DETAILED ACTION
Claims 1-12 are currently pending.
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 .
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US21/059137, filed November 12, 2021, which claims the benefit of provisional application No. 63/113,369, filed November 13, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/9/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification (pages 46-49) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: the abbreviation BHLHE40 ((Basic Helix-Loop-Helix Family Member E40) should first be spelled out upon its first usage in a claim. Appropriate correction is required.
Claim Interpretation
Regarding claim 11, claim 11 recites the following:
“An engineered cell population produced by the method of claim 1.”
It is noted the limitations “engineered” and “produced by the method of claim 1” are directed to the manner by which the T cell population has been produced. Such limitations are product-by-process limitations which appear to define the T cell population. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the claimed T cells have been produced is not sufficiently detailed so as to impart any unique structural/chemical properties to the T cells.
If the product by process limitations are considered, the process imparts the feature of T cells having some amount of expression of BHLHE40, or no expression due to mutation or deletion of BHLHE40. Thus, any T cell having any amount of BHLHE40, including no expression due to mutation or deletion of BHLHE40, would appear to read on the claimed T cells.
Further, it is noted various claims (3, 5, 7 and 8) recite the phrases “down-regulating” or “down-regulated” or “down-regulation”.
It is noted the specification does not provide any specific definition or parameters regarding said limitations. Therefore, it is noted the dictionary definition of said terms indicates the process of reducing or suppressing a response to stimulus (see Merriam-Webster, downregulation; see PTO-892).
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 10 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.
Claim 10 depends directly from claim 1. Claim 10 recites the limitation “wherein a CAR T cell is engineered to over-express BHLHE40, which cells are reduced in their tendency to exhaustion.”
Given claim 1 recites a plurality of T cells and claim 10 recites “a CAR T cell”, singular, claim 10 is rendered indefinite since it is unclear if the CAR T cell recited in claim 10 is the population of T cells recited in claim 1 or if the claim means a CAR T cell is combined with the population of T cells of claim 1.
Further regarding claim 10, it is unclear if the phrase “which cells are reduced in their tendency to exhaustion” means the plurality of cells of claim 1.
In the interest of compact prosecution, it is noted claim 10 is interpreted as CAR T cell is combined with the population of T cells of claim 1 and expression of BHLHE40 reduces the tendency of exhaustion for the CAR T cell.
Additionally, regarding claim 10, it is noted the term “over-express” in claim 10 is a relative term which renders the claim indefinite. The term “over-express” is 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. One of ordinary skill in the art would not understand the metes and bounds of the term since this term is relative to an unidentified basal expression. Moreover, protein expression is ever changing as it is influenced by numerous environmental or chemical factors, such as temperature or pH, for example. The specification does not define any parameters regarding what is meant by “over-express”.
Appropriate clarification is appreciated.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 11 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon, without significantly more. The claim(s) recite(s)
“An engineered cell population produced by the method of claim 1.”
As set forth above at Claim Interpretation, it is noted the method by which the claimed T cells have been produced, i.e., “engineered” and by “modulating expression”, is not sufficiently detailed so as to impart any unique structural/chemical properties to the T cells, and if the product by process limitations are considered, the process imparts the feature of T cells having some amount of expression of BHLHE40, or no expression due to mutation or deletion of BHLHE40. Thus, the claimed population of T cells are not markedly different from their naturally occurring counterpart as evidenced by Ishigaki et al., (International Journal of Rheumatic Diseases, 2025; 28:e70219; see PTO-892).
Ishigaki discloses assessing BHLHE40 expression in CD4+ T cells in peripheral blood (PB) samples and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and healthy control (HC) samples (ABSTRACT: Methods and Results; Introduction, page 2, left col, first paragraph). Figure 3b illustrates BHLHE40 gene expression for unstimulated and stimulated CD4+T cells.
Thus, the claim recites a natural product.
The claim as a whole, considering all claim elements, does not amount to significantly more than the natural product of T cells. Thus, the claimed composition does not have a markedly different characteristic from what occurs in nature and is a "product of nature" exception. Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
The next part of the analysis involves whether the claimed invention recites additional elements that integrate the judicial exception into a practical application (Step 2A, prong two).
