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 .
Information Disclosure Statement
The information disclosure statement (IDS) filed 01/19/2024 has been considered and the references therein are of record.
Claim Rejections - 35 USC § 112 (b)
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.
Claims 1-7, 19, 21, 28, 31-32, 40-41, 43, 66, and 71 are 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.
Claims 1, 2, 32, and 40 are indefinite for reciting “suitable” conditions and solid supports. It is unclear what structures, amounts, and components are required to perform the claimed functions. For example, it is unclear as to what conditions and components are required to produce the function of inducing 3D cell aggregate formation and hematopoietic differentiation in PSC. Subsequent dependent claims define these “suitable” conditions and solid supports to specific embodiments, yet these are only individual embodiments and do not define the scope of what conditions and solid supports are “suitable.” For the purpose of compact prosecution, “suitable” conditions and solid supports will be interpreted to mean the specific embodiments recited in dependent claims.
Likewise, claims 3, 7, 32, and 43 are rejected for recitation of intended result/effect without conferring some structural or material difference on the scope of the claim. The claims recite the functional language of an inhibitor of apoptosis, inhibitor of ALK receptors, immunomodulatory protein, target peptide antigen, CD3 stimulatory binding molecule, anti-CD3 antibody, and OKT-3 antibody , and OKT-3 Fab fragment, without specifying any specific structures required to perform the functions. The mechanism steps and requisite structure are merely implied by the functional language and thus the scope of the claim is undefined. Absent additional active method steps and structure, it is unclear how these claims further limit the scope of the parent claim. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim.” The claims are rejected since they fail to meet all (3) criteria set forth in MPEP 2173.05(g).
Claim 28 contains the trademarks/trade names AggreWell, StemCell Technologies, BIOFLOAT 96-well plate, faCellitate, ThermoFisher, and Nunclon Sphera 3D culture. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademarks/trade names are used to identify/describe microwell culture plates and, accordingly, the identification/description is indefinite.
Claims 3, 7, 32, and 43 are indefinite in the recitation of the phrase “preferably” because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP §2173.05(d).
Claims 7 and 43 are indefinite in the recitation of the phrase “essentially” because “essentially” is a relative term which renders the claim indefinite. The term “essentially” 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.
Claims 32 and 40 recites the limitation “step (iii)” and “step (iv)”. There is insufficient antecedent basis for these limitations in the claims and parent claim. In regards to claim 32, since the claim only requires one limitation from the options in the group, there is insufficient antecedent basis for “step (iii)” and “step (iv)” when the limitations reciting those phrases are viewed alone and not in combination with other limitations of the claims.
Claims 7, 21, 28, 32, and 43 are indefinite for reciting that the method of claim 1 can be characterized by one or more limitations selected from the options listed in each claim, yet reciting limitations within the options listed that lack antecedent basis when selected alone and not in combination with other options. For example, claim 7 recites “the target peptide antigen is covalently linked to the single chain fusion HLA class I protein.” The method of claim 1 does not recite a “target peptide antigen,” so when this limitation is selected alone, there is a lack of antecedent basis. Claim 7 also recites “ the immunomodulatory protein” and “the single chain fusion HLA” in limitations that when selected alone lack antecedent basis for the same reason of “the target peptide antigen.” Likewise, claims 21, 28, 32, and 43 share this same issue of reciting limitation that when selected alone lack antecedent basis.
Claim 32 is indefinite in the recitation of the phrases “T cell like cells” and “NK cell like cells” because “like” is a relative term which renders the claim indefinite. The term “like” 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.
