DETAILED ACTION
This action is in reply to papers filed 01/29/2026.
Claims 1-8 and 12-19 are pending and examined herein.
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 elected without traverse Group I, drawn to claims 1-8, in the reply filed on 09/08/2025.
Claim 12, which has been amended to depend from claim 1, and new claims 13-19 are examined herein as part of Group I.
Claims 10-11 are withdrawn from consideration as being drawn to a non-elected invention.
Status of Rejections
The rejection of claims 1-6 and 8 under 35 U.S.C. 102(a)(1) as being anticipated by Ng (Biotechnology Journal, 2021, 16(3)) is withdrawn in light of the amendment to claim 1 to recite the limitation “the separation device has a pore size of 20 to 50 μm” in the last line. Applicant’s arguments are addressed following the new grounds of rejection.
The rejection of claims 1 and 7 under 35 U.S.C. 103 over Ng (Biotechnology Journal, 2021, 16(3): 2000048), in view of Häring (STAR Protocols, 2020, 1(1): 100030), is maintained. Applicant’s arguments are addressed following the body of the rejection.
Claim Objections
Claim 7 is objected to because of the following informalities: the phrase “claim ,6 wherein” (line 1) should be corrected to “claim 6, wherein”. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: the phrase “wherein t the size” (line 1) should be corrected to “wherein the size.” Appropriate correction is required.
Claim Interpretation
Claim 1, drawn to a method, comprises a preamble reciting intended use or purpose (“A culture manufacturing method” in line 1; “culture manufacturing” is interpreted as a preamble for the method as claimed in claim 1). The body of claim 1 sets forth the limitations of the method as claimed, and therefore, the preamble is not considered a further limitation to the claim. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020). See MPEP 2111.02(II).
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.
Claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 19 recites the limitation " the cell detachment agent" in line 4. There is insufficient antecedent basis for this limitation in the claim.
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.
Claim(s) 1-8 and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (Biotechnology Journal, 2021, 16(3): 2000048), in view of Häring (STAR Protocols, 2020, 1(1): 100030), as evidenced by Cytiva (“CytodexTM Microcarriers,” 2024; cited in IDS 08/14/2025).
Regarding claim 1: Ng teaches Cytodex-1 and Cytodex-3 microcarriers, which are microporous (p 2, col 1, para 2), and the use of said microcarriers for expanding adherent mesenchymal stromal cells (MSCs) in a suspension culture (Abstract; p 2, col 1, para 2; p 3, col 1, para 2). Both the Cytodex-1 and Cytodex-3 microcarriers are larger than MSCs (Fig 2f).
Ng teaches an experiment, wherein MSCs and Cytodex microcarriers are seeded in a 24-well ultralow attachment well plate (p 5, col 2, para 1). After an overnight incubation, the samples were incubated with Pronase for 30 minutes to detach the cells from the microcarriers (p 5, col 2, para 1). Pronase partially dissolved the Cytodex microcarriers (p 5, col 1, para 1; Fig 3a). The size of the Cytodex microcarriers following Pronase treatment is at least 50% prior to the treatment (Fig 2f, 3a). The detached cells were passed through a 70µm cell strainer to filter out microcarrier particles or cell aggregates (p 5, col 2, para 1).
Ng does not teach the use of a separation device with a pore size of 20µm to 50µm.
Häring teaches that a suitable cell strainer should be selected depending on the cell size of interest (p 7, para 3). For example, the protocol taught in Häring uses a 40µm strainer because the diameter of the largest murine vagal sensory neurons, which are the cells of interest therein, is smaller than 40µm (p 7, para 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the method of Ng by utilizing a cell strainer with the optimal pore size according to the cell size of interest, as taught in Häring, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. No evidence has been presented that using a cell strainer with pore size of 70µm as taught by Ng, instead of a pore size of 20µm to 50µm as claimed, was other than routine, that the separation of cells and culture carrier resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
Regarding claims 2-3: Cytiva shows that both the Cytodex-1 and Cytodex-3 microcarriers comprise a cross-linked dextran matrix (p 2, “Properties and Characteristics”). Ng teaches that the Cytodex-3 microcarrier is coated with a microlayer of denatured collagen (p 3, col 1, para 2).
Regarding claim 4: Ng teaches that the Cytodex microcarriers are microporous (p 2, col 1, para 2)
Regarding claim 5: Ng teaches that the samples were incubated with Pronase, which is a surface modifier, to detach the cells from the microcarriers (p 5, col 2, para 1).
