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 .
Election/Restrictions
Applicant’s election without traverse of Invention Group III (claims 5-12, 18-19 and 21) and Species Group III (The combination of THBS1, CCN2, EDN1, ACTA2, PDCD1LG2, TNFAIP6, ANGPTI1, CXCL8, TSG101, THBS1, PDGFA, VEGFA, EDIL3, ANGPT1, ANG and the level of TGF-beta protein) in the reply filed on 03/24/2026 is acknowledged.
Claims 1-4, 13-17, 20 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/24/2026.
As a result of the election of species, claim 5 is being examined as “steps a)a.i and a)a.ii” rather than “steps a)a.i and/or a)a.ii. Similarly, claim 8 is being interpreted as “a) comprises a.i. and a.ii” rather than “a) comprises a.i and/or a.ii.”
Claim Status
Claims 1-22 are currently pending.
Claims 1-4, 13-17, 20 and 22 are withdrawn as discussed above.
Claims 5-12, 18-19 and 21 are herein under examination.
Claims 5-12, 18-19 and 21 are rejected.
Claims 5-9 are objected.
Priority
The instant application claims domestic benefit to U.S. Provisional Application No. 63/428,499 filed 11/29/2022. The claim to domestic benefit is acknowledged. As such, the effective filing date for claims 5-12, 18-19 and 21 is 11/29/2022.
Information Disclosure Statement
The IDS filed 09/07/2023 (1/2) follows the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of the list of references cited from this IDS is included with this Office Action.
The IDS filed 09/07/2023 (2/2) fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. NPL ref. 22 (1 page in length) is illegible. Therefore, this document has not been considered and is crossed out on the IDS. A signed copy of the list of references cited and crossed out from this IDS is included with this Office Action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because they recite “Figure” instead of “FIG.” Amend the drawings so that they recite “FIG. 1”, “FIG. 2A”, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. References 68-72 on specification pg. 100-101 recite hyperlinks.
Abstract
The abstract of the disclosure is objected to because is recites implied language of “The present disclosure provides”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 5-9 are objected to because of the following informalities:
Claim 5, line 1, “CQAs” should be spelled out first.
Claims 5 and 7-9 each recite more than one period. Each claim should only have one period. The additional periods should be replaced by parentheses. See MPEP 608.01(m).
Claim 5, step b), recites “each sample of MSC” which should be “each sample of the MSC samples” to clarify antecedent basis.
Claim 5, step b), recites “sample;” which should be “sample; and”.
Claim 5, step c), line 2, recites “b);” which should be “b),”.
Claim 5, step c), line 3, recites “samples and using” which should be “samples, and using”.
Claim 6, step e), recites “use of desirability” which should be “using desirability” to correct grammar.
Claim 6, step e), recites “values; wherein” which should be “values, wherein”.
Claim 7, line 1, should recite “:” instead of “;”.
Claim 7, steps iv)I-iv)II, and claim 9 recite “pre treatment” and/or “post treatment” which should be “pre-treatment” and “post-treatment” to maintain consistent claim terminology.
Claim 8 recites “the method of a)” which should recite “step a)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 5-12, 18-19 and 21 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 dependent from a rejected claim are also rejected unless otherwise noted.
Claim 5, steps a)a and a)b, recites “the sample” which render the claim indefinite. It is unclear which sample is being referenced because the preamble of claim 5 recites “the MSC samples”. Clarify which sample is being referenced.
Claim 5, steps a)ai-a)aii, recites “the mRNA levels” which renders the claim indefinite. It is unclear if the recitation means absolute, relative, or normalized mRNA levels or some other mRNA level. Alternatively, does it refer to mRNA levels of all MSCs? Clarify which mRNA levels are being referenced.
Claim 5, step a)aii, recites “the level of TGF-beta protein ” which lacks antecedent basis. Provide antecedent basis.
Claim 5, step b), recites “the sample” which render the claim indefinite. It is unclear which sample is being referenced because the preamble of claim 5 recites “the MSC samples” and step b) recites “each sample”. Clarify which sample is being referenced.
Claim 5, step c), recites “the immunomodulatory fitness of b)” which renders the claim indefinite. It is unclear which immunomodulatory fitness is being referenced because step b) tests each sample for immunomodulatory fitness. Alternatively, does the recitation refer to the immunomodulatory fitness status of the singular sample in step b). Clarify what the recitation refers to. For examination purposes, this limitation is being interpreted to mean that the CQAs from each MSC sample are regressed with the immunomodulatory fitness obtained in b) from their respective sample of MSCs.
