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 .
Priority
The instant application is a continuation of PCT/JP2022/005294 (filed 02/10/2022). Acknowledgement is made of Applicants’ claim for priority to Japanese Application Nos. JP2021-177737 (filed 10/29/2021) and JP2021-117019 (filed 07/15/2021).
Response to Amendment
The amendment filed on 07/08/2026 has been received and entered into the application file.
Claim 2 has been cancelled; claims 1 and 3-15 are pending in the instant application.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-15 under 35 U.S.C. 112(b):
The cancellation of claim 2 renders the rejection thereof moot.
Respectfully, while the amendment filed in 07/08/2026 is sufficient to remedy the grammatical errors of claims 1, 4-6, and 15, it is insufficient to overcome the lack of clarity.
Accordingly, the remaining rejections of record are maintained.
RE: Rejection of claim 1, 4-6, and 15 under 35 U.S.C. 101 as directed to an abstract idea without significantly more:
The amendment incorporates the limitations of cancelled claim 2 into claim 1. Applicants assert this is sufficient to overcome the rejections of record.
Respectfully, upon reconsideration, the limitations of cancelled claim 2 do not constitute significantly more than the abstract idea judicial exception. Accordingly, the remaining rejections of record are reinstated below.
RE: Rejection of claims 1-3, 7-13, and 15 under 35 U.S.C. 102(a)(1) and (a)(2) over Robey, as evidenced by Liu:
The cancellation of claim 2 renders the rejection thereof moot.
Applicants assert Robey does not disclose managing a behavior of one or more specific protein molecules essential for the cells to exhibit therapeutic effects and managing an expression behavior of a related gene group characteristic of the cells. Applicants further assert there is no disclosure of a group of related genes consisting of 10 to 20,000 genes.
Respectfully, these arguments are found unpersuasive. As set forth in the claim interpretation section below: the managing a behavior of one or more specific protein molecules which is essential for exhibiting a therapeutic effect due to a cell limitation is interpreted as identifying a specific protein, wherein the protein is itself therapeutic or is characteristic of a cell with therapeutic properties; the managing an expression behavior of a related gene group that is characteristic of the cell, is interpreted as identifying a cell which expresses said specific protein; and the related gene group portion of this limitation is interpreted as genes known to be characteristic of the cell of interest per se, or characteristic of cellular processes of which the cell of interest is involved.
Robey teaches a method wherein bone marrow-derived mesenchymal stem cells (BMSCs) are attached to a scaffold comprising fibrin microbeads crosslinked to hyaluronic acid (HyA-FMBs) and administered to a subject in need (pars. 0027-0028); as the HyA-FMBs slowly degrade, the BMSCs form stable cartilage in vivo that does not undergo hypertrophy or degradation (pars. 0026-0027). The BMSCs are identified and selected based on CD29 expression (par. 0041). Therefore, Robey teaches the identification of a protein molecule (i.e., CD29) which is characteristic of a cell with therapeutic properties (i.e., BMSCs), and identifying cell(s) which express the protein molecule (i.e., identifying CD29+ BMSCs) for administration. Robey teaches the BMSCs undergo chondrogenesis to form cartilage in vivo (pars. 0026-0027, 0040, 0043, 0095), and Liu evidences the genes encoding transcription factors involved in chondrocyte fate and differentiation is a group comprising greater than ten genes (pgs. 37-39; Table 1). Thus, the Robey disclosure anticipates the instant claims.
Accordingly, the remaining rejections of record are maintained.
RE: Rejection of claims 1, 3, 7-10, and 14-15 under 35 U.S.C. 102(a)(1) and (a)(2) over Daly:
Applicants assert Daly does not disclose managing a behavior of one or more specific protein molecules essential for the cells to exhibit therapeutic effects and managing an expression behavior of a related gene group characteristic of the cells. Applicants further assert there is no disclosure of a group of related genes consisting of 10 to 20,000 genes.
