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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/24/2026 has been entered.
Claims 1-16, 30-32 and new claims 33-40 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Claims 15-16 were withdrawn previously from further consideration because they are directed to a non-elected species.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 30-40 are examined on the merits herein with the above elected species.
Response to Amendment
All provisional nonstatutory double patenting rejections 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14, 18, 24, 28, 31, 33, 37, 40, 42, 50, 53 and 56 of copending Application No. 18/013,868 (reference application) were withdrawn because the copending Application has been abandoned.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 39 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The terms “high levels” and “low levels” in claim 39 are relative terms which render the claim indefinite. The terms “high levels” and “low levels” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Please note that a level that is considered to be high for an individual may not be high for another individual. Similarly, a level that is considered to be low for an individual may not be high for another individual. Accordingly, clarification is requested because the metes and bounds of the claim are not clearly determined.
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 30-40 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) and Sourdive et al (WO 2015/075175; IDS). This is a new ground of rejection.
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 HLA 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.
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/or CD8+ T cells (paragraphs [0010] and [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]). Yee et al also taught specifically that an engineered composition from an individual donor is combined with an engineered composition from one or more other individual donors to produce a pooled engineered composition from a plurality of different donors (paragraph [0123]). 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]).
Additionally, Sourdive et al already taught the generation of at least one batch of inactivated TCR lymphocytes originating from different donors to avoid NK alloreactivity and anti-HLA immune response for the treatment of cancer, viral infection, or auto-immune disease (Abstract; and Summary of the Invention). Sourdive stated “a batch is considered here as the result of pooling different cells from different donor samples” (line 18 at page 16). Sourdive disclosed that the inactivation of TCRalpha or TCRbetaq can result in the elimination of the TCR from the surface of T cells preventing recognition of alloantigen and thus graft versus host disease (GVHD) (lines 11-17 at page 2). Sourdive et al also stated “The generation and the use of a batch of T cells originating from different donors, preferably selected to express varied HLA types increase the probability to have a population of cells which express appropriate HLA class I molecule recognized by the KIR of NK cells, and thus inhibit the attack of the NK cells. 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” (lines 9-14 at page 5); and “For instance, in situations where a minimal number of donors is sought for limiting the risk of infectious diseases, while providing sufficient diversity for a high probability of engraftment, sufficient HLA diversity can be obtained by pooling lymphocytes originating from at least three donors, preferably between 3 and 50 donors, more preferably between 3 and 30, even more preferably between 3 and 10 donors” (lines 17-22 at page 5).
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 CD4+ T cells in that population collectively have six, seven, eight, nine, ten, eleven, twelve, or more different HLA haplotypes, wherein all 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 and Sourdive et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Yee et al already taught 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; and (ii) Sourdive et al also taught the generation of at least one batch of inactivated TCR lymphocytes originating from different donors (e.g., pooling lymphocytes originating from at least three donors, preferably between 3 and 50 donors, more preferably between 3 and 30, even more preferably between 3 and 10 donors) to avoid NK alloreactivity and anti-HLA immune response for the treatment of cancer, viral infection, or auto-immune disease. Thus, the concept of pooling engineered T cells from at least three different donors for adoptive therapy such as cancer immunotherapy has been taught by both Yee et al and Sourdive et al. Moreover, please also note that each homogenous IL-10-engineered CD4+ T (CD4IL-10) cell population from an individual donor of Gregori et al already exhibits Tr1-like cells that suppress T-cell responses primarily via the secretion of IL-10 and TGF-beta, having an anergic phenotype, an ability to suppress in a cell-to-cell contact independent manner in vitro, and prevent xeno-GVHD function in vivo.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Gregori et al, Yee et al and Sourdive 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 Sourdive 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 claims 13, 33-34 and 36-37 reciting that the genetically modified CD4+ T cells express one or more of the recited markers that includes 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 the same recited markers including CD49b. With respect to 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 at page 6, lines 33-34), an anergic phenotype, an ability to suppress in a cell-to-cell contact independent manner in vitro (Gregori at page 2, lines 10-13), and prevent xeno-GVHD 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 Gregori); 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 also viable due to the lack of fratricide for the rationale set forth above 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]). With respect to claims 38-40, since the modified population of CD4IL-10 cells resulting from the combined teachings of Gregori et al, Yee et al and Sourdive et al is indistinguishable from that of the presently claimed invention, such modified population of CD4IL-10 cells also possess the recited characteristics such as an ability to inhibit or reduce GvHD, recited cytokine production profile, and/or an elevated IL-10 level relative to unmodified CD4+ cells).
