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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/29/2026 has been entered.
Claims 1, 2, 5, 8, 10 and 11-14 are pending in this application, Claims 11-14 are acknowledged as withdrawn, Claims 1, 2, 5, 8 and 10 were examined on their merits.
The rejection of Claim(s) 1, 2, 5, 8 and 10 under 35 U.S.C. § 103 as being
unpatentable over Eisenberg (WO 91/16010) in view of Newton et al. (2016), cited in the IDS, Viswanathan et al. (2016) and Kaira et al. (2016), both of record, has been withdrawn, as necessitated by Applicant's amendments to the claims filed 06/29/2026.
Claim Interpretation
Claim 1 recites, “wherein the dermis layer comprising a concave-convex structure on the surface is manufactured in a shape-changing hydrogel mold prepared by at least one method selected from the group consisting of a shape-changing ductility technique, a three-dimensional lithography technique and a 3D printing technique”. Note the 35 USC § 112(b) rejections set forth below. In light of the Specification, it is the artificial skin which is produced in the mold not the “dermis layer” which is part of skin. Therefore, “the dermis layer comprising a concave-convex structure on the surface is manufactured” is interpreted as meaning “the concave-convex structure is manufactured in a shape-changing mold...”. Further, the language ''...prepared by at least one method selected from...” is construed as a product-by-process limitation; i.e., the statement is indicating how the mold is made. Therefore, this statement is not being interpreted as a positively-recited method step but instead as a Product-by-Process limitation consistent with the MPEP at 2113, I. and II. Notably, any of the three recited alternative processes, and any other unrecited methods for producing a mold, have the ability to produce the same, exact mold. In-turn, the same exact mold will produce the same exact concave-convex structure in the artificial skin. For this reason, the Product-by-Process limitations are too broad to have any material effect on the final mold which is used to make the concave-convex structure and thus too broad to have any material effect on the structure of the artificial skin.
For purposes of application of prior art, therefore the product has been evaluated to assess whether it is the same as or obvious from a product of the prior art. If so, the claim is unpatentable even though the prior product was made by a different process. That is, any shape changing hydrogel mold structure would meet the limitation even if produced by a different process. Further, the process steps have been evaluated for any impartation of distinctive structural characteristics to the final product.
Claim Objections
Claim 1 is objected to because of the following informalities: The word “mechanical” should be inserted between “and” and “properties” in Line 1. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: The words “of the artificial skin” should be inserted between “layer” and “comprising” in Line 16. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: The words “of the dermis layer” should be inserted between “surface” and “is” in Line 16. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: The words “of the dermis layer” should be inserted between “properties” and “are” in Line 34. Appropriate correction is required.
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, 5, 8 and 10 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 1 recites, “controlling mechanical properties”. It is unclear if the mechanical properties being controlled are that of the artificial skin or some other component. If it is the artificial skin, the claim should recite “controlling mechanical properties of the artificial skin”. Claim 1 recites, “is manufactured”. This is passive language indicating the manufacturing has already taken place. It is therefore unclear if the limitation is drawn to an active method step or not. Claim 1 recites, “wherein the shape-changing hydrogel mold changes shape depending on temperature to control a concave-convex structure of the dermis layer”.
The recitation appears to merely describe a property of the hydrogel mold as the claim does not require any application of any particular temperature. It is therefore unclear if the limitation is drawn to an active method step or not. Claim 1 recites, “wherein the dermis layer comprising a concave-convex structure on the surface is manufactured”, however the dermis layer already appears to be made in step 2 of the claim and does not require a hydrogel mold and it appear it is the artificial skin comprising the dermis layer which is what is made in the mold not the dermis layer. Claim 1 recites, “wherein the mechanical properties are controlled by adding methacrylic alginate to the ECM-derived substances”. This is passive language indicating the addition of methacrylic alginate has already taken place. It is therefore unclear if the limitation is drawn to an active method step or not. Claim 1 recites “wherein artificial skin to be manufactured”, however the limitations occur subsequent to the active process/manufacturing steps. It is unclear if therefore if the limitations are directed to a putative artificial skin or to the formed artificial skin of Claim 1, step 3. Claims 2, 5, 8 and 10 are rejected as being dependent upon rejected Claim 1 and for failing to rectify the indefiniteness thereof.
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, 2, 5, 8 and 10 are rejected under 35 U.S.C. § 103 as being
unpatentable over Eisenberg (WO 91/16010) in view of Newton et al. (2016), cited in the IDS, Viswanathan et al. (2016) and Kaira et al. (2016), both of record, and Shoseyov et al. (CA 3065481 A1).
Eisenberg teaches a method of preparing a composite living skin comprising a
porous, cross-linked collagen (an ECM derived substance) sponge (a dermis layer with
controlled mechanical properties [solid] formed by introduction of collagen, thereby
mimicking the structure of glycosaminoglycan to provide structural support for cells) (Pg.
17, step d);
inoculating the porous, cross-linked collagen sponge with fibroblasts and
then inoculating keratinocytes on to the collagen sponge (Pg. 17, steps d), e) and f);
and the composition when grafted in vivo has a well differentiated and multilayered epidermis (stratum corneum) (Pg. 9, Lines 29-34 and Fig. 2A and Pg. 14, Lines 18-26), reading on Claims 1 and 10.
With regard to Claim 1, Eisenberg teaches the composite living skin equivalent after in vitro culture revealed a multilayered epidermis growing on a homogeneous membrane. Histological examination of a biopsy sample of a skin equivalent of the present invention taken 2 weeks after grafting confirmed the formation of stratum corneum with a fully keratinized epidermis on a dermis populated by non-inflammatory connective tissue cells (refer Figure 2a). Significantly, there is an undulating and morphologically mature epidermal-dermal junction when viewed by light and electron- microscopy. (Pg. 9, Lines 22-34). Thus, the composite living skin equivalent of the prior art comprises dermal-epidermal junctions derived from epidermal cells.