Claim 5, last two lines, recites “the directionality of correlation” which renders the claim indefinite. It is unclear what directionality of what correlation is being referenced. For example, a correlation associated with the regression analysis or some other yet unspecified correlation? Clarify what correlation is being referenced.
Claim 6, step d), recites “the R2 values” which lacks antecedent basis. Provide antecedent basis.
Claim 6, step e), recites “the range of data values” which renders the claim indefinite. It is unclear which range of data values is being referenced because claim 5, step c), determines a minimum and maximum value for each CQA in each sample. Clarify which range of values for which CQA is being referenced.
Claim 7, line 3, recites “monocyte/macrophages” which renders the claim indefinite. It is unclear if “/” means “and/or” or just “or”. Clarify the meaning of “/”.
Claim 7, step iii), recites “a clinical sample for which the immunomodulatory fitness or efficacy of the MSCs” which lacks antecedent basis. Although claim 5 discusses fitness and MSCs for samples of MSCs, there is no prior recitation of a clinical sample containing fitness or MSCs. Provide antecedent basis.
Claim 7, step iv)IV, recites “the size of the improvement” which lacks antecedent basis. Provide antecedent basis.
Claim 7, step iv)IV, recites the relative terms “high” and “low”, which render the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Because “high” and “low” are subjective terms, the metes and bounds of what constitutes a low and high immunomodulatory fitness score are indefinite.
Claim 10 recites “the MSC-treatable disease” which lacks antecedent basis. Provide antecedent basis. For examination purposes, claim 10 is being interpreted to depend on claim 7, step iv), because this is where “MSC-treatable disease” first appears.
Claim 11 recites “the assessment of the MSC-treatable disease” which lacks antecedent basis. Provide antecedent basis.
Claims 18-19 recite “the MSCs” which renders the claims indefinite. It is unclear which MSCs are being referenced because each sample has MSCs as recited in the preamble of claim 5.
Claims 18-19 recite “wherein the MSCs are derived” which renders the claims the claims indefinite. It is unclear if the wherein clause recites an active step of deriving the MSCs because claim 5 does not recite an active step of deriving the MSCs, or if it recites a product by process that defines how the MSCs were previously derived. For examination purposes, claims 18-19 are being interpreted as product by process limitations. See MPEP 2113.
Claim 21 recites “the proinflammatory cytokines stimulation post-harvest” which renders the claim indefinite. It is unclear if the phrase refers to claim 5 step a)ai “the presence of proinflammatory cytokines stimulation post-harvest” and claim 5 step a)aii “the absence of the proinflammatory cytokines stimulation post-harvest”, or if it refers to claim 5 step a)b “post-harvest without pro-inflammatory cytokine stimulation”. Clarify what the recitation refers to.
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 5-12, 18-19 and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant application, claims 5-12, 18-19 and 21 recite a method. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 5 recites “A method of determining quantitative values for a set of CQAs for assessing immunomodulatory fitness of samples of mesenchymal stromal cells (MSC), wherein the MSC samples are from donors and/or from samples grown using different critical processing parameters (CPPs), the method comprising: a) determining the values of the set of CQAs for each sample; wherein the set of CQAs comprise: a. from the sample cultured and harvested: i. in the presence of proinflammatory cytokines stimulation post-harvest: the mRNA levels of the following genes: THBS1, CCN2, EDN1, ACTA2, PDCD1LG2, TNFAIP6, ANGPT1, CXCL8; and/or ii. in the absence of the proinflammatory cytokines stimulation post- harvest: the mRNA levels of the following genes: CCN2, TSG101, THBS1, PDGFA, VEGFA, EDIL3, ACTA2, ANGPT1, ANG and the level of TGF-beta protein; b) testing each sample of MSC for immunomodulatory fitness using in vitro assays or obtaining immunomodulatory fitness status of the sample; c) conducting a regression analysis between each CQA of a) with the immunomodulatory fitness of b); determining minimum and maximum data values of each CQA of the samples and using multivariate dimension reduction statistical or mathematical methods to assign minimization or maximization functions to indicate whether higher or lower values are desirable based on the directionality of correlation respectively.”