Respectfully, these arguments are found unpersuasive. Daly teaches pericytes are an ideal cell type for drug screening and cell-based therapies (par. 0083), wherein the pericytes are identified based on expression of PDGFRβ; i.e., CD140b (par. 0039). Thus, Daly teaches the identification of a protein molecule (i.e., PDGFRβ) which is characteristic of a cell with therapeutic properties (i.e., pericytes), and identifying cell(s) which express the protein molecule (i.e., identifying PDGFRβ + pericytes) for downstream applications. As evidenced by Nwadozi, et al. (Front Cell Dev Biol. 2020), there are more than ten genes encoding proteins characteristic of pericytes and their cellular role; e.g., integrins α and β, Ang-1, PDGFRβ, TIMP-3, Notch3, N-cadherin, Jag1, PDGF-BB, Ang-2, and Tie-2 (Fig. 2). Therefore, the Daly disclosure anticipates the instant claims.
Accordingly, the rejections are maintained.
RE: Provisional rejection of claims 1-6 and 10-15 on the ground of nonstatutory double patenting over copending Application No. 18/412,092:
The terminal disclaimer filed on 07/08/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on copending Application No. 18/412,092 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Accordingly, the rejections of record are withdrawn.
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claim 1: This claim is directed to a quality management method for a cell, as recited in the preamble. This quality management method for a cell limitation is interpreted as its plain meaning; i.e., a method effective to achieve a standard or desired characteristic of a cell for its use in downstream applications. The method itself comprises two steps. The first of these, managing a behavior of one or more specific protein molecules which is essential for exhibiting a therapeutic effect due to a cell, is interpreted as identifying a specific protein, wherein the protein is itself therapeutic or is characteristic of a cell with therapeutic properties. The second step, managing an expression behavior of a related gene group that is characteristic of the cell, is interpreted as identifying a cell which expresses said specific protein; the related gene group portion of this limitation is interpreted as genes known to be characteristic of the cell of interest per se, or characteristic of cellular processes of which the cell of interest is involved (e.g., the genes which encode T cell marker CD3, genes encoding the molecules involved in cell adhesion).
Regarding claims 12-13: The instant claims are directed to the therapeutic use of the cell of claim 1; for arthrosis (claim 12), and for the meniscus or for osteoarthritis (claim 13). As evidenced by Talic-Tanovic, et al., the terms arthrosis and osteoarthritis are synonyms (Abstract). Therefore, a cell which satisfies the limitations of claim 12 will necessarily satisfy the osteoarthritis limitation of claim 13.
Regarding claim 15: This claim is directed to a method of producing a cell for a medical treatment or drug discovery, comprising two active steps. The first of these is obtaining a cell population including a candidate of a cell for a medical treatment or drug discovery. Drug discovery encompasses multiple stages, the first of which involves target selection for identifying a molecule or overall pathway involved in a disease or disorder; even cells which contribute or exacerbate a disease or disorder may be useful in the characterization of the processes involved. Thus, obtaining a cell population is the broadest reasonable interpretation of this limitation. The second active step recited in the method of the instant claim is sorting out a cell that satisfy a reference from the cell population with the method according to claim 1. Following the interpretation of claim 1 set forth above, the second active step of claim 15 is interpreted as identifying a specific protein and selecting a cell from the obtained cell population based on the expression of said specific protein.
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.
Claims 1 and 3-15 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.
Regarding claim 1: The claim interpretation for the quality management method of claim 1 is set forth above. However, as currently written, the method of claim 1 lacks clarity. What is meant by quality management? Quality management may refer to a number of factors; e.g., purity of a specific cell population, therapeutic quality of a protein. Indeed, quality is a subjective term; thus, it would not be immediately understood by a person having ordinary skill in the art what is meant by a quality management method.
Additionally, it is unclear what it meant by the managing a behavior of one or more specific protein molecules and managing an expression behavior of a related gene group that is characteristic of the cells limitations recited in the instant claim. Does managing a behavior of a protein molecule refer to identification of a protein, selection of a protein, inducing expression of a protein? The same questions may be asked in regards to managing a behavior of a related gene group. Does the managing a behavior of a related gene group refer to the inherent expression of at least one of the genes of the related gene group (i.e., identifying a cell which expresses said gene), selection thereof, or even inducing expression thereof? Broad does not necessarily confer indefiniteness; however, the limitations of claim 1 are so broad as to be confusing and open to any number of interpretations. This results in metes and bounds which are not clearly or precisely defined, rendering claim 1 indefinite.