Given the claims are directed to a composition, the claims do not recite additional steps that integrate the judicial exception into a practical application (Step 2A, prong two: No).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sun et al., (Nature Immunology, vol. 2, no. 11, November 2001, pages 1040-1047; see PTO-892) (“Sun”).
Regarding claim 11, it is initially noted, as set forth above at Claim Interpretation, if the product by process limitations are considered, the process imparts the feature of T cells having some amount of expression of BHLHE40, or no expression due to modulation by mutation or deletion of BHLHE40. Thus, any T cell having any amount of BHLHE40, including no expression due to mutation or deletion of BHLHE40, would appear to read on the claimed T cells.
Sun is directed to defective T cell activation and autoimmune disorder in Stra13-deficient mice and teaches Stra13 (synonymous with BHLHE40, see specification [0053]) expression is up-regulated (i.e., modulating expression) upon activation of CD4+ T cells (Abstract and Figure 1b). Thus, Sun anticipates claim 11.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Anderson et al., (WO 2019/068099; see PTO-892) (“Anderson”).
Regarding claim 11, as discussed immediately above, if the product by process limitations are considered, the process imparts the feature of T cells having some amount of expression of BHLHE40, or no expression due to modulation by mutation or deletion of BHLHE40. Thus, any T cell having any amount of BHLHE40, including no expression due to mutation or deletion of BHLHE40, would appear to read on the claimed T cells.
Anderson is directed to CD4+ and CD8+ T lymphocyte subtypes and their interactions associated with immune responses in cancer. Anderson teaches an isolated T cell characterized in that the T cell comprises expression of one or more genes selected from the group consisting of: TNFRSF9, PRF1, BHLHE40 (DEC1), IRF8, GLDC, STAT3, CST7, IL1R2, EEF2, SLC2A3, SQSTM1, RBPJ, NABP1, ACTN1, TNFRSF4, SERPINB9, FOSL2, CAPG, KLRC1, IL18R1, JUNB, EEF1A1, TNFRSF18, RGS2, NFKB2, RPL5, PEX16, LAT2, KDM5B, HILPDA, GEM ([0009]), thus anticipating claim 11.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 6-9 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Gregori et al., (Frontiers in Immunology, February 2018, Vol. 9, Article 233, 8 pages; see PTO-892) (“Gregori”), in view of Roncarolo (Immunity 49, December 18, 2018, pages 1004-1019; see PTO-892) (“Roncarolo”), Yu et al., (Journal of Experimental Medicine, 2018 Vol. 215, No. 7, pages 1813-1821; see PTO-892) (“Yu”), Sun et al., (Nature Immunology, vol. 2, no. 11, November 2001, pages 1040-1047; see PTO-892) (“Sun”) and Loo et al., (Journal of Leukocyte Biology, 2018; 104: 1069-1085; see PTO-892) (“Loo”).
Gregori 2018 is directed to engineered T regulatory type 1 (Tr1) cells for clinical application since these cells play a key role in modulating antigen (Ag)-specific immune response in vivo.
Regarding claims 1-4, 6-7 and 11, Gregori teaches a method for in vitro differentiating (recited in claim 4) a population of human T cells (CD4+ T cells) (recited in claim 2) wherein CD4+ T cells are cultured for 10 days with allogenic dendritic cells (DC)-10 in the presence of recombinant human IL-10, as described in Reference #45, Bacchetta et al, Haematologica (2010) 95:2134–43. doi:10.3324/ haematol.2010.025825, see PTO-892) (Figure 2A; page 5, left col, second paragraph).
Bacchetta et al evidences the exogenous IL-10 is rhIL-10 provided at a concentration of 10 ng/mL (page 2135, right col, Mixed lymphocyte cultures and proliferation assay), as disclosed in the instant specification ([0126]).
Gregori teaches that functional assays demonstrated that stimulation of the human CD4+ T cells with allogeneic DC-10 induced the differentiation of anergic alloAg-specific IL-10-producing Tr1 cells, i.e., T-allo10/T10 cells. Culturing in the presence of DC-10 cells provided anergized T cells containing up to 15% of differentiated alloAg-specific CD49b+LAG-3+ Tr1 cells (as recited in claim 9) (Figure 2A, right; page 5, left col, second paragraph).
