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 .
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.
Claim Status
Applicant’s arguments and amendments dated 4/28/26 have been received and entered in the application.
Claims 1-11, 16-20 are currently pending and examined on the merits.
Claims 1, 3-4, 7-8, 18-20 are currently amended.
Claim 21-22 are newly added.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections rejections not specifically reiterated are hereby withdrawn.
Claim Objections
Applicant is advised that should claim 17 be found allowable, claim 22 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 8-10, 20 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.
Claim 8 contains the limitation “measuring the permittivity and cell density of at least two different cell densities of a reference suspension culture”. It is unclear if this limitation is indicating that the permittivity and cell density of a single reference suspension culture is measured at two different time points, or if this limitation is indicating that the permittivity and cell density of two different reference suspension cultures is measured.
Claim 20 contains the limitation “measuring the permittivity and cell density of at least three different cell densities of a reference suspension culture”. It is unclear if this limitation is indicating that the permittivity and cell density of a single reference suspension culture is measured at two different time points, or if this limitation is indicating that the permittivity and cell density of two different reference suspension cultures is measured.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-11,17-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Justice et al., (2011) Online- and offline- monitoring of stem cell expansion on microcarrier. Cytotechnology, 63: 325-335 (cited on IDS dated 6/7/24, hereinafter Justice) in view of Heilman et al., (2017) Dielectric spectroscopy platform to measure MCF10A epithelial cell aggregation as a model for spheroidal cell cluster analysis. Royal Society of Chemistry, 142:1601-1607 (hereinafter Heilman).
Regarding claims 1, 8, 20, Justice discloses methods for determining viable cell density by measuring permittivity of the culture (Abstract, Introduction). Justice explains that dielectric spectroscopy is a promising technology for monitoring of cell density in stem cell cultures (Introduction). Justice discloses culturing human mesenchymal stem cells (hMSCs) on RapidCell microcarriers to form cell aggregates (Cell expansion in T-flasks and stirred tank reactor). Permittivity of the cell aggregates is measured at multiple cell concentrations and compared to cell concentrations determined using a hemocytometer (Permittivity measurements, Online permittivity measurement, Fig. 4). Justice explains that the disclosed methods allow for cell density determination of anchorage dependent cells (Conclusions).
Regarding claims 2-3, Justice discloses that the culture is performed in a 2 L stirred bioreactor system (Cell expansion in T-flasks and stirred tank bioreactor).
Regarding claims 4, 21, Justice discloses that cells grown on microcarriers are monitored by throughout the whole cultivation time (i.e., in-line monitoring) (Permittivity measurements).
Regarding claims 5-6, Justice discloses measuring permittivity using a dielectric spectroscopy probe (Permittivity measurements
Regarding claim 7, Justice disclose that the cells are human mesenchymal stem cells (hMSCs) (Cell expansion in T-flasks and stirred tank reactor).
Regarding claim 9, Justice discloses that cell concentrations are calculated from known growth kinetics and correlated to fluorescence intensity in a linear correlation (Online fluorescence assay, Online permittivity measurement, Figs. 3-4).
Regarding claim 10, Justice discloses using hMSCs for both reference and aggregate culture (Cell expansion in T-flasks and stirred tank reactor, Permittivity measurements).
Regarding claim 9, Justice discloses that cell concentrations are calculated from known growth kinetics and correlated to fluorescence intensity in a linear correlation (Online fluorescence assay, Online permittivity measurement, Figs. 3-4).
Regarding claim 11, Justice explains that viable cells remain adherent on the carrier, such that they reflect the viable cell concentration (Online fluorescence assay).
Regarding claims 17-19, Justice does not explicitly disclose that the cells are pluripotent stem cells, such as induced pluripotent stem cells. However, Heilman explains the disclosed methods are highly useful for the monitoring expansion processes of stem cells generally. Therefore, there is a suggestion present in Justice that the disclosed methods may be useful in monitoring of other stem cell types. A skilled artisan would understand that well-known stem types, such as iPSCs, could be substituted into the methods of Justice as suggested.
Justice does not disclose that the cell are not in a microcarrier culture.
Heilman discloses methods of monitoring cell aggregates for cell position, density, and morphology using dielectric spectroscopy (Abstract, Introduction). Heilman explains that cell aggregates have been demonstrated to be relevant 3D cell culture models such that non-invasive monitoring techniques would be highly advantageous (Introduction). Heilman discloses 3D culturing MCF10A epithelial cells in aggregate without the use microcarriers (Cell aggregate assay). Dielectric spectra of the cell aggregates is compared to a control (Dielectric spectroscopy). Heilman concludes that the disclosed methods allow for monitoring cell density, cell migration and, tissue morphology in cell aggregates (Conclusion).
As both Justice and Heilman are directed to methods of monitoring cell aggregates using dielectric spectroscopy, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to utilize a microcarrier free carrier in the methods of Justice as Heilman explains that cell aggregates are a highly relevant cell culture model.
Response to Arguments
Applicant's arguments dated 4/28/26 have been fully considered but are moot in part and not persuasive in part. To the extent that applicant’s arguments are pertinent to the current grounds of rejection they are responded to in detail below.
Claim(s) 1-11,17-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Justice in view of Heilman.
Applicant argues that Justice measures cell concentration in terms of cells per cm2 and not cell density as a volumetric measure (Response p9). Applicant argues that determination of cell surface measurement is specific to a microcarrier or 2D system and has no bearing on a cell aggregate culture (Response p6).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., volumetric cell density) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims as presented merely require determining cell density; nothing in the claims requires a volumetric determination. Therefore, determining the cell density on the surface of a microcarrier as in Justice reads on the claims as presented.
With respect to cell aggregates, the claims as presented do not limit the size of the aggregates, nor the characteristics of the aggregate. Therefore, under a broadest reasonable interpretation, a cell aggregate reads on any size cluster of cells, (e.g., 3 cell clusters) and hollow cell clusters (e.g., neurosphere). Consequently, Justice is considered relevant to the claims as currently presented.
Applicant argue that Heilman does not disclose suspension culture (Response p9) .
In response, Heilman is not used to demonstrate suspension culture. Heilman is used solely to demonstrate that cell density may be determined in microcarrier-free cell aggregates, and the advantages thereof.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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