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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/14/2026 has been entered.
Status of the Claims
Claims 13- 27 are currently pending.
Claim 13, 16, and 17 are amended.
Claims 20-23 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.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 13-19 and 24-27 have been considered on the merits.
New and Maintained Rejections
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 13-19 and 24-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. Based upon an analysis with respect to the claim as a whole, the claims do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
The claims are directed to:
Three-dimensional, multilayered engineered skin composition that encompasses natural skin.
The claim recites “engineered”, “in vitro”, and “synthetic support structure” ; however, there are no limitations in the claim that require the composition differ from skin in nature. Further, the claim recites that the skin contains a synthetic support structure which can be chosen from “a scaffold, mash, solid support, tube, porous structure, and a hydrogel”. These support structures are broad and include synthetic hydrogels which are not markedly different from naturally occurring products/hydrogels.
The claims are directed to a composition using only a nature-based product, i.e., multilayered skin, this nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. In this regard, the disclosed multilayered skin exists entirely in nature (e.g., same genotype and phenotype potential and structure).
In reference to the multilayered skin, the art teaches that multilayered skin “mimic the biochemical and morphologic properties of human skin, known as skin-equivalent (organotypic) cultures” (see abstract of Margulis et al, Methods Mol Biol., 2005; 289:61-70; Reference of Record). Further, Margulis, like the instant specification, teaches culture of keratinocytes and fibroblasts, which “enable the generation of human epidermal tissues that show in vivo-like tissue architecture and phenotype” (abstract, Margulis et al).
In reference to the synthetic support structure, the art, Kyburz et al (Ann Biomed Eng. 2015) teaches “water soluble polymers, such as poly(ethylene glycol) (PEG), poly(vinyl alcohol), poly(2 hydroxyethyl methacrylate), can be crosslinked to form elastic materials that recreate basic aspects of ECM mechanics of soft tissues” (pg. 3, para 2). Additionally, Kyburz teaches that “synthetic hydrogels have been engineered with properties that change with time, such as degrading through specific mechanisms (e.g., hydrolytic, enzymatic) and on specific time scales (Fig. 1c). These processes can better capture aspects of cells degrading and/or remodeling their local microenvironment in vivo, while simultaneously allowing a researcher to investigate how cells exchange and interpret information received from their niche” (pg. 3, para 3). Thus, Kyburz demonstrates that synthetic hydrogels can be manufactured to mimic the extracellular matrix and although they may have a slightly different structure, synthetic hydrogels do not exhibit markedly different characteristics than the naturally occurring extracellular matrix counterpart.
The claims thus encompass a multilayered skin that is identical (no difference in characteristics) to naturally occurring multilayered skin. Since there is no difference between the multilayered skin claimed and naturally occurring multilayered skin, the multilayered skin do not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, the claimed invention is directed to an exception. Because the claimed invention does not include any additional features that could add significantly more to the exception, the claimed culture does not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
PNG
media_image1.png
311
389
media_image1.png
Greyscale
Step 2A has recently been revised to include two prongs (Federal Register / Vol. 84, No. 4 / Monday, January 7, 2019):
PNG
media_image2.png
447
453
media_image2.png
Greyscale
An examination of Step 2A in the revised 101 guidance, with respect to the claimed invention, the answer is yes since the claimed invention comprises naturally occurring products (judicial exceptions), in the instant case these naturally occurring products are multilayered skin. When examining the claimed invention with regards to Step 2A prong 1, the answer is yes since the claimed invention encompasses naturally occurring products. When examining the claimed invention with regards to Step 2A prong 2, the answer is no since the claimed invention does not recite additional elements that integrate the judicial exception, in the instant case a multilayered skin, into a practical application.
It is only the recited limitations in the claims that are examined under 101 and not aspects such as what the multilayered skin is capable of treating or used for (i.e. multilayered skin for transplant). In this case only multilayered skin is examined with respect to its status as a judicial exception. It is again emphasized that the claimed invention is a composition and not a method.
An examination of Step 2B, the answer is no with respect to the claimed invention. There are no other additional elements recited in the claim that would amount to significantly more than the judicial exceptions. The multilayered skin as claimed encompasses a composition that is indistinguishable from those that exist in nature and there are no limitations that add any additional elements to the claimed multilayered skin. The multilayered skin has the same function as it does in nature and the fact that they may exist in an isolated system does not change the multilayered skin in a significant or meaningful way to amount to more than the judicial exception.
The only factors which can be examined under 101 in the claimed composition are those that are recited in the claim i.e. a multilayered skin. How the multilayered skin was obtained and the knowledge of using it is not considered with respect to a composition claim, it is only the judicial exceptions themselves that are analyzed under 101 and in this case all of the components in the claimed composition are naturally-occurring products and thus qualifies as a judicial exception.
Applicant argues (Remarks, 10/02/2025, pg. 5, last 4 para) that the 101 product of nature rejection should be withdrawn due to the inclusion of the “synthetic” support structure, which is not found in nature.
In response, this argument is not found persuasive due to the teachings of Kyburz, cited above, who demonstrates that certain synthetic hydrogels are not markedly different from the natural counterpart, even though they contain a slightly different structure. Therefore, the rejection has been reinstated.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 13-19 and 24-27 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wu et al (US20150104432A1).
