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 .
Claims 1-8, of record 1/16/2026, are pending and subject to prosecution. Claims 1-4 and 7 are amended. Claim 8 is newly added.
Status of Prior Rejections/Response to Arguments
RE: Objection to the specification:
The amendments to the specification are effective to obviate the objection. The objection is withdrawn.
RE: Objection to claims 1-2 and 7:
The amendment to claims 1-2 and 7 are effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 1-5 under 35 U.S.C. 112(b):
The amendment to claims 1 and 3-4 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1-7 under 35 U.S.C. 103 over Fukuda et al. (US 20190062687 A1) in view of Eddington et al. (US 20170261496 A1):
The applicant asserts that modification of the teachings of Fukuda et al. to add the mixture of mesenchymal and epithelial cells on a patterned surface, as taught by Eddington et al., would defeat the purpose of Fukuda et al. and that it would not be possible to form spheroids on such a surface (Applicant Remarks, page 15). The applicant also asserts that culturing the cell aggregates on a patterned substrate would require a detachment step prior to transplantation that would be inefficient and possibly damaging (Applicant Remarks, page 15). The applicant further asserts that the experimental conditions of Fukuda et al. differ fundamentally from the claimed invention and that Eddington et al. do not provide guidance on size control of cell proliferative regions or seeding ratios (Applicant Remarks, page 15-16).
The applicant’s arguments have been fully considered but are not found persuasive. The rejection of the claims is based upon the combination of Fukuda et al. and Eddington et al.; their combined teachings are what encompass every limitation of the claims and render the claimed invention obvious. Fukuda et al. teach that dimensions of the microwell dictate the size of hair follicle primordia and that the diameter of the microwell may be the same as a mammal’s pore (See ¶0064-0065), which suggest a need for size constraint in culturing the hair follicle primordia. Eddington et al. teach a micropatterned substrate that enables lateral confinement of cell growth and spread for modulating cell-cell and cell-matrix interaction (See ¶0002-0006 and 0167). The plate/culture surface of Eddington et al. therefore provides an alternate strategy for generating cell aggregates such as hair follicle primordia.
The applicant argues that cell spheroids such as those taught by Fukuda et al. cannot be formed on a patterned substrate such as that taught by Eddington et al. However, it was known in the art that MSCs can form 3D aggregates on surfaces, such as patterned substrates, using spatial confinement to increase cell-cell contacts (See Sart et al., page 367, col. 1, ¶1 and Wang et al., page 2706, col. 1, ¶4-5 and fig. 2). It was also shown that at least one type of epithelial cell, MDCK cells, formed 3D spheroids on a glass substrate and that cell spreading was dictated by cell-adhesive surface area (See Ravasio et al., page 7, ¶1 and page 11, ¶1). Because MSCs and MDCK cells had been demonstrated to form spheroids on flat surfaces wherein cell spreading was constrained, one of ordinary skill in the art could reasonably expect the combination of MSCs and epithelial cells taught by Fukuda et al. to be capable of forming an aggregate, as well, under related conditions. Modification of the method of Fukuda et al. for forming hair follicle primordia as set forth in the 103 rejection would therefore not defeat its intended purpose (i.e., forming hair follicle primordia).
Regarding the argument that culture on the substrate of Eddington et al. would be incompatible for removing the cell aggregates of Fukuda et al. for transplantation, the instant method claims are directed only to the formation of a hair follicle primordium, and the rejection focuses on combined teachings which make render such formation obvious. This line of argument is therefore spurious.
The rejection is maintained in modified form to address amended claims.
Maintained Rejections
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.
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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Fukuda et al. (US 20190062687 A1), of record in IDS dated 8/21/2023, in view of Eddington et al. (US 20170261496 A1).