As an additional matter, based on the current claim interpretation, as claim 1 does not set forth any active steps involved in the quality management method, it is unclear what method or process Applicants intend to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced. See MPEP 2173.05(q).
Claims 3-15 depend from claim 1, inherit its deficiencies, and are likewise rejected as indefinite.
Regarding claim 4: This claim further defines the managing the expression behavior of the related gene group that is characteristic of the cells limitation of claim 1, reciting, “…wherein in the managing the expression behavior of the related gene group that is characteristic of the cells, in a case where a correlation between an expression pattern of the gene group obtained by measuring an expression state of the related gene group that is characteristic of the cells and an expression pattern that serves as a reference is equal to or higher than a certain level, the cells are determined to be usable.” Following the claim 1 discussion, there is a necessarily a degree of confusion surrounding the instant claim due to the confusion surrounding the managing the expression behavior of the related gene group that is characteristic of the cells limitation. However, it is also unclear if the italicized limitation following the phrase ‘in a case where’ is merely exemplary or a required feature, rendering the instant claim indefinite.
Claims 5-6 depend from claim 4, inherit its deficiencies, and are likewise rejected as indefinite.
Regarding claim 5: This claim is replete with idiomatic errors; it is not understood what the individual limitations are or how they fit into the broader method.
Claim 6 depends from claim 5, inherit its deficiencies, and is likewise rejected as indefinite.
Regarding claim 6: This claim is replete with idiomatic errors; it is not understood what the individual limitations are or how they fit into the broader method. Additionally, it is not clear what is meant by the read count limitation recited in part (iii) of the instant claim.
Regarding claim 9: This claim narrows the behavior limitation recited in claim 1. However, it isn’t clear if this is directed to the first active step of managing a behavior of one or more specific protein molecules, or if this is directed to second active step of managing an expression behavior of a related gene group. Thus, the metes and bound are not clearly or precisely defined, rendering claim 9 indefinite.
Regarding claim 15: This claim is directed to a method of producing cells for a medical treatment or drug discovery. The method comprises two active steps: the first is obtaining a cell population; the second is sorting out cells that satisfy a reference from the cell population. It is unclear what is meant by the satisfy a reference limitation recited in line 5. As such, the metes and bound are not clearly or precisely defined, rendering claim 15 indefinite.
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 1 and 3-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Determination of a claimed invention’s subject matter patent eligibility is set forth in MPEP § 2106 in a stepwise analysis.
Regarding claim 1: The instant claim is directed to a method that is a quality management method for a cell for a medical treatment or drug discovery.
Step 1 of the analysis asks if the claim is directed to one or more of the appropriate categories: process, machine, manufacture, composition of matter. In response to Step 1, the instant claim is directed to a process (Step 1: YES).
Step 2A of the analysis is a two-prong inquiry. The first of these asks if the claim recites a judicial exception: abstract idea, law of nature, product of nature. In the instant case, the method of claim 1 comprises two active steps. As set forth in the claim interpretation above, the first active step comprises identifying a specific protein. Identification of a protein can be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas. Therefore, the instant claim recites a judicial exception (Step 2A, Prong 1: YES), and requires further analysis.
The second prong of Step 2A asks if the claim recites additional elements that integrate the judicial exception into a practical application. As set forth in the claim interpretation above, the second active step of claim 1 comprises identifying a cell which expresses a specific protein. A consideration when determining whether a claim integrates the judicial exception into a practical application in Step 2A Prong 2 is whether the additional elements add more than insignificant extra-solution activity to the judicial exception. Such activities can be understood as incidental to the primary process. In the instant case, the identification of the protein is the primary process of the claimed method; the cell’s inherent expression thereof is incidental, and does not constitute an active part of the claimed process. Thus, the judicial exception is not integrated into a practical application (Step 2A, Prong 2: NO), and further analysis is required.