Claim 3 recites the limitation “step (0i)”. Claim 4 recites the limitations of “the ROCK inhibitor” and “the inhibitor of ALK.” Claim 43, 66, and 71 recites the limitation of “The non-immunogenic T cell.” Claim and “step (iv)”. There is insufficient antecedent basis for these limitations in the claims and parent claim 1. For the purposes of compact prosecution, claim 3 will be interpreted to be dependent on claim 2, claim 4 will be interpreted to be dependent on claim 3, and claim 43 will be interpreted to dependent on claim 41.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-7, 19, 21, 31-32, 40-41, 43, 66, and 71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. The claims recite, or are dependent upon, “suitable” conditions and solid supports, inhibitors of apoptosis, inhibitors of ALK receptors, immunomodulatory proteins, target peptide antigens, CD3 stimulatory binding molecules, anti-CD3 antibodies, and OKT-3 antibodies, and OKT-3 Fab fragments, each of which encompasses a genus of agents. Claim 4, which is interpreted to be dependent on claim 3 for the purposes of compact prosecution, and claim 28 both materially limit the genus of agents and are therefore not included in this rejection. The rejected claims do not require that the genera possess any particular structure or other distinguishing feature that is characteristic of the genera as a whole. Therefore the claims are drawn to genera for which there is inadequate written description.
Further, claim 19 recites the PSC are pluripotent stem cells being deficient of endogenous MHC class II; and/or the PSC are deficient of endogenous MHC class II by disrupting the C2TA gene-MHC class II transactivator. Claim 43 recites non-immunogenic T cells characterized by the T cell is deficient of endogenous MHC class I molecules presented on the cell surface of the T cell and the T cell comprises an immunomodulatory protein on its surface; the non-immunogenic T cell expresses a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR) on its surface; essentially all copies of the beta-microglobulin 2 gene are disrupted in the T cell, thereby rendering the T cell deficient of endogenous MHC class I molecules on the cell surface; the immunomodulatory protein is a single chain fusion HLA class I protein; the single chain fusion HLA class I protein comprises at least a portion of B2M covalently linked to at least a portion of an HLA class Ia chain selected from the group consisting of HLA-A, HLA-B, HLA-C, HLA-E, HLA-F and HLA-G; the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-A; the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-A0201; the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-E;- the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-G; the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-B; the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-C; the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-F; the non-immunogenic T cell further expresses a target peptide antigen that is presented by the single chain fusion HLA class I protein on the pluripotent cell surface;- the target peptide antigen is covalently linked to the single chain fusion HLA class I protein; the target peptide antigen comprises the sequence VMAPRTLFL (SEQ ID NO: 1); the gene of the immunomodulatory protein is integrated into the (endogenous) B2M locus of the T cell genome; the CAR or the exogenous TCR is integrated into an endogenous TCR-a gene, into an endogenous TCR-3 gene or both into an endogenous TCR-a gene and an endogenous TCR-3 gene; the CAR or the exogenous TCR binds an antigen presented on the surface of a target cell;- the antigen is a tumor-associated antigen, a viral antigen or a bacterial antigen, preferably a tumor-associated antigen; and/or the antigen is CD19 or a CMV-derived antigen. Claim 71 recites a pharmaceutical composition of non-immunogenic T cells of claim 43.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
From the specification, it is clear that Applicant is in possession of the specific embodiments recited in subsequent dependent claims for the conditions, solid supports, target peptide antigen with SEQ ID NO: 1, and HLA class 1 protein. The claims, however are not limited to those species but also includes any and all “suitable” conditions and solid supports, inhibitors of apoptosis, inhibitors of ALK receptors, immunomodulatory proteins, target peptide antigens, CD3 stimulatory binding molecules, anti-CD3 antibodies, OKT-3 antibodies, and OKT-3 Fab fragments. Furthermore, the specification provides no evidence of possession of the compositions recited in claims 19, 43, and 71. The specification fails to provide a representative number of species within each of the recited genera. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics of the genus as a whole, or representative number of species within each genus, the specification does not provide adequate written description of the claimed genera.