Claim 6 recites “d) assigning a weighting to each CQA for desirability analysis based on the R2 values from the regression analysis; and e) use of desirability analysis methods to assign a score from zero to one to each sample based on the range of data values; wherein zero is undesirable and one is highly desirable to obtain a set of values for MSCs for each donor grown using particular CPPs.”
Claim 7 recites “wherein the testing for immunomodulatory fitness in step b); ii) comprises evaluating immunomodulatory effects of MSC using preclinical animal models; iii) is obtained from a clinical sample for which the immunomodulatory fitness or efficacy of the MSCs were previously evaluated clinically; or iv) comprises:1. determining at least one patient-reported outcome measure (PROM) score from an assessment of an MSC-treatable disease from a subject with the MSC-treatable disease pre treatment; II. determining the at least one PROM score from the assessment of the MSC-treatable disease from the subject post treatment; III. comparing the at least one PROM score in I) and II); and IV. assigning an immunomodulatory fitness score to the sample based on the size of the improvement in the at least one PROM score post- treatment compared to pre-treatment, wherein an improvement in the at least one PROM score post-treatment is indicative that the immunomodulatory fitness score of the sample is high, and wherein no improvement or a worsening in the at least one PROM score post- treatment is indicative that the immunomodulatory fitness score of the sample is low.”
Claim 9 recites “wherein step iv) II. is performed 12 or 24 months post treatment with the sample.”
Claim 10 recites “wherein the MSC-treatable disease comprises osteoarthritis, lupus, scleroderma, rheumatoid arthritis, graft versus host disease, stroke, inflammatory bowel disease, or cardiac disease.”
Claim 11 recites “wherein the osteoarthritis comprises knee osteoarthritis, and wherein the assessment of the MSC-treatable disease comprises an assessment of knee osteoarthritis.”
Claim 12 recites “wherein the assessment of knee osteoarthritis comprises Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analogue Scale (VAS), Short Form 36 (SF-36) or Short Form 12 (SF-12), Tegner Lysholm Knee Score, Knee Society Clinical Rating System, Lequesne Index for Knee Osteoarthritis, Oxford Knee Score (OKS) and/or International Knee Documentation Committee (IKDC) Questionnaire.”
Claim 18 recites “wherein the MSCs are derived from adipose tissue, bone marrow, dental pulp, synovium, placenta, or umbilical cord.”
Claim 19 recites “wherein the MSCs are derived from adipose tissue or from bone marrow”
Limitations reciting a mental process.
Claims 5-9, 11-12 and 18-19 contain limitations recited at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mental process.
Claim 5, steps a)ai–a)aii, and claim 8 include assessing previously generated RNA-seq or western blotting data and identifying an expression value of selected genes/proteins from the previously generated data. This interpretation is reinforced by the fact that claim 5 does not require an active step of generating the data. Claim 5, step b), and claim 7, step iii), include collecting previously generated immunomodulatory fitness data. Claim 5, step c), includes performing a regression, analyzing and organizing values of CQAs to determine a minimum and maximum value, performing linear discriminant analysis and assigning functions. A human is capable of performing on pen and paper these calculations recited at a high level. Claim 7, step ii), includes making observation from animal models. Claim 7, step iv), includes analyzing data to generate a score, comparing scores, and mental determinations of assigning fitness scores. Claim 6, step d), includes assigning weights to values based on analyzing R2 values. Claim 6, step e), includes performing the calculations specified in Derringer et al. (NPL ref. 46 on IDS filed 09/07/2023; Journal of quality technology, 12(4), 214-219) (pg. 214-215) (pg. 214-215).
Claims 11-12 include performing mental evaluations of a patient with knee osteoarthritis as well as following the steps of a SF-12.
Limitations reciting a mathematical concept.
Claims 5-7 recite limitations that equate to a mathematical concept because they are similar to the concepts of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. Claim 5, step c), includes calculations performed by equations/functions such as regressions and multivariate dimensionality reductions such as PCA. Claim 6, step d), includes mathematical correlations of generating weights based on R2 values. Claim 6, step e), includes performing the calculations specified in Derringer et al.
Limitations reciting a natural phenomenon.
Claims 5 recites limitations that are similar to the concept of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017), which the courts have established as a natural phenomenon. Claim 5 recites a natural relationship by correlating expression of genes/proteins and/or cell morphology to immunomodulatory fitness of mesenchymal stromal cells.