Regarding claims 6-7: Ng teaches the use of a separation device with a pore size of 70µm (p 5, col 2, para 1). Ng does not teach the use of a separation device with a pore size of 20µm to 40µm (claim 6) or 20µm to 30µm (claim 7). Following the discussion of Häring in the rejeciton for claim 1, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the method of Ng by utilizing a cell strainer with the optimal pore size according to the cell size of interest, as taught in Häring, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Regarding claim 8: Ng teaches that Cytodex-1 and Cytodex-3 microcarriers have diameters ranging from 131µm to 220µm and 133µm to 215µm, respectively (p 3, col 1, para 1).
Regarding claims 13-15: Ng teaches that the size of the Cytodex microcarrier following Pronase treatment is at least 90% prior to the treatment (Fig 2f, 3a), which is larger than the size of the cells (Fig 3a).
Regarding claim 16: Cytiva shows that both the Cytodex-1 and Cytodex-3 microcarriers comprise a cross-linked dextran matrix (p 2, “Properties and Characteristics”).
Claim(s) 1 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (Biotechnology Journal, 2021, 16(3): 2000048), in view of Häring (STAR Protocols, 2020, 1(1): 100030) and Zeigler (US 2019/0032017 A1).
The teachings of Ng and Häring are set forth above.
Ng, in view of Häring, renders obvious claims 1 and 16.
Regarding claim 17: Ng, in view of Häring, does not teach conducting the modification treatment by using a surface modifier containing dextranase.
Zeigler teaches the manufacture of an extracellular matrix comprising collagen (para 7), wherein the method comprises culturing pluripotent cells or fibroblasts on a substrate which comprises dextran, including dextran microcarriers (para 50). Zeigler teaches that dextran substrates can be digested using dextranase to isolate and purify the extracellular matrix (para 50). Zeigler teaches that dextranase in cell culture can be used for a variety of applications, including cell isolation from dextran microcarriers (para 52-53).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ng, in view of Häring, by using a surface modifier containing dextranase, as taught in Zeigler. One of ordinary skill in the art would have been motivated to make this modification because Zeigler teaches that the use of dextranase to digest dextran substrates can facilitate isolation and purification of cell culture (para 50). One of ordinary skill in the art would have had a reasonable expectation of making this modification because Ziegler teaches that dextranase in cell culture can be used for a variety of applications, including cell isolation from dextran microcarriers (para 52-53).
Regarding claim 18: Following the discussion of claim 17, Ziegler teaches that dextranase can be used at a relatively low concentration, including at concentrations less than 1000 U/mL, including 900 U/mL and 1 U/mL (para 54, 64). Ziegler teaches that the lower concentrations of dextranase are less likely to non-specifically degrade other non-dextran carbohydrates (para 54).
Zeigler does not teach a dextranase concentration, relative to the total volume of the cell suspension, from 0.001 to 0.1 v/v %.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the concentration of dextranase on factors including pH of the solution, whether non-dextran carbohydrates are to be degraded, and the desired size of the microcarrier at the end of treatment, to arrive at the claimed invention. Routine optimization is not considered inventive and no evidence has been presented that changing the concentration of dextranase from the concentrations taught in Zeigler to the claimed concentrations was other than routine, that the results resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Claim(s) 1 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (Biotechnology Journal, 2021, 16(3): 2000048), in view of Häring (STAR Protocols, 2020, 1(1): 100030), Zeigler (US 2019/0032017 A1), and Goh (BioResearch Open Access, 2013, 2(2): 84-97).
The teachings of Ng, Häring, and Zeigler are set forth above.
Ng, in view of Häring, renders obvious claims 1 and 16.
Ng, in view of Häring and Ziegler, renders obvious claims 17-18.
Regarding claim 19: Ng, in view of Häring and Ziegler, does not teach further conducting a cell detachment treatment for promoting a detachment of the adherent cells from the surface of the dissolvable culture carrier consecutively with, or separately from, the modification treatment, and wherein the cell detachment agent used in the cell detachment treatment contains trypsin and EDTA.
