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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 27 October 2025.
ELECTION
Applicants’ election with traverse of Group I (Claims 1-2, 4-6, 9 , 12-16 and 20-21; drawn to a method of constructing a skin organoid) in the reply filed on 27 October 2025 is acknowledged. The Applicant argues the Examples in the specification produce an organoid that has an epithelium, on the outer side and a dermal/subcutaneous layer on the inner side and does not include cartilage. In response: the limitations argued by the Applicant are not claim limitations. The arguments do not address the technical feature cited in the Restriction Requirement mailed on 27 August 2025. The requirement is still deemed proper and is therefore made FINAL. Claims 22-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
CLAIMS UNDER EXAMINATION
Claims 1-2, 4-6, 9 , 12-16 and 20-21 have been examined on their merits.
PRIORITY
The Applicant claims priority to KR10-2020-0136977 (filed 21 October 2020) and KR10-2021-0140422 (filed 20 October 2021). Certified translations have not been provided.
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 1-2, 4-6, 9 , 12-16 and 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.
Regarding claim 1” steps (b) and (c) recite culturing and cutting “a culture product”. It is unclear if “a culture product” is referring to the cultured organoid in step (a). The metes and bounds of the claim are unclear. Appropriate correction is required. All dependent claims are included in this rejection.
Claim 2 recites Wnt agonist is added on days 5 to 7 of “culturing pluripotent stem cells”. The base claim recites culturing an organoid derived from pluripotent stem cells with a Wnt agonist. It is unclear if claim 2 is referring to the derived organoid. The metes and bounds of the claim are unclear. Appropriate correction is required.
Claim 4 recites GlutaMaxTM. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a medium component and, accordingly, the identification/description is indefinite. Appropriate correction is required.
Claim 14 recites “such that the dermal layer and the epidermal layer on a collagen-coated transwell, culture insert are exposed to the collagen side and air”. There is a lack of antecedent basis for a dermal layer, epidermal layer on a collagen-coated transwell culture insert in claim 1. The metes and bounds of the claim are unclear. Appropriate correction is required.
Claim 16 recites KRT10, KRT15 and KRT17. It is unclear what these are abbreviations for. If the Applicant means Keratin 10, Keratin 15 and Keratin 17, the claim should be rewritten to recite Keratin 10 (KRT10), Keratin 15 (KRT15) and Keratin 17 (KRT17). Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 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.
Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nakatsuji et al. (Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression. J Invest Dermatol. 2016 Jul 2;136(11):2192–2200).
To understand how Staphylococcus aureus may enter the dermis, Nakatsuji compared the capacity of live and dead S. aureus to penetrate the epidermis of an organotypic human skin equivalent (page 3, section titled “S. aureus penetrates cultured human skin equivalents”. Bacteria is applied on the epidermis of cultured human skin equivalents (page 4, last paragraph).
Regarding independent claim 21: The claim recites a skin organoid constructed by the method of claim 1. This is a product by process limitation (See MPEP 2113 I). The PG Pub of the specification defines an “organoid” as a three-dimensional collection of one or more cell types that mimic(s) the superficial appearance or actual structure or function of a tissue or organ. Nakatsuji teaches an organotypic human skin equivalent (page 3, third paragraph). The skin is biopsied human skin (page 7, last paragraph). The skin contains multiple layers, including the stratum corneum and epidermis (page 7, second paragraph). The claimed organoid is indistinguishable from the human skin equivalent taught by Nakatsuji et al. See MPEP 2113 and II. Therefore the method recited in claim 21 is anticipated.
Applicant’s Invention is anticipated as claimed.
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 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.
Claims 1-2, 4-6, 9, 12-16 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Koehler et al. (Derivation of Human Skin Organoids From Pluripotent Stem Cells. US20180305671 25 October 2018) in view of Hannen et al. (Skin Culturing Apparatus And Method. US20210380912 with benefit of PCT/GB2019/052952 filed 16 October 2019) as evidenced by Sun et al. (Lowered Humidity Produces Human Epidermal Equivalents with Enhanced Barrier Properties. Tissue Engineering Part C: Methods Volume 21, Number 1, 2015).
Koehler et al. teach methods for directing differentiation of human pluripotent stem cells into human skin organoids comprising hair shafts ([0003] [0032]). Therefore the art teaches a pluripotent stem cell derived organoid. Koehler teaches skin organoids pre-treated with CHIR 99021, a Wnt signaling agonist, during days 8-12 produce pigmented hair follicles ([0019]). Therefore the art teaches culturing an organoid in the presence of a Wnt agonist.
It is noted Koehler teaches skin organoids containing basal keratinocytes and dermal fibroblasts are produced by day 30 of the differentiation process ([0034]). The art teaches after about 75 days to about 120 days, the skin produces hair follicles ([0034]). Examiner notes the difference between 30 days and 75 days reads on “40 days or more”. Figure 1 discloses an “organoid medium”. Koehler teaches an organoid maturation medium ([0084]). Therefore the art is interpreted to teach culturing a culture product in a medium for skin organoid maturation for 40 days or more.