Gregori teaches establishing clinical grade protocols for producing the alloAg-specific Tr1 cells for use in the T-allo10 clinical trial in HSCT hematological malignancies in order to suppress GvHD after allo-HSCT, i.e., introducing into a subject in need thereof a therapeutically effective quantity of an engineered cell population) (page 5, left col, last paragraph and Table 1).
Gregori does not further teach modulating expression of BHLHE40 in the population of Tr1 cells (claim 1), or down-regulating BHLHE40 expression (claim 3).
However, Gregori does teach that the expression of IL-10 is essential for the suppressive function of the Tr1 cells (page 3, left col, second paragraph) and provides alternative modulation of IL-10 expression via lentiviral vector LV-1L-10 (Figure 2C).
Roncarolo further teaches IL-10 is the principal cytokine for generation of human Tr1 cells (page 1005, right col, last paragraph). Yu further shows that knocking out, i.e., modulating expression (as recited in claims 1 and 6) of BHLHE40 in CD4 Th1 cells resulted in increased expression of IL-10 as compared to wild type T cells and the BHLHE40-deficient T cells did not induce colitis in an in vivo inflammatory bowel disease mode and thus had a desirable anti-inflammatory characteristic (Abstract; page 1815, right col.). Yu thus concluded that BHLHE40 is a molecular switch for determining the fate of inflammatory and anti-inflammatory T cells (Abstract). Sun further teaches knockout of Stra13 (synonymous with BHLHE40, specification [0053]) resulted in CD4+ T cells having substantially increased expression of IL-10 and IL-4 (page 1044, left col, first paragraph; Figure 6d) and Loo further teaches the transcription factor Bhlhe40 acts a suppressor of the Il10 gene wherein CD4+ T cell-specific deletion of Bhlhe40 resulted in the reprograming of proinflammatory TH1 cells into anti-inflammatory, IL-10-producing TH1 cells (2.2 Transcriptional regulation of pathogenic TH1 cells).
Therefore, given the intention of Gregori is to provide a population of immunosuppressive T cells, thus suppressing GvHD in patients undergoing hematopoietic stem cell transplant (HSCT), and expression of IL-10 in said T cells is essential for the suppressive function of Tr1 cells, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modulate expression of BHLHE40 by down-regulating/knocking out BHLHE40 in the therapeutic human T-cells, thus meeting the limitation of claims 1-4, 6-7 and 11.
The person of ordinary skill in the art would have been motivated to modify the method of Gregori to include down-regulating BHLHE40, as taught by Roncarolo, Yu, Sun and Loo, for the predictable result of increasing the expression of IL-10 in the therapeutic T cells.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Gregori with Roncarolo, Yu, Sun and Loo because each of these teachings are directed at therapeutic uses of T cells.
Regarding claims 8 and 12, Gregori teaches the T-allo10/T10 cells (i.e., allo-antigen specific anergic T cells) are administered to patients having received HSCT to down-regulate GvHD, thus meeting the limitations of claims 8 and 12.
Regarding claim 9, Gregori teaches the cells are characterized by co-expression of CD49b and LAG3, thus meeting the limitation of claim 9.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Gregori, in view of Roncarolo, Yu, Sun and Loo, as applied to claims 1-4, 6-9 and 11-12 above, and further in view of Duran-Reyes et al., (Biological Sciences 45, 24 pages; see PTO-892) (“Duran-Reyes”), as evidenced by ThermoFisher, RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression, retrieved from the internet; see PTO-892) (“ThermoFisher”).
The teaching of Gregori, in view of Roncarolo, Yu, Sun and Loo is set forth above.
Regarding claim 5, the cited prior art does not teach the down-regulation is transient. However, it is noted that Duran-Reyes is directed to the effects of cellular protein expression and down-regulation of DEC1 (synonymous with BHLHE40) (Abstract, page 2). Duran-Reyes tested various anti-sense oligonucleotides (ASOs) and siRNAs for down-regulating DEC1 (pages 6 and 13; Figures 3 and 4). ThermoFisher evidences that siRNA provides short-term, i.e., transient, down-regulation (Figures 1 and 2).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute siRNAs, as taught by Duran-Reyes, for Yu and Sun’s knockouts for down-regulating expression, since both techniques are known to reduce gene expression. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of down-regulating technique for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Gregori, in view of Roncarolo, Yu, Sun and Loo, as applied to claims 1-4, 6-9 and 11-12 above, and further in view of Smith et al., (Blood 8 March 2018, vol 131, no. 10, pages 1045-1052) (“Smith”), MacDonald et al., (J Clin Invest. 2016 ;124(4): 1413-1424) (“MacDonald”) and Piper et al., (Blood 20 February 2020, vol. 135, no. 8, pages 568-581) (“Piper”).