Claim Rejections - 35 USC § 112(a) – Enablement
Claims 1-3, 5-7, 19, 21, 31-32, 40-41, 43, 66, and 71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific embodiments recited in dependent claims for the conditions, solid supports, target peptide antigen with SEQ ID NO: 1, and HLA class 1 protein, does not reasonably provide enablement for the genera of suitable conditions and solid supports, inhibitors of apoptosis, inhibitors of ALK receptors, immunomodulatory proteins, target peptide antigens, CD3 stimulatory binding molecules, anti-CD3 antibodies, and OKT-3 antibodies, and OKT-3 Fab fragments. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed composition is that it covers any suitable conditions and solid supports, inhibitors of apoptosis, inhibitors of ALK receptors, immunomodulatory proteins, target peptide antigens, CD3 stimulatory binding molecules, anti-CD3 antibodies, OKT-3 antibodies, and OKT-3 Fab fragments. As the breath of the claims encompass a wide scope of compositions, a skilled artisan would not know how to make the compositions used in the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification does not provide direction as to any and all suitable conditions and solid supports, inhibitors of apoptosis, inhibitors of ALK receptors, immunomodulatory proteins, target peptide antigens, CD3 stimulatory binding molecules, anti-CD3 antibodies, and OKT-3 antibodies, and OKT-3 Fab fragments that can be used in the claimed method. The art at the time of filing does not provide enabling guidance and the specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: the specification discloses Examples 1-5 (pg. 21-25) and embodiments within the Sequence Listing, but not does provide working examples for the genera recited above.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentec, Inc., V. Novo Nordisk, 42 USPQ 2d 100, (CAFC 1997), the court held that: "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all of the disclosure related to the process is within the skill of the art","[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". The instant specification is not enabling for the full scope of the claimed invention because one cannot follow the guidance presented therein and practice the claimed method without first making a substantial inventive contribution.
Given that the nature of the invention is a method of producing T-cells, a person having ordinary skill in the art would have to perform multiple further experiments in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to make every embodiment of the claimed method with a reasonable expectation of success. Therefore, the claims lack enablement.
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.
Claims 41, 43, 66, and 71 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite the nature-based product of T cells. MPEP 2106 sets forth the multistep process for determining subject matter eligibility.
Considering the flowchart of subject matter eligibility in MPEP § 2106, the claim is directed to a product, which is a statutory category of invention. (Step 1: YES).
These claims recite a composition of T-cells, which is a product of nature as described in MPEP § 2106.04(b): Therefore the claims recite at least one judicial exception (STEP 2A, Prong One: YES).
Step 2A, Prong One sets forth the markedly different characteristics analysis that the courts use to identify product of nature exceptions (MPEP 2106.04(c)). The analysis requires determining if the claimed product has "markedly different characteristics from any found in nature".
The naturally-occurring counterpart to the instant claimed product is human T cells, which is taught by the Specification and Montel-Hagen et al., 2019. Claim 41 requires that the T-cell is non-immunogenic. Claim 43 only requires that the T cell is a human T cell. Claims 66 and 71 requires the T cells in a pharmaceutical composition. First, T cells of an individual do not induce an immune response against themselves, as evidence by the teaching of Yin et al., 2013 that human T-cells can distinguish between self MHC and foreign peptides, and therefore are not immunogenic to oneself (abstract & page 10-11). Second, a pharmaceutical composition could be saline, which merely amounts to isolating the naturally occurring product. The claims require no different characteristics than those identified in there naturally-occurring counterpart and is therefore not markedly different. There is no evidence within the specification as filed that the claimed composition has any structural or functional differences from the naturally-occurring counterparts that amount to a markedly different characteristic. Therefore, the claims are directed to a product that does not markedly differ from the nature-based product, and are not eligible subject matter under 35 U.S.C. 101.
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.
Claims 1-7, 21, 31-32, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Montel-Hagen et al., 2019 in view of Lancaster et al., 2014 (see instant PTO-892).