With regards to claim 13, Wu teaches a three dimensional multilayered engineered human skin composition as required by claims 13 and 26 (abstract). Wu teaches that there is an epidermal layer comprising keratinocytes as required by claim 13 and 26 ([0019]), and further that all cell types used in the skin construct can be made from induced pluripotent stem cells as required by claim 13 and 26 ([0047]). Wu teaches that there is a layer of dermal fibroblasts as required by claim 13 and 26 ([0019]/fig. 1), and further that all cell types used in the skin construct can be made from induced pluripotent stem cells ([0047]). Wu teaches that the dermal and epidermal layer are in direct contact as required by claim 13 and 26 (figure 1 and [0019]). Wu teaches that the skin construct contains a functional hair follicle which is formed though dermal papilla cells as required by claim 13 ([0024]-[0028]). Wu teaches that a biodegradable or synthetic substrate can be used as a support scaffold, such as and not limited to collagen, gelatin, silicon, or PET, as required by claims 13, 16-18, and 26 ([0053]). Wu teaches that the engineered skin composition contains mesenchymal stem cells ([0047]), dermal sheath cells ([0024]), and follicular epidermal stem cells ([0013]/[0045]/[0024]) as required by claims 14 and 24-27. Wu teaches that the skin construct contains functional sebaceous glands and nerves as required by claim 15 ([0058]/[0061]). Wu teaches that the skin construct is capable of viable transplantation and engraftment to a human subject as required by claim 19 ([0058]-[0060]).
Therefore, Wu anticipates the claims.
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.
Claims 13, 26, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over unpatentable over Wu et al (US200100104432A1), in view of Hoeffler et al (US20010048917 A1), as evidenced by Perdigoto et al (Stem Cells and Regeneration, 2014).
Regarding claims 28-29, the limitations of the independent claims 13 and 26 are taught above.
Although Wu teaches the inclusion of epithelial cells in general ([0019]), Wu is silent to the inclusion of specifically Merkel epithelial cells which are ISL1+ in the engineered skin construct as required by claims 28-29.
However, Hoeffler teaches engineered skin equivalent and methods of forming an engineered skin equivalent (abstract). Hoeffler teaches that it may be desirable to add other cell types to the skin equivalents including Merkel cells ([0057]). Hoeffler teaches that the skin equivalents “reconstitute[s] full-thickness human skin by allowing a mixed cell population to “cell-sort” such that the inherent cell adhesive properties of keratinocytes and dermal fibroblasts are maintained” ([0008]).
Hoeffler meets the limitations of the Merkel cells being ISL1+ as evidenced by Perdigoto. Perdigoto teaches that “Isl1 expression in the epidermis is restricted to Merkel cells and is not present in the basal or suprabasal layers” (pg. 4692, col. 2, para 4). Thus, Perdigoto demonstrates that Merkel cells are ISL1+.
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the engineered skin composition containing epithelial cells taught by Wu with the engineered skin composition comprising Merkel epithelial cells taught by Hoeffler to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because both Wu and Hoeffler teach an engineered skin equivalent and Hoeffler teaches that the skin equivalents “reconstitute[s] full-thickness human skin by allowing a mixed cell population to “cell-sort” such that the inherent cell adhesive properties of keratinocytes and dermal fibroblasts are maintained” ([0008]). One of ordinary skill in the art would have a reasonable expectation of success when combining Wu with Hoeffler because both teach an engineered skin equivalent and methods of making the engineered skin equivalent.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 04/14/2026 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 6) that Wu does not teach an in vitro culture rather a mixed slurry of dermal and epidermal cells which are grafted into a mouse.
In response to this argument, Wu does teach an embodiment of the invention that requires a mixed slurry of the cells be grafted into a mouse. However, Wu teaches that the isolated cells can also be cultured, and that an example cell culturing method is provided in Fig. 4 ([0052]). Fig. 4 provides a method of culturing that does not require that the cells be grafted into a mouse, in comparison Fig. 3 provides the method of culturing including grafting the cells into a recipient (mouse).
Additionally, Applicant’s argument appears to hinge on the method of making a skin equivalent in an embodiment of the prior art, Wu, and not the engineered multilayer skin product made. The claim is drawn to a product of a three-dimensional multilayered human skin composition and not drawn to a methods of making the three-dimensional multilayered human skin composition.
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 7, para 2 spanning pg. 8) that Wu does not teach that the dermal papillae are pluripotent stem cell derived dermal papillae, rather “Wu suggests that multipotent dermal cells could be derived from an induced pluripotent stem cell (iPSC) source ([0047]), this is not demonstrated in Wu”. Additionally, Applicant argues that Wu does not provide guidance sufficient for a person of skill in the art to generate the claimed PSC-derived structures and that Gnedeva, published after Wu, shows low frequency of 1 out of 50 transplants being able to form hairs.
In response to this argument, Wu states that the “skin organ 110 generation method may use cell for the development of iPSC strains, and differentiate iPSCs into dermal papilla cells” ([0061]). Thus, Wu describes the claimed limitation. The MPEP states at 2152.02(b) that “While the conditions for patentability of AIA 35 U.S.C. 112(a) require a written description of the claimed invention that would have enabled a person skilled in the art to make as well as use the invention, the prior art provisions of AIA 35 U.S.C. 102(a)(1) and (a)(2) require only that the claimed invention is "described" in a prior art document (patent, published patent application, or printed publication).”
Wu states that the “skin organ 110 generation method may use cell for the development of iPSC strains, and differentiate iPSCs into dermal papilla cells” ([0061]). Thus, Wu describes the claimed limitation. The MPEP states at 2152.02(b) that “While the conditions for patentability of AIA 35 U.S.C. 112(a) require a written description of the claimed invention that would have enabled a person skilled in the art to make as well as use the invention, the prior art provisions of AIA 35 U.S.C. 102(a)(1) and (a)(2) require only that the claimed invention is "described" in a prior art document (patent, published patent application, or printed publication).”
Therefore, the argument is not found persuasive.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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 on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
Prosecution Insights