Limitations included in the recited judicial exception.
Claim 10 is included in the judicial exception in claim 7, step iv), because it further limits the MSC-treatable disease, which is part of limitations that recite a mental process. Claims 18-19 and 21 are included in the judicial exception in claim 5, steps a)ai–a)aii, because they further limit, for example, how the previously generated RNA-seq or western blotting data was previously acquired before mental analysis to determine mRNA and protein levels.
As such, claims 5-12, 18-19 and 21 recite an abstract idea and a natural phenomenon (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 5 recites “b. from a single cell suspension of the sample: cell diameter and cell circularity post-harvest without pro-inflammatory cytokine stimulation;”
Claim 7 recites “i) comprises measuring in vitro MSC-mediated polarization of monocyte/macrophages toward inflammation-resolving phenotypes, regulatory T cell (Treg) induction, suppression of peripheral blood mononuclear cells (PBMC) or T cell proliferation;”
These above recited additional elements are analyzed below under both Step 2A, Prong 2 and Step 2B:
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2).
The additional elements recited above in claims 5 and 7 are optional limitations that are not required by the claim. Claim 5, step a)b, is optional as indicated by “and/or”, and claim 7, step i), is optional as indicated by “or”. As such, these additional elements are not being evaluated under Step 2A, Prong 2 because they are not required.
As such, claims 5-12, 18-19 and 21 are directed to an abstract idea and a natural phenomenon (Step 2A, Prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B).
The additional elements recited above in claims 5 and 7 are optional limitations that are not required by the claim. Claim 5, step a)b, is optional as indicated by “and/or”, and claim 7, step i), is optional as indicated by “or”. As such, these additional elements are not being evaluated under Step 2B because they are not required.
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they are not required by the claims. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 5-12, 18-19 and 21 are not patent eligible.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 5, 7, 9-12, 18-19 and 21 are rejected under 35 USC 103 for being unpatentable over Klinker et al. (“Klinker”; NPL ref. 15 on IDS filed 09/07/2023; Proceedings of the National Academy of Sciences, 114(13), E2598-E2607) in view of Kuhn et al. (“Kuhn”; The desirability package; published online 22 September 2016).
The bold and italicized text below are the limitations of the instant claims, and the italicized text maps the prior art onto the claims.
Claim 5:
A method of determining quantitative values for a set of CQAs for assessing immunomodulatory fitness of samples of mesenchymal stromal cells (MSC), wherein the MSC samples are from donors and/or from samples grown using different critical processing parameters (CPPs), the method comprising:
Klinker recites “To identify features associated with immunosuppressive capacity in MSCs, we developed a robust in vitro assay that uses principal-component analysis to integrate multidimensional flow cytometry data into a single measurement of MSC-mediated inhibition of T-cell activation. We used this assay to correlate single-cell morphological data with overall immunosuppressive capacity in a cohort of MSC lines derived from different donors and manufacturing conditions” (abstract).
a) determining the values of the set of CQAs for each sample; wherein the set of CQAs comprise: a. from the sample cultured and harvested: i. in the presence of proinflammatory cytokines stimulation post-harvest: the mRNA levels of the following genes: THBS1, CCN2, EDN1, ACTA2, PDCD1LG2, TNFAIP6, ANGPT1, CXCL8; and/or ii. in the absence of the proinflammatory cytokines stimulation post-harvest: the mRNA levels of the following genes: CCN2, TSG101, THBS1, PDGFA, VEGFA, EDIL3, ACTA2, ANGPT1, ANG and the level of TGF-beta protein; and/or b. from a single cell suspension of the sample: cell diameter and cell circularity post-harvest without pro-inflammatory cytokine stimulation; b) testing each sample of MSC for immunomodulatory fitness using in vitro assays or obtaining immunomodulatory fitness status of the sample;
The BRI of step a) includes only performing step a)b because step a)a is optional. Regarding steps a)b and b), Klinker performed morphological and immunosuppressive assays in parallel on early- and late-passage MCS to identify morphological features associated with immunosuppression under stimulated and unstimulated conditions (pg. 2602, col. 1, para. 2) (Figure 3 and S1B) (pg. 2606, col. 1, para. 2). The morphological features are listed in Figure 4. The morphological measurements were of single cell suspensions using CellProfiler (abstract) (Table S8) (Figure 4) (pg. 2606, col. 1, para. 2).