The instant claims are drawn to a method of producing a population of immune cells from pluripotent stem cells (PSC), the method comprising the steps of: (0i) inducing mesodermal differentiation by (a) seeding PSC under suitable conditions in a serum-free medium; and (b) culturing the PSC under suitable conditions in a serum-free medium for about 2 to 4 days, and (c) resuspending cells with serum-free medium; then step (i) inducing 3D cell aggregate formation and hematopoietic differentiation by (a) culturing under suitable conditions PSC having undergone mesenchymal differentiation in the presence of Notch-ligand Delta-like ligand 4 (DLL4) signaling activity, on a solid support suitable for formation of 3D - cell aggregates, in a serum-free medium, thereby allowing the formation of 3D - cell aggregates; (b) collecting the 3D - cell aggregates and culturing under suitable conditions in a suspension culture in a serum-free medium for about 3 to 6 days; and (c) culturing the 3D - cell aggregates under suitable conditions for about further 4 to 7 days in a serum-free medium; (ii) inducing immune cell differentiation by culturing the 3D-cell aggregates of (i) under suitable conditions in a suspension culture for a suitable time in a serum-free medium for about 21 to 50 days; thereby providing a population of immune cells. The instant claims are drawn to the serum-free medium in step (0i)(a) comprising Activin A, bone morphogenic protein 4 (BMP4), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and an apoptosis inhibitor, preferably a ROCK inhibitor, each in a concentration of about 10 to 50 ng/mL. The instant claims are drawn to the serum-free medium in step (0i)(b) comprising BMP4, VEGF, and FGF, each in a concentration of about 5 to 15 ng/mL. The instant claims are drawn to the serum-free medium in step (0i)(c) comprising an apoptosis inhibitor, preferably a ROCK inhibitor. The instant claims are drawn to the serum-free medium in step (i)(a) comprising an inhibitor of ALK receptors and a ROCK inhibitor, each in a concentration of about 5 to 15 pM. The instant claims are drawn to the ROCK inhibitor being Y-27632 dihydrochloride and the inhibitor of ALK receptors being SB43152. The instant claims are drawn to the serum-free medium in step (i)(b) comprising about 5 to 15 ng/mL of an inhibitor of ALK receptors. The instant claims are drawn to the serum-free medium in step (i)(c) comprising about 5 to 15 ng/mL of an inhibitor of ALK receptors, about 40 to 60 ng/mL stem cell factor (SCF), about 5 to 15 ng/mL FMS-like tyrosine kinase 3 ligand (Flt-3L), and about 5 to 15 ng/mL Thrombopoietin (TPO). The instant claims are drawn to the serum-free medium in step (ii) comprising about 1 to 3% B27 supplement, about 5 to 15 ng/mL SCF, about 5 to 15 ng/mL Flt-3L, about 5 to 15 ng/mL IL-7, and about 15 to 45 mM L-ascorbic acid 2-phophatate sesquimagnesium salt hydrate. The instant claims are drawn to the method being characterized by in step (i) Notch-ligand Delta-like ligand 4 (DLL4) signaling activity is provided by co- culturing PSC with stromal cells expressing DLL4, or by incubating PSC with beads which are coated with DLL4. The instant claims are drawn to the 3D - cell aggregates after step (ii) being separated such that single cells are provided. The instant claims are drawn to the population of immune cells being characterized by expression of CD4, CD8, CD56, CD3, and CD45. The instant claims are drawn to the PSC being human iPSC. The instant claims are drawn to the method being suitable for production of a population of immune cells with high cell numbers by using bioreactor conditions in any one or all of the steps (ii). For the purpose of compact prosecution, “suitable” conditions, times, and solid supports will be interpreted to mean the specific embodiments recited in dependent claims.