Step 2B of the analysis asks if the claim recites additional elements that amount to significantly more than the judicial exception. In the instant case, there is no additional element or active step for the claimed method. Thus, there is no recited element in claim 1 which amounts to significantly more than the judicial exception (Step 2B: NO), concluding the analysis.
For the reasons set forth above, claim 1 does not recite patent eligible subject matter.
Regarding claim 3: The analysis for claim 3 follows the same analysis for claim 1 through Step 2A Prong 2, and thus requires further analysis.
Step 2B of the analysis asks if the claim recites additional elements that amount to significantly more than the judicial exception. In the instant case, claim 3 narrows the related gene group limitation with the gene groups recited therein. Therefore, the instant claim does not recite additional elements that amount to significantly more than the laws of nature and natural phenomena judicial exception (Step 2B: NO), concluding the analysis.
For the reasons set forth above, claim 3 does not recite patent eligible subject matter.
Regarding claims 4-6: The indefiniteness issues for these instant claims are set forth above. However, it would appear the instant claims narrow the second active step of the method of claim 1 by comparing the expression level of the protein identified in the first active step against expression levels of said protein in a reference cell or database. These additional limitations are considered as part of Step 2B: additional elements. When recited at this high level of generality, there is no additional limitation recited in claims 4-6 that distinguish these claims from well-understood, routine, and conventional data gathering and analysis activity commonly performed by any number of professionals in the art. For example, Clarke, et al. (US 2010/0255471) evidences microRNA analysis comparing the expression of microRNAs in metastatic tumor initiating cells (TICs) isolated from pleural effusions against the expression in primary TICs isolated from the breast cancer primary site (pars. 0161-0163) is well-understood, routine, and conventional in the field. Thus, the additional elements do not amount to significantly more than the abstract idea judicial exception (Step 2B: NO).
Accordingly, claims 4-6 do not recite patent eligible subject matter.
Regarding claims 7-8: The analysis for claims 7-8 follows the same analysis for claim 1 through Step 2A Prong 2, and thus requires further analysis.
Step 2B of the analysis asks if the claims recite additional elements that amount to significantly more than the judicial exception. In the instant case, claims 7 and 8 merely narrow the type of protein identified in the method of claim 1. Thus, the instant claims do not recite additional elements that amount to significantly more than the abstract idea judicial exception (Step 2B: NO), concluding the analysis.
For the reasons set forth above, claims 7-8 do not recite patent eligible subject matter.
Regarding claim 9: The analysis for claim 9 follows the same analysis for claim 1 through Step 2A Prong 2, and thus requires further analysis.
Step 2B of the analysis asks if the claim recites additional elements that amount to significantly more than the judicial exception. In the instant case, claim 9 narrows the behavior limitation by specifying it is an expression level. It is not clear if this is directed to the managing a behavior of one or more specific protein molecules or managing an expression behavior of a related gene group limitations recited in claim 1. However, selecting a cell based on protein expression is well-understood, routine, and conventional; thus, if the additional element of claim 9 is directed to the first active step of the claimed method, it does not constitute significantly more than the abstract idea judicial exception. If the additional element of the instant claim is directed to the second active step, it is merely reciting a narrower law of nature/natural phenomena, and thus does not constitute significantly more than the judicial exception directed thereto.
Therefore, the instant claim does not recite additional elements that amount to significantly more than the judicial exceptions (Step 2B: NO), concluding the analysis.
For the reasons set forth above, claim 9 does not recite patent eligible subject matter.
Regarding claims 10-14: The analysis for these claims follows the same analysis for claim 1 through Step 2A Prong 2, and thus requires further analysis.
Step 2B of the analysis asks if the claim recites additional elements that amount to significantly more than the judicial exception. In the instant case, claims 10-14 narrow the scope of claim 1 by specifying the cell type; e.g., mesenchymal cells (claim 11), cells for drug discovery (claim 14). Therefore, the instant claims do not recite additional elements that amount to significantly more than the laws of nature and natural phenomena judicial exception (Step 2B: NO), concluding the analysis.