c) conducting a regression analysis between each CQA of a) with the immunomodulatory fitness of b);
Klinker performed a regression analysis on each morphological feature to determine correlation with immunosuppression, using both INF-y stimulated and unstimulated MSC samples (Fig. S1B) (caption of Table S4) (pg. 2602, col. 1, para. 2).
determining minimum and maximum data values of each CQA of the samples and
Klinker shows in Figures 5A and S3A-B a range of values for each morphological feature.
using multivariate dimension reduction statistical or mathematical methods to assign minimization or maximization functions to indicate whether higher or lower values are desirable based on the directionality of correlation respectively.
Klinker performed a regression analysis on each morphological feature to determine correlation with immunosuppression (directionality of correlation) (Fig. S1B) (caption of Table S4) (pg. 2602, col. 1, para. 2). Immunosuppression was scored as a principal component (multivariate dimension reduction) (pg. 2598, col. 1, para. 1) (Figure 2). However, Klinker does not assign maximization or minimization functions to indicate whether higher or lower values are desirable for a predictive morphological feature.
Kuhn discloses multivariate optimization using a desirability function (pg. 1, sec. 1). Individual desirability functions are constructed which are high when fr(x) is at a desirable level (such as maximum or minimum) or low when fr(x) is at an undesirable level (pg. 2, para. 1). Equations 1 and 2 on pg. 2 show maximization and minimization functions. A maximization function is used when a higher value is better and a minimization function is used when a lower value is better (caption of Figure 1).
It would have been prima facie obvious to have assigned maximization/minimization functions for desirability analysis, as taught by Kuhn, to each morphological feature in Klinker based on directionality of correlation derived from regression analysis (i.e. assigning a minimization function to a low value of a morphological feature negatively correlated with high immunosuppression). Kuhn teaches motivation for doing so because the desirability function optimizes multiple variables to optimize an overall metric (i.e. optimizing morphological features to optimize immunosuppression) (pg. 2, sec. 2, para. 1-2). This motivation aligns with Klinker who better predicts immunosuppression capacity of different cell lines and monitors effects of changes in manufacturing conditions such as culturing conditions (pg. 2605, col. 2, para. 3). Klinker also teaches “morphological characterization must be performed with each manufacturing process to establish useful criteria for identifying MSC preparations with desired immunosuppressive potential” (pg. 2605, col. 2, last para. 3).
There would have been a reasonable expectation of success to perform a desirability analysis using the predictive morphological features and immunosuppression scores of Klinker because Kuhn states that the desirability function can represent model predictions (pg. 2, sec. 2, para. 1).
Claim 7:
The BRI of claim 7 includes performing just step i) because all other steps are optional. Klinker measures immunosuppression by measuring in vitro T cell proliferation in the presence of MSCs (Figure 2A) (pg. 2606, col. 2, para. 1).
Claims 9-12:
Claims 9-12 are not required by the claims. Claim 9 depends on claim 7 step iv), which is not required by claim 7. As discussed in 35 USC 112(b), claims 10-12 are being interpreted to depend on claim 7, step iv), which is not required by claim 7. As such, claims 9-12 are rejected for their dependency on rejected claim 7.
Claims 18-19:
Klinker uses human bone marrow-derived MSCs obtained from six different donors and AllCells (pg. 2606, col. 2, para. 2).
Claim 21:
Claim 21 depends on claim 5, steps a)ai–a)aii, which are optional limitations. Claim 21 is also an optional limitation and is thus not required to be performed. As such, claim 21 is rejected for its dependency on rejected claim 5.
Claim 8 is rejected under 35 USC 103 for being unpatentable over Klinker et al. (“Klinker”; NPL ref. 15 on IDS filed 09/07/2023; Proceedings of the National Academy of Sciences, 114(13), E2598-E2607) in view of Kuhn et al. (“Kuhn”; The desirability package; published online 22 September 2016) and in further view of Kentaro et al. (“Kentaro”; WO 2023/286305 A1; effective filing date 10 February 2022).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
The limitations of claim 5 are taught in the rejection above by Klinker and Kuhn.