Montel-Hagen teaches a method of producing a population of immune cells from pluripotent stem cells (PSC) (abstract), the method comprising the steps of: (0i) inducing mesodermal differentiation (Results; Graphical Abstract; Fig 1; Method Details, Generation and isolation of human embryonic mesodermal progenitors; & Method Details, Pluripotent stem cell-derived Embryonic mesoderm organoids and ATO cultures) by (a) seeding PSC in a serum-free medium containing 10 ng/ml Activin A, 10 ng/ml BMP4, 10 ng/ml VEGF, 10 ng/ml FGF, and 10 uM Y-27632 dihydrochloride; and (b) culturing the PSC in a serum-free medium containing 10 ng/ml BMP4, 10 ng/ml VEGF, and 10 ng/ml FGF for 3 days; and (c) resuspending cells with serum-free medium containing 10 uM Y-27632 dihydrochloride; and then step (i) inducing 3D cell aggregate formation and hematopoietic differentiation (Results; Graphical Abstract; Fig 1; & Method Details, Pluripotent stem cell-derived Embryonic mesoderm organoids and ATO cultures) by (a) culturing PSC having undergone mesenchymal differentiation in the presence of MS5-hDLL4 cells, on a solid support suitable for formation of 3D-cell aggregates, in a serum-free medium containing 10 uM Y-27632 dihydrochloride and 10 uM SB-431542, thereby allowing the formation of 3D-cell aggregates; (b) collecting the 3D-cell aggregates and culturing in a serum-free medium containing 10 uM SB-431542 for 7 days; and (c) culturing the 3D-cell aggregates for further 7 days in a serum-free medium containing 10 uM SB-431542, 50 ng/mL SCF, 5 ng/mL FLT3L, and 5 ng/mL Thrombopoietin (TPO); and then step (ii) inducing immune cell differentiation by culturing the 3D-cell aggregates of (i) in a culture in a serum-free medium containing 4% B27 supplement, 10 ng/mL SCF, 5 ng/ml Flt-3L, 5 ng/ml IL-7, and 30 mM L-ascorbic acid 2-phophatate sesquimagnesium salt hydrate for up to 50 days; which thereby providing a population of immune cells (Results, STAR methods, Fig 1., Experimental Models and Subject Details & Method Details). Montel-Hagen teaches that the 3D - cell aggregates after step (ii) are separated such that single cells are provided and sorted using FACS (Flow cytometry and antibodies). Montel-Hagen teaches the PSC being human iPSC (T Cell Differentiation from Multiple ESC and iPSC Lines in PSC-ATOs & Detailed Methods). Montel-Hagen teaches the population of immune cells being characterized by expression of CD4, CD8, CD56, CD3, and CD45 (results). Montel-Hagen teaches a pharmaceutical composition comprising PBS and immune cells (In vivo Tumor Assay, Short term in vivo analysis of adoptively transferred T cells, methods, & results).
Montel-Hagen does not explicitly teach that the culture is a suspension culture and that step (i) and (ii) comprise a dynamic suspension culture by culturing on an orbital shaker, at rotations of about 60 to 80 rpm. Montel-Hagen does not explicitly teach the method being suitable for production of a population of immune cells with high cell numbers by using bioreactor conditions in any one or all of steps (ii).
Lancaster teaches a method of first culturing PSC on a solid support until they form 3D-cell aggregates and then moving the 3D-cell aggregates to a suspension culture (Protocol & Fig. 1-2). Lancaster teaches that the suspension culture is an agitated bioreactor or orbital shaker with rotations of 85 rpm, and that these suspension cultures markedly improve tissue survival of organoids produced by pluripotent stem cells or embryonic stem cells by effectively diffusing oxygen and nutrients (Figure 1; Establishment of 3D spatial organization; Growth of cerebral tissue; Experimental design; & Equipment Setup). Lancaster teaches that using the bioreactor resulted in many cells (Fig 2).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Montel-Hagen and Lancaster. One with ordinary skill in the art would be motivated to make and use the claimed invention because Lancaster teaches an improvement to the method taught by Montel-Hagen, that improvement being to culture the 3D-cell aggregates in a suspension culture by using either a bioreactor or orbital shaker plate, instead of a stationary culture where the cells adhere to the plate, to increase tissue survival. An ordinary artisan would find it obvious to use a suspension culture in view of Lancaster’s teaching that suspension cultures improve tissue survival of organoids produces through PSC by effectively diffusing oxygen and nutrients through the media. Further, an ordinary artisan would find it logical and obvious that a culture of suspended cells in a bioreactor would be able to produce a high number of cells and would allow the method taught by Montel-Hagen to be scaled in such a way as to produce more cells via a suspension culture than can be produces via a stationary, adherent culture. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-7, 19, 21, 31-32, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Montel-Hagen et al., 2019 and Lancaster et al., 2014, as applied to claims 1-7, 21, 31-32, and 40 above, in view of Han et al., 2019 (see instant PTO-892).