For the reasons set forth above, claims 10-14 do not recite patent eligible subject matter.
Regarding claim 15: The second active step of the method of claim 15 comprises the method of claim 1. Accordingly, claim 15 follows the same analysis as set forth above for claim 1 and is likewise directed to an abstract idea.
Therefore, the first active step of the method is considered as part of Step 2B: additional elements. The step of obtaining a cell population, however, is not a meaningful limitation relevant to this subject matter eligibility analysis. As a first matter, the claim does not recite how the cell population is obtained; e.g., purchasing an aliquot of cells from a vendor is certainly not a meaningful limitation which confers patentability to a judicial exception, but is within the scope of claim 15 as currently written. Second, obtaining a population of cells directly from a subject or tissue thereof is likewise not a meaningful limitation. As Clarke, et al. evidences, obtaining cells from a subject, such as isolating cells (e.g., from a biopsy, blood, synovial fluid, inter alia) and culturing the cells to obtain a population thereof (see e.g., pars. 0013, 0042-0044, 0088) is an insignificant pre-solution activity that is well-understood, routine, and conventional to the skilled artisan. As such, the additional elements recited in the instant claim do not amount to significantly more than the judicial exception (Step 2B: NO).
Thus, claim 15 does not recited patent eligible subject matter.
Claim Rejections - 35 USC § 102
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.
Claims 1, 3-13, and 15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Robey, et al. (US 2020/0171215), as evidenced by Liu, et al. (Semin Cell Dev Biol. 2017), Wagey (“Mini-Review: Mesenchymal Cells”. 2015), and McKinnon (Curr Protoc Immunol. 2018).
Robey, et al. (hereinafter Robey) teaches methods for promoting cartilage growth and/or repair (Abstract).
Regarding claims 1, 3, 7-11, 15: Robey teaches a method wherein bone marrow-derived mesenchymal stem cells (BMSCs) are attached to a scaffold comprising fibrin microbeads crosslinked to hyaluronic acid (HyA-FMBs) and administered to a subject in need (pars. 0027-0028), wherein, as the HyA-FMBs slowly degrade, the BMSCs form stable cartilage in vivo that does not undergo hypertrophy or degradation (pars. 0026-0027); the administration of BMSCs reads on the medical treatment limitation recited in claim 1.
Robey teaches an embodiment wherein BMSCs are identified and selected based on CD29 expression using fluorescence activated cell sorting, or FACS (par. 0041); the CD29 reads on the specific protein molecule limitation of claim 1. The BMSCs, which form cartilage in vivo (pars. 0026-0027), undergo chondrogenesis to form chondrocytes comprising the cartilage (pars. 0040, 0043, 0095). As evidenced by Liu, et al., the genes encoding transcription factors involved in chondrocyte fate and differentiation is a group comprising greater than ten genes (pgs. 37-39; Table 1). As evidenced by Wagey, BMSCs express CD105, CD73, CD29, CD44, CD90, CD71, CD106, CD166, STRO-1, GD2, and CD146 (pg. 1; col. 2, par. 3); i.e., BMSCs express at least these eleven mesenchymal stem cell surface markers.
Thus, the method of Robey anticipates:
the quality management method for cells for a medical treatment, comprising managing a behavior of one or more specific protein molecules, which is essential for exhibiting a therapeutic effect due to the cells; and managing an expression behavior of a related gene group that is characteristic of the cells, wherein the related gene group that is characteristic of the cells is composed of 10 to 2,000 genes limitation recited in claim 1;
the wherein the related gene group that is characteristic of the cells is a mesenchymal stem cell marker-related gene group, a surface marker-related gene group, and the chondrogenesis-related gene group limitations recited in claim 3;
the wherein the specific protein molecule is a cell surface antigen limitation recited in claim 7;
the wherein the specific protein molecule is CD29 limitation recited in claim 8;
the wherein the behavior of the specific protein molecule is an expression level limitation recited in claim 9;
the wherein the cells are somatic stem cells limitation recited in claim 10;
the wherein the cells are mesenchymal stem cells limitation recited in claim 11;
and the method of producing cells for a medical treatment comprising obtaining a cell population including candidates of cells for a medical treatment and sorting out cells that satisfy a reference from the cell population with the method according to claim 1 limitation recited in claim 15.
