, and thus ameliorate a symptom of a disease (paragraph [0104]).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 5, 9 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 (reference application) in view of Hamburger et al (US 2022/0315931 with the effective filing date of 03/26/2021), Gregori et al (WO 2016/146542) and Yee et al (WO 2021/231661 with an effective filing date of 05/13/2020).
The instant claims differ from claims 1, 3-4, 14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 in reciting specifically “wherein all the CD4+ T cells in the population have an A*02 allele” (claim 5); “wherein the exogenous polynucleotide further comprises lentiviral vector sequences” (claim 9), and “wherein the CD4+ T cells are in a frozen suspension” (claim 14).
Before the effective filing date of the present application (06/28/2021), Hamburger et al already disclosed immune cells (e.g., T cells, B cells, or NK cells) expressing engineered receptors for use in adoptive cell therapy, wherein the immune cells comprising an inhibitory receptor comprising a ligand binding domain specific to a class I major histocompatibility complex (MHC-I) molecule, or a peptide-MHC complex thereof; and particularly the HLA class I allele comprises HLA-A*02, and wherein expression and/or function of beta-2-microglobulin (B2M) in the immune cells has been reduced or eliminated (see at least Summary; particularly paragraphs [0007]-[0010], [0014] and [0049]). Hamburger et al also taught that the immune cells use a two- receptor system, in which activator and inhibitory signals are integrated at the cellular level within the immune cells, by which selective targeting of tumor but not non-tumor cells based on loss of heterozygosity is achieved (paragraph [0038]; and Figs. 2A, 2B, 3A and 3B); and the two receptor system can be expressed in allogeneic immune cells specifically engineered to decrease complications such as graft versus host disease (GvHD) and host versus graft disease (HvG) (paragraph [0039]). Hamburger et al stated “In some embodiments, the allogeneic immune cells comprise an activator receptor, an inhibitory receptor, and an endogenous TCR (i.e., the allogeneic immune cells have not been modified to reduce or eliminate expression of one or more TCR subunits). In some embodiments, expression of the inhibitory receptor by the allogeneic immune cells, for example an inhibitory receptor that targets HLA-A*02, reduces or eliminates GvHD” (paragraph [0115]).
Additionally, Gregori et al already disclosed a homogenous IL-10-engineered CD4+ T (CD4IL-10) cell population that was generated by transducing human CD4+ T cells with a bidirectional lentiviral vector (LV) encoding for human IL-10 and ∆NGFR, as clinical grade marker gene, leading to a constitutive over-expression of IL-10 (Abstract; Summary of the Invention; and Fig. 1).
Moreover, Yee et al also disclosed an engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells derived from a plurality of donors (e.g., at least about two different donors, about 5 different donors, at least about 10 different donors, or at least about 25 different donors or more), including the plurality of different donors in which two or more donors that are less than 100% human leukocyte antigen (HLA) matched, less than about 90%, less than about 80% or less than about 70% HLA matched; wherein the engineered T cell composition is used for adoptive therapy such as cancer immunotherapy and/or allogeneic therapies (see at least Abstract; Summary; particularly paragraphs [0003], [0005]-[0008], [0010], [0017], [0020], [0054], [0070]-[0071], [0122]-[0129], [0150]-[0151] and [0189]-[0191]). Yee et al taught that the engineered T cell composition contains CD4+ and CD8+ T cells (paragraph [0020]), and the engineered T cell composition is formulated, cryopreserved, and then stored for an amount of time (e.g., 1 day to six months) (paragraph [0858]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the population of CD4+ T cells that have been genetically modified to comprise an exogenous polynucleotide encoding IL-10 in claims 1, 3-4, 14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 by also preparing the CD4IL-10 cell population obtained from at least three different T cell donors, in which cell population all the CD4+ T cells have an “A*02 allele; using a bidirectional lentiviral vector (LV) encoding for human IL-10 and ∆NGFR for transducing CD4+ T cells; as well as preparing the CD4IL-10 cell population obtained from at least three different T cell donors in a form of a frozen suspension; in light of the teachings of Hamburger et al, Gregori et al and Yee et al as set forth above with a reasonable expectation of success.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) to take advantage of the use of a two-receptor system comprising an inhibitory receptor that targets HLA-A*02 in allogeneic immune cells as described by Hamburger et al to reduce or eliminate GvHD; (ii) Gregori et al already successfully prepared a homogenous IL-10-engineered CD4+ T (CD4IL-10) cell population that was generated by transducing human CD4+ T cells with a bidirectional lentiviral vector (LV) encoding for human IL-10 and ∆NGFR, as clinical grade marker gene, leading to a constitutive over-expression of IL-10; and (iii) Yee et al also taught successfully an engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells derived from a plurality of donors, and that such engineered T cell composition is formulated, cryopreserved, and then stored for an amount of time (e.g., 1 day to six months) until use.
The genetically modified population of CD4+ T cells resulting from claims 1, 3-4, 14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 along with teachings of Hamburger et al, Gregori et al and Yee et al is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
In the Amendment dated 11/14/2015 (pages 8-9), Applicant simply stated that the above provisional double patenting rejections would be addressed upon an indication of allowable subject matter in this application.
Conclusions
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631