Goh teaches the use of 0.25 % Trypsin-EDTA to harvest human fetal MSCs from Cytodex microcarriers (Abstract; p 86, col 1, para 4). Goh teaches that harvesting using trypsin generated single cell suspensions with higher osteogenic potential compared to the use of collagenase or TrypLE Express for harvest (p 91, col 1, para 4).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ng, in view of Häring and Ziegler, by conducting a detachment treatment of adherent cells using an agent comprising Trypsin and EDTA, in addition to the modification treatment. One of ordinary skill in the art would have been motivated to make this modification because Goh teaches that the use of a 0.25 % Trypsin-EDTA solution to detach MSCs from microcarriers resulted in single cell suspensions with high osteogenic potential. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Goh teaches that Trypsin-EDTA can be used to detach MSCs from Cytodex microcarriers.
Response to Arguments
Re: Claim Interpretation
Applicant argues: Applicant respectfully submits that the interpretation set forth in the office action does not accurately and fully consider the law on whether a preamble is a limitation. As is evident in section 2111.02, a preamble is not per se non limiting. Without acquiescing to the Examiner's interpretations, Applicant nonetheless has amended claims, rendering the Examiner's interpretation moot.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In the instant case, the body of the claim, including the amendments therein, sets forth the limitations of the claimed method, and therefore, the preamble, which recites the method is “A culture manufacturing method,” is not considered a further limitation to the claim. See MPEP 2111.02(II).
Re: Rejection of claims 1-6 and 8 under 35 U.S.C. 102(a)(1) as being anticipated by Ng (Biotechnology Journal, 2021, 16(3): 2000048)
As stated above, the rejection of claims 1-6 and 8 under 35 U.S.C. 102(a)(1) as being anticipated by Ng has been withdrawn in light of the amendment to claim 1 to recite the limitation “the separation device has a pore size of 20 to 50 μm” in the last line. Arguments regarding Ng are addressed as they pertain to claim rejections under 35 U.S.C. 103 over Ng, in view of Häring, as set forth above.
Applicant argues: The office action identifies gelatin-based and Cytodex-3 microcarriers as allegedly satisfying the claimed "dissolvable culture carrier," but neither satisfied the claimed feature recited above. First, the Gelatin-based microcarrier cannot satisfy the claimed "dissolvable culture carrier" because it is entirely dissolved and does not retain "at least 50%" of the size prior to the modification treatment. See Ng at page 5, col. 1, first paragraph ("In contrast, gelatin MCs were fully dissolvable with Pronase treatment. Particles could be dissolved within 5 min with 0.1 % Pronase solution without agitation, thus eliminating the need to perform separation of cells from the particles (Figure 3b).").
In response: Applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on gelatin-based microcarriers disclosed in Ng.
Applicant argues: Second, Cytodex-3 microcarrier also fails to satisfy the claimed "dissolvable culture carrier" because NG does not teach that it retained "at least 50%" of its size "following the modification treatment."
In response: Applicant’s arguments have been fully considered, but are not persuasive. As set forth above, Figures 2a and 3a of Ng, both of which comprise scale bars, show that the Cytodex-3 microcarrier retains at least 50% of its size following treatment with Pronase.
Applicant argues: Further, Ng discloses that "cells did not fully detach from the Cytodex MCs even after 30 min of enzymatic treatment." Id. Indeed, Ng characterizes Cytodex MCs as inferior choices resulting in poor cell harvesting efficiency, id. at page 6, column 1, first paragraph, that becomes "a key bottleneck of adherent cell expansion on MCs," id. page 8, column 1, second paragraph, while describing gelatin as the "superior" and "suitable substrate for the growth of MSC," id. at page 7, column 1; at page 8, column 2, last paragraph. Accordingly, a person of ordinary skill in the art would NOT have been motivated to select Cytodex MCs in culturing cells in view of the clear teach-aways in Ng.
In response: Applicant’s arguments have been fully considered, but are not persuasive. A reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed. See MPEP 2145(X)(D)(1), UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023).
Re: Rejection of claims 1 and 7 under 35 U.S.C. 103 over Ng (Biotechnology Journal, 2021, 16(3): 2000048), in view of Häring (STAR Protocols, 2020, 1(1): 100030).
Applicant argues: Ng fails to disclose each and every feature of pending claim 1, on which claim 7 depends. Haring fails to remedy the deficiency in Ng because it was cited specifically for allegedly disclosing a feature specifically found in claim 7.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Applicant’s arguments regarding Ng have been addressed above. Applicant did not present arguments regarding Haring specifically. As Applicant stated, Haring was cited as a secondary reference in the previous Office Action for the feature of claim 7 regarding the pore size of the separation device, which has now been incorporated into amended claim 1.
Allowable Subject Matter
Claim 12 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is 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 Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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