Please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
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 in part to the above 103 rejection in the Amendment filed on 04/24/2026 (pages 7-17) along with the 1.132 Declaration of Dr. Robertson Parkman have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
A. Applicant argued that the combination of Gregori and Yee does not provide an adequate motivation to combine.
Specifically, Applicant argued that the Examiner relies on the anergic phenotype of CD4IL10 cells as a basis for expecting no adverse immune response in a pooled setting, while also relying on Yee’s multi-donor pooling strategy as a basis for combining cells from multiple donors; and that these two positions rest on opposing biological properties which a person of ordinary skill would have recognized, particularly Yee identifies donor-to-donor variability in T-cell expansion as the central problem that its selection strategy is designed to solve and selects for CD57- and/or CD27+ T cells, because these subpopulations exhibit superior proliferative capacity and more consistent expansion kinetics across different donors (Declaration No. 4). This proliferative capacity is precisely the property that the Examiner treats as absent from CD4IL-10 cells by virtue of Gregori’s anergic phenotype. Since the Yee and Gregori platforms are built on opposing biological premises, an ordinary skill in the art would not have a motivation to combine two platforms built on such opposing biological premises (Declaration No. 4); and Yee teaches away from applying its multi-donor pooling strategy to the CD4IL-10 platform. Applicant also cited In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) and DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1326-27 (Fed. Cir. 2009) to support the teaching-away of Yee from applying its multi-donor pooling strategy to Gregori’s CD4IL-10 platform.
First, the only difference between the teachings of the primary Gregori reference and the presently claimed invention is that a population of CD4IL-10 T cells is obtained or pooled from at least three different T cell donors, rather than from a single T cell donor as taught by Gregori. However, the concept of pooling engineered T cells from at least three different donors for adoptive therapy such as cancer immunotherapy has been taught by both Yee and Sourdive, and therefore it would have been obvious for an ordinary skill in the art to modify the teachings of Gregori by also preparing an IL-10-engineered CD4+ T (CD4IL-10) cell population that was obtained/pooled from at least three different T cell donors with a reasonable expectation of success, particularly each homogenous IL-10-engineered CD4+ T (CD4IL-10) cell population from an individual donor of Gregori already exhibits Tr1-like cells that suppress T-cell responses primarily via the secretion of IL-10 and TGF-beta, having an anergic phenotype, the ability to suppress in a cell-to-cell contact independent manner in vitro, and prevent xeno-GVHD function in vivo. Please refer to the above modified 103 rejection for details along with the provided motivations.
Second, please note that the IL-10-engineered CD4+ T (CD4IL-10) cell population of Gregori, the engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells of Yee, and the inactivated TCR lymphocytes of Sourdive are distinct T cell populations having different properties from one another. The pooling strategy is not dependent on any particular property exhibited by any particular T cell population. For examples, Yee taught specifically that an engineered composition from an individual donor is combined with an engineered composition from one or more other individual donors to produce a pooled engineered composition from a plurality of different donors (paragraph [0123]). Similarly, Sourdive stated “a batch is considered here as the result of pooling different cells from different donor samples” (line 18 at page 16). Thus, there is no teaching away whatsoever by Yee, and based on the teachings of Gregori, Yee and Sourdive an ordinary skill in the art would readily recognize that an IL-10-engineered CD4+ T (CD4IL-10) cell population obtained from at least three different T cell donors could readily be prepared by pooling CD4IL-10 cell populations derived from a plurality of different T cell donors.
B. Applicant argued that Sourdive confirms that TCR inactivation is a prerequisite for multi-donor pooling and does not support combining Gregori with Yee.