Regarding claims 4-6: It is set forth above Robey teaches the identification and selection of BMSCs based on CD29 expression using FACS (par. 0041). As evidenced by McKinnon, flow cytometry analysis comprises drawing a region around a population of cells (i.e., gating), and applying that region to other parameters within the experiment (pg. 5.1.9; col. 2, par. 5). Cells are first gated to remove doublets, for viability, for light scatter, and then for specific lineage or other desired markers; positive expression for gating parameters requires a value above 0 along the x-axis (Fig. 5.1.3). The CD29 gating reads on correlation between an expression pattern of the gene group, which necessarily requires an expression pattern equal to or higher than a certain level; the 0 value along the x-axis reads on the lower limit value of measurement. Thus, Robey anticipates:
the wherein in the managing the expression behavior of the related gene group that is characteristic of the cells, in a case where a correlation between an expression pattern of the gene group obtained by measuring an expression state of the related gene group that is characteristic of the cells and an expression pattern that serves as a reference is equal to or higher than a certain level, the cells are determined to be usable limitation recited in claim 4;
the wherein the case where the correlation is equal to or higher than a certain level is a case where a coefficient of correlation or a coefficient of determination is equal to or higher than a certain level in a case where the coefficient of correlation or the coefficient of determination, or the coefficient of correlation and the coefficient of determination are evaluated limitation recited in claim 5; and
the replacing a missing value, which is for a gene of which an expression level cannot be measured, with a low limit value of measurement limitation recited in part (i) of claim 6.
Regarding claims 12-13: Following the above discussion, Robey teaches an embodiment wherein the BMSCs attached to HyA-FMBs are used to treat osteoarthritis (par. 0028); this anticipates:
the wherein the cells are cells that are used as a therapeutic drug for arthrosis limitation recited in claim 12; and
the wherein the cells are cells that are used as a therapeutic drug for osteoarthritis limitation recited in claim 13.
Claims 1, 3-10, and 14-15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Daly, et al. (US 2019/0316094), as evidenced by Nwadozi, et al. (Front Cell Dev Biol. 2020).
Daly, et al. teaches methods of differentiating pericytes from pluripotent stem cells (Abstract).
Regarding claims 1, 3, 7-10, 14-15: Daly, et al. teaches pericytes are a critical component of the neurovascular unit, making them an ideal cell type for disease modeling, drug screening, and cell-based therapies (par. 0083). Disclosed is a method wherein a population of pericytes is obtained via differentiation from pluripotent stem cells (pars. 0021-0022), and wherein the pericytes are identified by the expression of pericyte markers including PDGFRβ, i.e., CD140b (par. 0039); downstream applications for use include tissue engineering, as well as drug discovery and safety pharmacology, e.g., drug toxicity screening (par. 0040). Daly, et al. further teaches pericytes are perivascular contractile cells which contribute to angiogenic sprouting, migrate to vascularizing tissues, and promote mutual communication with the endothelium (par. 0004).