The teaching of Gregori, in view of Roncarolo, Yu, Sun and Loo is set forth above.
Regarding claim 10, it is noted as set forth above at the rejection under 35 USC 112(b), claim 10 is interpreted as CAR T cells expressing BHLHE40 are combined with the population of T cells of claim 1 and expression of BHLHE40 reduces the tendency of exhaustion for the CAR T cell.
Gregori does not further comment on the presence of CAR T cells expressing BHLHE40.
Smith is directed to an article discussing strategies to improve graft-versus-leukemia (GVL) effects by employing post-transplant chimeric antigen receptor (CAR) therapy. Smith teaches that therapeutic T cell engineering is a powerful approach to treating hematological malignancies, specifically using CAR T cells targeting CD19, which is expressed on most B-cell leukemias and lymphomas. Smith further notes that allogeneic CAR T cells may be an effective tool for treating relapse after allo-geneic hematopoietic stem cell transplant (HSCT), without incurring GVHD (Abstract).
Smith further teaches of cellular therapies to control GVHD using CAR Tregs (CD4+ T-regulatory cells), specifically wherein genetic modification of polyclonal Tregs with CAR to promote antigen-specificity (CAR Tregs, page 1049). Smith teaches the use of allo-geneic CAR T cells hold great promise to addressing pos-transplant relapse (Perspectives, right col, first paragraph).
MacDonald is directed to and article discussing alloantigen-specific regulatory T cells (Tregs) generated with a chimeric antigen receptor (CAR), and teaches that adoptive immunotherapy using regulatory T cells (Tregs) is a promising treatment for allograft rejection and graft-versus-host-disease (GVHD). MacDonald teaches that antigen-specific Tregs, as compared to polyclonal Tregs, have numerous advantages including a need for fewer cells and reduced risk of nonspecific immune suppression. MacDonald teaches of successfully employing chimeric antigen receptors (CARs) for generation of antigen-specific T cells, specifically an HLA-A2 CAR, which maintained their immunosuppressive phenotype. MacDonald’s results suggest use of the alloantigen-specific CAR Treg cells enhances therapeutic potential in transplantation and thus suggests this therapy for multiple diseases (Abstract).
Lastly, Piper discusses the effect of BHLEH40-expressing CD4+ T cells and their effect on graft-versus-host disease (GVHD), specifically that BHLEH40 is a transcription factor that is key to regulating production of the pro-inflammatory GM-CSF and contributes to pathological damage in GVHD (Abstract and KEY POINTS, page 568).
Therefore, given the intention of Gregori is to provide a population of immunosuppressive T cells, thus suppressing GvHD in patients undergoing hematopoietic stem cell transplant (HSCT), the teachings of Smith, MacDonald and Piper, would motivate the skilled artisan to include CAR T cells expressing BHLHE40 since doing so would provide specific targeting of BHLEH40, known to exacerbate GVHD.
It would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to modify the method of Gergori to include CAR T cells expressing BHLHE40, for the predictable result of successfully targeting BHLEH40, known to exacerbate GVHD, thus meeting the limitation of claim 10.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Gregori with Smith, MacDonald and Piper, because each of these teachings are directed at T cell therapies.
As to the limitation “which cells are reduced in their tendency to exhaustion”, it is noted this limitation appears to simply express the intended result of a process step positively recited (i.e., expression of BHLHE40), and as noted at MPEP 2111.04, such limitations are not given weight.
As discussed above, the cited prior art renders obvious a CAR T cell comprising BHLHE40 as a specific antigen, as disclosed in the instant specification (paragraphs [0011] and [0133]), thus the method disclosed by the prior art would necessarily result in cells that are reduced in their tendency to exhaustion.
Conclusion
No claim is allowed. No claim is free of prior art.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633