Applicant argued that Sourdive underscores the biological risk of pooling as understood in the art prior to Applicant’s invention. Specifically, Sourdive requires TCR inactivation as the specific engineering solution, stating that TCR inactivation “allows pooling cells from different donors and avoiding GvHD”. In contrast to Sourdive, TCR activation of CD4IL-10 cells of the present application is necessary for activation and IL-10 production of these cells, meaning that in a multi-donor pooled setting, the very TCR-mediated allorecognition that poses a fratricide risk is also the mechanism required to elicit the immunosuppressive IL-10 response (Declaration No. 2). Applicant also argued that because both Gregori’s CD4IL-10 cells and CD4IL-10 of the present application retain functional TCRs, Sourdive does not provide a motivation to pool them in the manner the Examiner proposes.
Like inactivated TCR lymphocytes originating from different donors of Sourdive, each homologous IL-10 engineered CD4+ T cell population obtained from an individual donor of Gregori 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), an anergic phenotype, an 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 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 Gregori). Because of the immunosuppressive nature of CD4IL-10 cells and particularly the potent immunosuppressive cytokine IL-10, an ordinary skill in the art would reasonably expect that homologous IL-10 engineered CD4+ T cell populations obtained from multiple donors would not cause fratricide. Once again, the concept of pooling engineered T cells from at least three different donors for adoptive therapy such as cancer immunotherapy has been taught by both Yee and Sourdive (a motivation).
C. Applicant argued that the cited references do not provide a reasonable expectation of success for multi-donor pooling of CD4IL-10 cells.
(i) Unresolved scientific questions preclude a reasonable expectation of success.
Gregori describes a specific killing mechanism in which CD4IL-10 cells recognize and destroy target cells that display a particular surface marker called CD13, which is found in certain myeloid cells, via HLA class I-dependent killing mechanism; but CD4IL-10 cells themselves do not express CD13, and therefore cannot activate this particular killing pathway against each other (Declaration No. 1). However, Applicant argued that this observation does not address the relevant biological risk in a multi-donor pooling context that occurs through an entirely different mechanism: TCR-mediated allorecognition (Declaration Nos. 1-2); and the Examiner failed to address the distinct TCR-mediated allorecognition that poses the actual biological risk of fratricide when cells from multiple HLA-mismatched donors are combined. This risk of fratricide through TCR-mediated allorecognition is real since Sourdive expressly identified this problem and requires TCR inactivation as a prerequisite for multi-donor pooling; as well as previously submitted Exhibits A-B further corroborate this risk. Applicant also argued that the Examiner has not identified any reference addressing whether the immunosuppressive (Tr1-like) properties of CD4IL-10 cells could serve as a substitute for TCR inactivation that Sourdive requires for multi-donor pooling (Declaration 2-3); nor any reference addressing at least the issue whether the immunosuppressive properties of CD4IL-10 cells would suffice to prevent fratricide or functional impairment, and/or whether CD4IL-10 cells bearing functional TCRs would trigger cytotoxicity against allogeneic CD4IL-10 cells through TCR-mediated allorecognition. Applicant further argued that the Examiner’s assertion that the immunosuppressive properties of Gregori’s CD4IL-10 cells would prevent any significant adverse immune response in a pooled multi-donor setting is a scientific inference that is not supported by experimental data or mechanistic teaching in the prior art (Declaration No. 6); and this type of unpredictability weighs against a finding of reasonable expectation of success.
First, both previously sumitted 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; Gregori 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 at page 6, lines 33-34), an anergic phenotype, the ability to suppress in a cell-to-cell contact independent manner in vitro (Gregori at page 2, lines 10-13), and prevent xeno-GVHD 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 Gregori). These immunosuppressive characteristics of CD4IL-10 cells and particularly the potent immunosuppressive cytokine IL-10 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).