As further evidenced by Nwadozi, et al., pericytes reside within the basement membrane on the abluminal surface of most capillaries and some larger blood vessels; the pericyte basement membrane is contiguous with that of the endothelial cells and is composed of extracellular matrix proteins (predominantly collagen IV and the glycoprotein laminin) secreted by both cell types; morphologically, pericytes are characterized by numerous cytoplasmic processes (pg. 1; par. 1). Pericytes themselves can be identified based on PDGFRβ, NG2, or CD146 expression (pg. 2; col. 2, par. 2). The interaction between endothelial cells and pericytes is critical to the stability and maintenance of the integrity of mature capillary networks, as pericytes restrict capillary expansion and promote endothelial cell viability and quiescence through physical connections and via secretion of paracrine factors; e.g., Ang-1, TIMP-3 (pg. 2; col. 1, par. 2). As seen in Fig. 2, pericyte-endothelial cell interactions are characterized by at least the genes which encode the ten proteins involved in these pericyte-endothelial cell interactions; i.e., integrins α and β, Ang-1, PDGFRβ, TIMP-3, Notch3, N-cadherin, Jag1, PDGF-BB, Ang-2, and Tie-2 (pg. 2; Fig. 2). This doesn’t include the additional genes involved in pericyte metabolism; e.g., GLUT-1, GLUT-4, FGF-2, FoxO3A (Figs. 3, 4). Thus, Nwadozi, et al. evidences there are at least seventeen genes which encode molecules characteristic of pericytes or the cellular processes in which they are involved.
Thus, the method of Daly, et al. reads on:
the quality management method for cells for a medical treatment or drug discovery, comprising managing a behavior of one or more specific protein molecules, which is essential for exhibiting a therapeutic effect due to the cells; and managing an expression behavior of a related gene group that is characteristic of the cells, wherein the related gene group that is characteristic of the cells is composed of 10 to 2,000 genes limitation recited in claim 1;
the wherein the related gene group that is characteristic of the cells is an angiogenesis-related gene group, a migration-related gene group, an adhesion-related gene group, a surface marker-related gene group, a growth factor-related gene group, and a chemokine- or cytokine-related gene group limitations recited in claim 3;
the wherein the specific protein molecule is a cell surface antigen limitation recited in claim 7;
the wherein the specific protein molecule includes is CD140b limitation recited in claim 8;
the wherein the behavior of the specific protein molecule is an expression level limitation recited in claim 9;
the wherein the cell is a differentiated cell derived from an induced pluripotent stem cell limitation recited in claim 10;
the wherein the cell is a cell for drug discovery limitation recited in claim 14;
and the method of producing cells for a medical treatment or drug discovery, comprising obtaining a cell population including candidates of cells for a medical treatment or drug discovery, and sorting out cells that satisfy a reference from the cell population with the method according to claim 1 limitation recited in claim 15.
Regarding claims 4-5: Following the above discussion, Daly teaches pericytes selected for pericyte markers CD13 and CD140b (i.e., PDGFRβ) using flow cytometry (par. 0013); as seen in Fig. 2A, selected pericytes within the desired population are above the estimated 103 gating threshold along the x-axis (Fig. 2A). Under broadest reasonable interpretation, this reads on:
the wherein in the managing the expression behavior of the related gene group that is characteristic of the cells, in a case where a correlation between an expression pattern of the gene group obtained by measuring an expression state of the related gene group that is characteristic of the cells and an expression pattern that serves as a reference is equal to or higher than a certain level, the cells are determined to be usable limitation recited in claim 4; and
the wherein the case where the correlation is equal to or higher than a certain level is a case where a coefficient of correlation or a coefficient of determination is equal to or higher than a certain level in a case where the coefficient of correlation or the coefficient of determination, or the coefficient of correlation and the coefficient of determination are evaluated limitation recited in claim 5.
Regarding claim 6: Following the above discussion, and under broadest reasonable interpretation, the 100 unit of measurement of expression along the x-axis of the flow cytometry panel disclosed by Daly (Fig. 2) reads on the replacing a missing value, which is for a gene of which an expression level cannot be measured, with a low limit value of measurement limitation recited in part (i) of claim 6.
Claims 1 and 3-15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Larocca (US 2014/0051600), as evidenced by Wagey (“Mini-Review: Mesenchymal Cells”. 2015) and McKinnon (Curr Protoc Immunol. 2018).
Larocca teaches cells and methods for reprogramming iPS cells from a supercentenarian (Abstract).