Instant claims 1-7, 21, 31-32, and 40 are recited above. Instant claim 19 is drawn to the PSC being deficient of endogenous MHC class II and/or deficient of endogenous MHC class II by disrupting the C2TA gene-MHC class II transactivator.
The teachings of Montel-Hagen and Lancaster and how they meet the limitations of claims 1-7, 21, 31-32, and 40 are outlined above in the preceding rejection and are hereby incorporated. Montel-Hagen further teaches that the T-cell obtainable by the method can express a CAR or TCR (results; detailed methods). Montel-Hagen teaches that generating T cells from pluripotent stem cells (PSCs) has the potential to transform autologous T cell immunotherapy by facilitating universal, off-the-shelf cell products (Summary & Introduction). Montel-Hagen teaches that, analogous to observations from TCR-transduced HSPCs, introduction of a fully rearranged TCR at the PSC stage induced allelic exclusion of endogenous TCR Vβ rearrangement during T cell differentiation, which may serve as a built-in mechanism to mitigate graft-versus-host-disease risk upon adoptive transfer of PSC-ATO-derived engineered T cells in the allogeneic setting (Discussion). Montel-Hagen teaches the method is an efficient and readily deployable method for modeling hematopoietic specification and T cell differentiation from human PSCs (Discussion). Montel-Hagen teaches that, as a platform for therapeutic T cell generation, PSC-ATOs present the opportunity to combine technologies to gene-modify, screen, and expand self-renewing PSC clones for the unlimited production of non-alloreactive and optimized T cells, and may serve as the basis for the development of universal, ‘off-the-shelf’ T cell therapies (Discussion).
Neither Montel-Hagen or Lancaster explicitly teaches the PSC being deficient of endogenous MHC class II and/or deficient of endogenous MHC class II by disrupting the C2TA gene-MHC class II transactivator.
Han teaches that ablation of MHC class II in stem cells allows for the stem cells to be differentiated and administered to a subject without activating an endogenous T cell response against the differentiated cells (abstract, significance, & results). Han teaches that this allows for the enablement of cell therapies on a broader scale by developing a universal donor stem cell that can be differentiated into various non-immunogenic cell types (abstract, significance, & results).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Montel-Hagen, Lancaster, and Han. An ordinary artisan would be motivated, and find it obvious, to genetically modify the T-cells to be non-immunogenic since Montel-Hagen implies that for the T-cells produced by their method could be gene-modified to make a universal, off-the-shelve, donor T-cell that is not alloreactive and doesn’t produce graft-verse-host-disease. Since Montel-Hagen implies that the T-cells produced via their method would have to be further gene-modified to create a non-immunogenic, universal donor T-cell, but do not teach what specific gene-modification would be required to make the T-cell non-immunogenic, an ordinary artisan would look to the prior art and find that Han remedies this deficiency by teaching that MHC class-II ablation can make donor T-cells not produce an endogenous immune response against them. It would therefore be logical and obvious to an ordinary artisan that for the T-cells produced via Montel-Hagen and Lancaster to be used in a universal, off-the-shelve T-cell therapy, they would have to be non-immunogenic and this could be achieved by Han’s teaching to ablate MHC class-II from the T-cells. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-7, 19, 21, 28, 31-32, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Montel-Hagen et al., 2019, Lancaster et al., 2014, and Han et al., 2019, as applied to claims 1-7, 19, 21, 31-32, and 40 above, in view of StemCell Technologies, 2020 (see instant PTO-892).