Second, the Examiner has cited experimental data in Gregori along with other evidences in the form 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); and the rationale why an ordinary skill in the art would not expect that CD4IL-10 cell populations pooled from multiple donors cause fratricide. Particularly, Gregori demonstrated clearly at least that each CD4IL-10 cell population from a single donor already prevents xeno-GVHD function in vivo. Instead, Applicant has not provided any objective evidence to indicate otherwise and rely solely on arguments. Please also note that the standard under 35 U.S.C. is a “reasonable” expectation of success and not certainty. Moreover, please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
(ii) The immunosuppressive properties of CD4IL-10 cells were characterized only in single-donor systems, and Yee does not resolve the resulting uncertainty.
Applicant argued that the immunosuppressive of CD4IL-10 cells have been characterized in single-donor in which the CD4IL-10 cells are not themselves targets of allorecognition (Declaration No. 3), and thus Gregori’s data leave unaddressed whether the immunosuppressive properties of CD4IL-10 cells would prevent fratricide in a multi-donor pooled setting. Applicant also argued that Yee describes multi-donor pooling prophetically, without experimental data demonstrating functional properties or viability of pooled T cells from three or more different donors. Moreover, Yee’s pooling rationale is inapplicable to the anergic CD4IL-10 cells platform (Declaration No. 4), and Yee’s own contemplation of optional TCR and MHC I knockout steps appears to acknowledge, rather than resolve, the alloimmune risks inherent in multi-donor pooling (Declaration No. 5). Accordingly, the scientific uncertainty of pooling Gregori’s CD4IL-10 cells in multi-donor systems remains unresolved by the cited art.
Please refer to the Examiner’s responses in the above Sections. Basically, the Examiner has cited experimental data in Gregori along with other evidences in the form 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); and the rationale why an ordinary skill in the art would not expect that CD4IL-10 cell populations pooled from multiple donors cause fratricide. Particularly, Gregori demonstrated clearly at least that each CD4IL-10 cell population from a single donor already prevents xeno-GVHD function in vivo. It has been noted that the IL-10-engineered CD4+ T (CD4IL-10) cell population of Gregori, the engineered T cell composition enriched for CD57 negative and/or CD27 positive T cells of Yee, and the inactivated TCR lymphocytes of Sourdive are distinct T cell populations having different properties from one another. The pooling strategy is not dependent on any particular property exhibited by any particular T cell population. For examples, Yee taught specifically that an engineered composition from an individual donor is combined with an engineered composition from one or more other individual donors to produce a pooled engineered composition from a plurality of different donors (paragraph [0123]). Similarly, Sourdive stated “a batch is considered here as the result of pooling different cells from different donor samples” (line 18 at page 16). Thus, there is no teaching away whatsoever by Yee, and based on the teachings of Gregori, Yee and Sourdive an ordinary skill in the art would readily recognize that an IL-10-engineered CD4+ T (CD4IL-10) cell population obtained from at least three different T cell donors could readily be prepared by pooling CD4IL-10 cell populations derived from a plurality of different T cell donors.
D. The Examiner’s reliance on fully HLA-matched donors does not establish a reasonable expectation of success across the claimed scope.
Applicant argued that the claimed subject matter expressly encompasses partial HLA matching as low as 5/10 at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQBI loci (claim 4); and therefore a reasonable expectation of success must be established for the full scope of the claimed invention, including these partially HLA-mismatched embodiments. Moreover, even full HLA matching at the assessed loci does not preclude TCR-mediated allorecognition at unassessed loci. Accordingly, the Examiner’s reliance on fully HLA-matched donors therefore does not establish a reasonable expectation of success across the claimed scope.
The examiner merely noted that the instant claims encompass an embodiment in which at least three different T-cell donors are fully HLA-matched donors. The examiner does not rely solely fully HLA-matched donors to establish a reasonable expectation of success across the claimed scope as Applicant alleged. Once again, each homologous IL-10 engineered CD4+ T cell population obtained from an individual donor of Gregori 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), an anergic phenotype, an 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 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 Gregori). Because of the immunosuppressive nature of CD4IL-10 cells and particularly the potent immunosuppressive cytokine IL-10, an ordinary skill in the art would reasonably expect that homologous IL-10 engineered CD4+ T cell populations obtained from multiple donors would not cause fratricide.