It is noted Koehler teaches dissociating an organoid and culturing in an air-liquid interface culture ([0095]). This method produces full thickness skin with different layers. The deficiency of the art is that the art does not teach cutting the organoid and cultured at an air-liquid interface.
Hannen teaches a method of culturing mammalian skin or a mammalian skin substitute (Abstract). Hannen obtains human skin specimens ([0083]). Skin is cut into 2 cm2 pieces ([0085]).The specimens are cultured in an a skin culturing apparatus configured for biphasic culturing of ex vivo mammalian skin ([0084]; see Figure 1F). The basal side dermal side of the skin is fully immersed in culture media and the apical side of the epidermis is exposed to sterile atmospheric air (18-23° C., 0.03-0.05% CO2, 30-50% RH (relative humidity). This is interpreted to be an air-liquid interface. Hannen teaches biphasic culturing allows for physiologically relevant gradients of temperature, CO2 and relative humidity to be produced across the skin or skin substitute.
It would have been obvious to combine the teachings of Koehler and Hannen by cutting a skin organoid and culture it at an air-liquid interface. Koehler teaches a method of making a skin substitute Hannen teaches cutting a skin substitute and culturing it at an air-liquid interface. One would have been motivated to do so to allow for physiologically relevant gradients of temperature, CO2 and relative humidity to be produced across the skin substitute for maturation, as taught by Hannen. One would have had a reasonable expectation of success since Hannen teaches skin, or skin substitutes, can be cultured at an air-liquid interface. Therefore claim 1 is rendered obvious.
Koehler treats skin organoids with CHIR 99021 (supra). Therefore claim 2 is included in this rejection.
Koehler teaches an organoid maturation medium comprising glutamax, N2 and normocin ([0084]). Therefore claim 4 is included in this rejection.
Regarding claim 5: Koehler teaches culturing human pluripotent stem cell into spheroid aggregates (hence, embryoid bodies) in a culture medium comprising Bone Morphogenetic Protein 4 (BMP4) and an inhibitor of Transforming Growth Factor Beta (TGFβ) signaling for about eight to about ten days, whereby non-neural epithelium (also known as surface ectoderm) forms within the aggregates ([0006] [0033]). The surface ectoderm epithelium gives rise to both surface epithelial cells and cranial neural crest-like cells (CNCCs) ([0010]). Therefore claim 5 is rendered obvious.
Koehler teaches BMP4 and SB-431542 are added at day 3 to promote non-neural induction in the epithelium and induce a layer of mesodermal cells within the core of each aggregate. On day 4-5 the aggregates were treated with FGF-2 ([0073]), Therefore claim 6 is rendered obvious.
Koehler teaches skin organoids containing basal keratinocytes and dermal fibroblasts are produced by day 30 of the differentiation process ([0034]). The art teaches after about 75 days to about 120 days, the skin produces hair follicles ([0034]). Examiner notes the difference between 30 days and 75 days is 45 days. Therefore claim 9 is included in this rejection.
Regarding the gas phase, Hannen teaches optimum skin culture conditions have been determined in experimental analysis as 30-50% ([0033] [0061]). As evidenced by Sun, an incubator with 50% relative humidity is “dry” (page 17, right column, first paragraph of “Results” section). Hannen teaches culturing for 5 days ([0043]). Therefore claim 12 is rendered obvious. Because the art teaches the conditions recited in claim 12, it is for stratum corneum maturation. Therefore claim 13 is included in this rejection.
Hannen teaches the skin sample or equivalent is embedded or surrounded in a gel and is inside a transwell. The gel can be collagen ([0067]). The stratum corneum layer is exposed to the gaseous environment, but not to the tissue culture medium; and/or the stratum basal layer and/or the dermis or dermal equivalent is exposed to the tissue culture medium, but not to the gaseous environment ([0067]). Hannen teaches cutting into 2 cm2 pieces (uniform sizes). Hannen teaches assays are performed ([0085]). Hannen does not explicitly teach cutting into four.
It would have been obvious to cut the skin prepared by Koehler into four. One would do so to prepare uniform pieces to perform assays, as taught by Hannen. One would have had a reasonable expectation of success since Hannen teaches skin or skin equivalent can be cut and used in assays. One would have expected similar results since both references are directed to mammalian skin . Therefore claim 14 is rendered obvious as claimed.
Koehler teaches air-liquid interface culture is performed in the presence of “organoid medium” ([0095]). The art teaches generating full-thickness skin with different layers ([0095]). Therefore the medium is interpreted to be a medium for skin organoid maturation. Claim 15 is included in this rejection.
Koehler teaches the skin organoid comprises an epidermal and dermal layer ([0006]). The epidermal layer can comprise P63+KRT5+ epidermal keratinocytes ([0006]). Therefore the skin organoid expresses KRT5. Claim 16 is included in this rejection.
Koehler teaches suitable pluripotent cells for use include human embryonic stem cells (hESCs) and human induced pluripotent stem (iPS) cells ([0044]). Therefore claim 20 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653