Claim 8:
a) determining the values of the set of CQAs for each sample; wherein the set of CQAs comprise: a. from the sample cultured and harvested: i. in the presence of proinflammatory cytokines stimulation post-harvest: the mRNA levels of the following genes: THBS1, CCN2, EDN1, ACTA2, PDCD1LG2, TNFAIP6, ANGPT1, CXCL8; and ii. in the absence of the proinflammatory cytokines stimulation post-harvest: the mRNA levels of the following genes: CCN2, TSG101, THBS1, PDGFA, VEGFA, EDIL3, ACTA2, ANGPT1, ANG and the level of TGF-beta protein;
As discussed in Elections/Restrictions, claim 8 is being interpreted to require a) comprising both a.i and a.ii.
Klinker performed morphological and immunosuppressive assays in parallel on early- and late-passage MCS to identify morphological features associated with immunosuppression under stimulated and unstimulated conditions (presence/absence of proinflammatory cytokine stimulation) (pg. 2602, col. 1, para. 2) (Figure 3 and S1B) (pg. 2606, col. 1, para. 2). The stimulation is IFN-γ (pg. 2600, col. 2, last para.). The morphological features are listed in Figure 4.
However, Klinker and Kuhn do not measure mRNA or protein expression of the claimed genes/proteins.
Kentaro teaches quality control methods of MSC by controlling behavior of cells [1]. mRNA and proteins are measured using RNAseq or flow cytometry [35] [44] [48]. The genes/proteins are related to function and state of MSCs [41] [91]. 1200 genes/proteins are measured and include: THBS1 (pg. 96), CCN2 (pg. 78), EDN1 (pg. 82), ACTA2 (pg. 138), PDCD1LG2 (pg. 235), TNFAIP6 (pg. 96), ANGPT1 (pg. 233), CXCL8 (pg. 82), TSG101 (pg. 141), PDGFA (pg. 224), VEGFA (pg. 97), EDIL3 (pg. 82), ANG (pg. 76), and TGF-B (pg. 95).
It would have been prima facie obvious to have modified Klinker’s method of measuring morphological features predictive of immunosuppression effects of MSCs by also measuring proteins/genes indicative of MSC function for quality control as taught by Kentaro. Klinker discloses motivation for doing so by reciting “This study contains a substantial amount of information from characterization of in vitro MSC-mediated immunosuppression, which may be important for future correlational studies looking for other predictive factors associated with immunosuppressive capacity, including gene expression and secretome analyses” (pg. 2605, col. 1, para. 3). One of ordinary skill would have recognized that the genes/proteins related to MSC function in Kentaro constitute “other predictive factors” potentially correlated with MSC immunosuppression capacity. One of skill would want to determine whether these genes/proteins are correlated with immunosuppressive capacity to evaluate whether they are predictive.
There would have been a reasonable expectation of success to measure gene/protein expression of MSCs and correlate them with immunosuppression because it requires measuring expression levels using the cell lines of Klinker and performing the same regression analyses used by Klinker to associate morphological features with immunosuppression. Kentaro also teaches the necessary methods for measuring the genes/proteins in MSCs [35] [140].
Conclusion
No claims are allowed.
Claim 6 is free from the prior art because the prior art does not fairly teach or suggest “d) assigning a weighting to each CQA for desirability analysis based on the R2 values from the regression analysis”. The closest prior art Klinker et al. (“Klinker”; NPL ref. 15 on IDS filed 09/07/2023; Proceedings of the National Academy of Sciences, 114(13), E2598-E2607) and Kuhn et al. (“Kuhn”; The desirability package; published online 22 September 2016). Klinker performed regression analysis on each morphological feature to determine correlation with immunosuppression in MSCs (Fig. S1B) (caption of Table S4). Kuhn teaches the desirability function, wherein each function has a scaling factor as a weight (pg. 2), and an overall desirability function that is a weighted geometric mean (pg. 4, sec. 3). However, Klinker and Kuhn do not assign a weight to each morphological feature based on an R2 value derived from a regression of the morphological features correlated with immunosuppression.
Notable, but not relied upon, prior art includes: Srinivasan et al. (Cytotherapy 24, no. 5 (2022): 456-472; published online 22 May 2022) review on enhancing immunomodulatory properties in MSC with Figure 4 showing MSC potency assay matrix include secretome, gene expression, morphological features and immune co-culture assays. Marklein et al. (Cytotherapy 21, no. 1 (2019): 17-31) morphological profiling of MSCs that predict immunosuppression.
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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