Regarding claims 1, 4, and 6-7: Fukuda et al. teach a method for generating hair follicle primordium (See Abstract). Microwells were inoculated with a suspension of epithelial cells (which read on “ectoderm-derived cell”) and mesenchymal cells in a 1:1 mixture of hair papilla growth medium and keratinocyte growth medium (which reads on “a medium in which a mesenchymal cell and an epithelial cell have proliferating properties”) (See ¶0069, 0140, and 0204). The cells were cultured to form spheroids that formed hair follicle primordia (See ¶0011, 0049, and 0069-0071). In one embodiment, 10000 cells/well were used (which reads on “a total number of cells of the mesenchymal cell and the ectoderm-derived cell is 100 to 100,000 cells per unit area”) (See ¶0140). Fukuda et al. do not teach culturing the spheroids on a substrate having proliferative and non-proliferative regions.
Eddington et al. teach micropatterning of biomolecules onto a substrate such as a well plate for three-dimensional cell culture (See Abstract). Biomolecules such as Matrigel, fibronectin, laminin, and collagen can be physiosorbed onto a substate (which reads on “region having a cell proliferation property”) (See ¶0006). Gas plasma treatment (which reads on “plasma treatment”) can be used to ablate (which reads on “decomposing or modifying”) regions of the coated substrate not protected by a mask in order to create patterns (which reads on “a region adjacent… having no cell proliferation properties”) (See ¶0006, 0054, and 0063). The patterns can comprise 20 µm squares or 100 µm or 500 µm islands (which read on “island-shaped region with an area of 0.001 to 5 mm2”, “a circular region having a cell proliferation property and an area of 0.001 to 1 mm2” and “the region … has an area of 0.001 to 0.5 mm2”) (See ¶0057 and 0059). Cell culture plates made by this approach can be provided as part of a kit (See ¶0124-0125).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Fukuda et al. to comprise the patterned well plates taught by Eddington et al. One would have been motivated to make this modification Fukuda et al. teach that the diameter of the microwells should be large enough for accommodating and culturing the mixed spheroids and may be approximately the same diameter as a mammalian pore, for example, between 20 µm and 1 mm (See ¶0064), which suggests that limiting the size of the spheroid via culture surface area would be beneficial for trans. Inoculation of the cell suspension into a patterned microwell would read on “randomly adhering”. There would be a reasonable expectation of success in doing so because Eddington et al. teach that any type of cells, such as epithelium cells and stem cell-derived cells, can be adsorbed onto the surface, that more than one type of cell can be used, and that cell aggregates can be adsorbed onto the surface (See ¶0056, 0058, 0088, and 0110).
Regarding claim 2: Following the discussion of claims 1, 4, and 6-7, Fukuda et al. teach an embodiment wherein the ratio of mesenchymal cells to epithelial cells is 1:1 (which reads on “1:10 to 10:1”) (See table 1 and fig. 6).
Regarding claim 3: Following the discussion of claims 1, 4, and 6-7), Fukuda et al. teach that the cell suspension forms polarized spheroids, with alkaline phosphatase-stained mesenchyme cells at one end and epithelial cells at the other (which reads on “the cell mass comprises a portion having a larger content of the mesenchymal cell than the ectoderm-derived cell and a portion having a larger content of the ectoderm-derived cell than the mesenchymal cell”) (See ¶0028, 0159, and 0166 and fig. 6C). At lower total numbers of cells added, the polarized ends appear to have similar areas (which reads on “a ratio between the largest cross-sectional area of a portion having a larger content of the mesenchymal cell than the ectoderm-derived cell in the substrate in-plane direction and the largest cross-sectional area of a portion having a larger content of the ectoderm-derived cell than the mesenchymal cell in the substrate in-plane direction is 2:1 to 1:20”) (See fig. 6C).
Regarding claim 5: Following the discussion of claims 1, 4, and 6-7, Fukuda et al. teach that the transplanted spheroids form follicular structures that can be labeled with antibodies targeting versican (which reads on “Versican is present in the organ primordium”) (See ¶0034, 0173, and 0182 and fig. 9).
Conclusion
THIS ACTION IS MADE FINAL. 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 JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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