Regarding claims 1, 3, 7-15: Larocca teaches a method of cell replacement therapy conferring longevity and resistance to age-related diseases (e.g., osteoarthritis) to an individual in need of treatment, comprising transplanting MSCs derived from supercentenarian iPS (sciPS) cells into the individual, wherein the stem cells confer longevity and resistance to the age-related disease onto the individual (pars. 0011, 0016). Further disclosed is a method wherein the MSCs are used for screening candidate agents for age-related diseases (par. 0017). The cell replacement therapy and screen for candidate agents read on the medical treatment and drug discovery limitations of claim 1, respectively. The longevity and resistance to age-related diseases conferred by the MSCs reads on the therapeutic effect limitation of claim 1.
Larocca teaches the sciPS-derived MSCs are selected based on MSC surface markers, e.g., CD29, using flow cytometry (par. 0073); the CD29 reads on the specific protein molecule limitation of claim 1. In an embodiment, the sciPS-derived MSCs are BMSCs (par. 0055). As evidenced by Wagey, BMSCs express CD105, CD73, CD29, CD44, CD90, CD71, CD106, CD166, STRO-1, GD2, and CD146 (pg. 1; col. 2, par. 3); i.e., BMSCs express at least these eleven mesenchymal stem cell surface markers.
Thus, the methods of Larocca anticipate:
the quality management method for cells for a medical treatment, comprising managing a behavior of one or more specific protein molecules, which is essential for exhibiting a therapeutic effect due to the cells; and managing an expression behavior of a related gene group that is characteristic of the cells, wherein the related gene group that is characteristic of the cells is composed of 10 to 2,000 genes limitation recited in claim 1;
the wherein the related gene group that is characteristic of the cells is a mesenchymal stem cell marker-related gene group and a surface marker-related gene group limitations recited in claim 3;
the wherein the specific protein molecule is a cell surface antigen limitation recited in claim 7;
the wherein the specific protein molecule is CD29 limitation recited in claim 8;
the wherein the behavior of the specific protein molecule is an expression level limitation recited in claim 9;
the wherein the cells are somatic stem cells and induced pluripotent stem cells limitations recited in claim 10;
the wherein the cell is a mesenchymal stem cell limitation recited in claim 11;
the wherein the cells are cells that are used as a therapeutic drug for arthrosis limitation recited in claim 12;
the wherein the cells are cells that are used as a therapeutic drug for osteoarthritis limitation recited in claim 13;
the wherein the cells are cells for drug discovery limitation recited in claim 14; and
the method of producing cells for a medical treatment or drug discovery. The method comprising obtaining a cell population including candidates of cells for a medical treatment or drug discovery; and sorting out cells that satisfy a reference from the cell population with the method according to claim 1 limitations recited in claim 15.
Regarding claims 4-6: It is set forth above LaRocca teaches selecting CD29+ cells, using flow cytometry (par. 0073). As evidenced by McKinnon, flow cytometry analysis comprises drawing a region around a population of cells (i.e., gating), and applying that region to other parameters within the experiment (pg. 5.1.9; col. 2, par. 5). Cells are first gated to remove doublets, for viability, for light scatter, and then for specific lineage or other desired markers; positive expression for gating parameters requires a value above 0 along the x-axis (Fig. 5.1.3). The CD29 gating reads on correlation between an expression pattern of the gene group, which necessarily requires an expression pattern equal to or higher than a certain level; the 0 value along the x-axis reads on the lower limit value of measurement. Thus, LaRocca anticipates:
the wherein in the managing the expression behavior of the related gene group that is characteristic of the cells, in a case where a correlation between an expression pattern of the gene group obtained by measuring an expression state of the related gene group that is characteristic of the cells and an expression pattern that serves as a reference is equal to or higher than a certain level, the cells are determined to be usable limitation recited in claim 4;
the wherein the case where the correlation is equal to or higher than a certain level is a case where a coefficient of correlation or a coefficient of determination is equal to or higher than a certain level in a case where the coefficient of correlation or the coefficient of determination, or the coefficient of correlation and the coefficient of determination are evaluated limitation recited in claim 5; and
the replacing a missing value, which is for a gene of which an expression level cannot be measured, with a low limit value of measurement limitation recited in part (i) of claim 6.
Conclusion
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