Instant claims 1-7, 19, 21, 31-32, and 40 are recited above. Instant claim 28 is drawn to the solid support in step (i)(a) comprises one or more wells, wherein each well comprises a V-shaped or conical cavity; the solid support is a microwell culture plate; and/or the microwell culture plate is an AggreWell plate (available from StemCell Technologies), a BIOFLOAT 96-well plate (available from faCellitate), or a Nunclon Sphera 3D culture (available from ThermoFisher).
The teachings of Montel-Hagen, Lancaster, and Han and how they meet the limitations of claims 1-7, 19, 21, 31-32, and 40 are outlined above in the preceding rejection and are hereby incorporated. Neither prior art reference teaches the solid support in step (i)(a) comprises one or more wells, wherein each well comprises a V-shaped or conical cavity; the solid support is a microwell culture plate; and/or the microwell culture plate is an AggreWellTM plate (available from StemCell Technologies), an BIOFLOATTM 96-well plate (available from faCellitate), or a Nunclon Sphera 3D culture (available from ThermoFisher).
StemCell Technologies teaches that AggreWell Microwell Plates provide an easy, reproducible, size-controlled, high yield, and cost-effective solid support to generate highly uniform 3D cultures that is compatible with a wide range of cell types and applications, including directed differentiation of pluripotent stem cells (sections titled: Reproducible 3D Spheroid and Embryoid Body Production; and Why Use AggreWell to Generate EBs and Spheroids?).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Montel-Hagen, Lancaster, Han, and StemCell Technologies. One with ordinary skill in the art would be motivated to make and use the claimed invention because AggreWell Micro Plates are a solid support for 3D cultures that have the advantages of being easy, reproducible, size-controlled, high yield, and cost-effective. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-7, 19, 21, 28, 31-32, 40-41, 43, 66, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Montel-Hagen et al., 2019, Lancaster et al., 2014, Han et al., 2019, and StemCell Technologies, 2020, as applied to claims 1-7, 19, 21, 28, 31-32, and 40 above, in view of Yin et al., 2013, (see instant PTO-892).
Instant claims 1-7, 19, 21, 28, 31-32, and 40 are recited above. Instant claim 41 is drawn to a population of immune cells or a non-immunogenic T cell. Instant claim 43 is drawn to a human non-immunogenic T cell. Instant claim 66 is drawn to a pharmaceutical composition comprising a population of immune cells or a non-immunogenic T cell. Instant claim 71 is drawn to a pharmaceutical composition comprising a population of human non-immunogenic T cells. The recitation of limitations beginning with “obtainable or obtained by…” do not hold patentable weight, as these limitation are considered produce-by-process claims; only the product of the claims is under examination. In regards to the limitation of “a pharmaceutical composition,” this phrase amounts to isolating the human non-immunogenic T-cell in a saline.
The teachings of Montel-Hagen, Lancaster, Han, and StemCell Technologies and how they meet the limitations of claims 1-7, 19, 21, 28, 31-32, 40 are outlined above in the preceding rejection and are hereby incorporated. None of these prior art references explicitly teaches a pharmaceutical composition comprising a human non-immunogenic T cell.
Yin teaches that human T-cells can distinguish between self MHC and foreign peptides, therefore not being immunogenic to oneself (abstract & page 10-11).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Montel-Hagen, Lancaster, Han, StemCell Technologies, and Yin. One with ordinary skill in the art would be motivated to make and use the claimed invention because an ordinary artisan would readily understand that human T-cells could be isolated and put into saline. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claims are allowed.
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/JOSEPH D. CESARE/ Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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