E. The application’s demonstrated results are unexpected and constitute objective evidence of non-obviousness.
Applicant argued that the present application provides the first experimental evidence demonstrating that: (i) pooled allogeneic CD4IL-10 cells from multiple HLA-mismatched donors contained greater than 95% viable cells, indicating absence of fratricide (paragraph [0250] of the specification); (ii) the pooled population suppressed proliferative responses of allogeneic CD4+ and CD8+ T cells in mixed lymphocyte cultures (paragraph [0253] of the specification); and (iii) the pooled population reduced xeno-GvHD in a humanized mouse model (paragraphs [0267]-[0268] of the specification) (Declaration No. 6). Applicant further argued that the Examiner’s analysis appears to treat two distinct scientific concepts as interchangeable: single-donor purity and multi-donor viability. As explained in Declaration No. 6, Gregori’s greater than 95% purity is a measure of cellular composition within a single donor-preparation following purification, it is not a measure of cell viability in a pooled multi-donor setting exposed to the alloimmune interactions discussed previously. Once again, the Examiner’s reliance on Gregori’s single-donor purity does not establish a reasonable expectation that pooled multi-donor CD4IL-10 cells would satisfy the limitations recited in claims 30-32. The current application demonstrates that pooled allogeneic CD4IL-10 cells from multiple HLA-mismatched donors were viable, did not induce fratricide, and retained Tr1-like immunosuppressive function (paragraph [0250] of the specification). Thus, these are positive results that no cited reference provided an experimental basis for predicting (Declaration No. 6), and thus these results constitute objective evidence of non-obviousness applicable to the pending claims.
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; Gregori 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 at page 6, lines 33-34), an anergic phenotype, an ability to suppress in a cell-to-cell contact independent manner in vitro (Gregori at page 2, lines 10-13), and prevent xeno-GVHD 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 Gregori). Because of the immunosuppressive nature of CD4IL-10 cells and particularly the potent immunosuppressive cytokine IL-10 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), an ordinary skill in the art would reasonably expect that homologous purified IL-10 engineered CD4+ T cell populations obtained from multiple donors would not cause fratricide. Accordingly, due to the lack of fratricide for the rationale set forth above an ordinary skill in the art would also reasonably expect that at least 95% of cells in the pooled and purified CD4IL-10 cell population are viable and in a therapeutically effective amount. Moreover, please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
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) and Sourdive et al (WO 2015/075175; IDS) as applied to claims 1-4, 6-14 and 30-40 above, and further in view of Ellis et al (Human Immunology 61:334-340, March 2000). This is a new ground of rejection.
The combined teachings of Gregori et al, Yee et al and Sourdive 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), Ellis et al already disclosed that HLA-A2 is frequent in all ethnic groups, with many studies have shown there is a predominance of HLA-A*02011 in all ethnic groups (the paragraph bridging left and right columns at page 334; and Table 1). Ellis et al also taught that HLA-A2 is particular important because it is widely present in the human population; thus, it may be a powerful target for the design of peptide-based vaccines with various in vitro studies and clinical trials have used HLA-A2 as a target to present melanoma-associated antigens to CTLs (right column, first paragraph at page 335). Ellis et al further taught that HLA-A*02011 allele is the most frequently detected HLA-A2 allele in all five US population groups (Caucasian, African-American, Asian/Pacific Islander, Hispanic and Native American populations), and particularly predominant (96%) in the Caucasian population (Abstract; Fig. 1 and Table 2).
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, Yee et al and Sourdive et al by also preparing a 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 Ellis et al as presented above.
An ordinary skilled artisan would have been motivated to further carry out the above modification because Ellis et al taught that HLA-A*02011 allele is the most frequently detected HLA-A2 allele in all five US population groups (Caucasian, African-American, Asian/Pacific Islander, Hispanic and Native American populations), and particularly predominant (96%) in the Caucasian population.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Gregori et al, Yee et al, Sourdive et al and Ellis et al 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, Sourdive et al and Ellis 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.
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 30-40 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).
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]).
Please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In the Amendment dated 04/24/2026 (page 17), 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.
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
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