With regard to Claim 1, Eisenberg teaches the composite living skin equivalent after in vitro culture has an interdigitation of rete ridges (valleys) and dermal papillae (peaks) that are characteristic of normal skin and are important if the interface between the epidermis and the dermis are to be normalized (Pg. 9, Lines 29-38 and Pg. 10, Lines 1-2). Thus, the composite living skin equivalent of the prior art comprises undulating rete ridge (concave-convex) structure, see for Example Fig. 3 of the disclosure as filed.
With regard to Claim 1, Eisenberg teaches the differentiation of the keratinocytes
by exposure at an air-liquid interphase (Pg. 10, Lines 5-11).
With regard to Claim 2, Eisenberg teaches the fibroblasts are human dermal
fibroblasts (Pg. 12, Lines 9-11 and 29-31) and a porous, cross-linked collagen (an ECM
derived substance) sponge (Pg. 17, step d).
With regard to Claim 8, Eisenberg teaches the skin equivalent is cultured initially
immersed (submerged) (Pg. 10, Lines 3-4).
Eisenberg does not teach a method wherein the dermis layer is manufactured in a shape-changing hydrogel mold prepared by at least one-method selected from the group consisting of a shape-changing ductility technique, a three-dimensional lithography technique and a 3D printing technique, wherein the shape-changing hydrogel changes shape depending on temperature to control a concave-convex structure of the dermis layer;
a method of making an artificial skin wherein the average difference in height between peaks and valleys of the concave-convex structure is 100 µm or more to 200 µm or less, in the case of artificial skin at the age of
20 or more to less than 40,
wherein the average difference in height between peaks and valleys of the
concave- convex structure is 50 µm or more to less than 100 µm, in the case of artificial
skin at the age of 40 or more to less than 60,
and wherein the average difference in height between peaks and valleys of the concave-convex structure is less than 50 µm, in the case of artificial skin at the age of 60 or more,
wherein the modulus of elasticity is 20 to 30 kPa, in the case of artificial skin at the age of 20 or more to less than 40, wherein the modulus of elasticity is 10 to 20 kPa, in the case of artificial skin at the age of 40 or more to less than 60, and wherein the modulus of elasticity is 10 kPa or less, in the case of artificial skin at the age of 60 or more,
and wherein the mechanical properties are controlled by adding methacrylic alginate to the ECM derived substance, as required by Claim 1.
Newton et al. teaches a method of characterizing age-related remodeling of the dermal-epidermal junction (Title) wherein the peaks and valleys of the concave-convex structure (rete ridges) in young (18-30 years, median 24 ± 3 years) and old (65 years and older, median 71 ± 4 years) (Pg. 133, Column 1, Lines 3-6) were measured and the average rete ridge height in the buttock of the young group was 61.7 ± 13.2 µm and 46.0 ± 15.3 µm in the buttock of the old group (Pg. 135, Column 1, Lines 6-13).
Viswanathan et al. teaches an artificial skin with a patterned substrate which mimics the topographical features of the epidermal-dermal interface (Pg. 21, Abstract) wherein substrates have a concave-convex structure wherein the distance between a valley to adjacent valleys is 250 µm or less (Pg. 25, Fig. 2),
wherein the concave-convex structure of the dermis layer is prepared by 3D photolithography coated with collagen (hydrogel) which conforms to the shape on which it is applied (Pg. 26, Fig. 3 and Pg. 23, Column 1, Lines 33-35).
Kaira et al. teaches that that the Young's modulus of skin (kPa) varies with age and gender (Pg. 2, Fig. 2).
Shoseyov et al. teaches hydrogels which may be made of collagen polymeric chains (Pg. 38, Lines 1-7);
wherein mechanical properties of hydrogels (reinforcing the hydrogel’s fibrous network) may be altered by macromolecular polymeric and/or fibrous elements, such macromolecules may be alginate methacrylate (Pg. 38, Lines 18-24).
While the references listed above do not specifically teach the limitation of Claim 1, that the average difference in height between peaks and valleys of the concave- convex structure is 100 µm or more to 200 µm or less, in the case of artificial skin at the age of 20 or more to less than 40, wherein the average difference in height between peaks and valleys of the concave-convex structure is 50 µm or more to less than 100 µm, in the case of artificial skin at the age of 40 or more to less than 60, and wherein the average difference in height between peaks and valleys of the concave-convex structure is less than 50 µm, in the case of artificial skin at the age of 60 or more, one of ordinary skill in the art would recognize that the height of the rete ridges (concave- convex structure with peaks and valleys) of the artificial skin would decrease with the intended age of the artificial skin and vice versa, and is therefore a result-effective optimizable variable. Newton et al. teaches there is a measurable difference in the natural rete ridge height between aged and young natural skin.
This is motivation for someone of ordinary skill in the art to practice or test the artificial skin rete ridge parameter values widely to find those that are functional or optimal to sufficiently mimic the age of the skin they are intended for (such as a graft) which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the differences in height of the rete ridges in artificial skin intended to mimic a certain age, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a more physiologically relevant age-matched artificial skin. There would have been a reasonable expectation of success in making these modifications because all of the references are reasonably drawn to the same field of endeavor, that is, the characteristics of skin.
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of preparing a composite living skin of Eisenberg and Newton to use the substrate of Viswanathan because this would provide an artificial skin which mimics the topographical features of the epidermal- dermal interface in vivo. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain an artificial skin which is as close to natural skin as possible.
There would have been a reasonable expectation of success in making this modification because at least both the Eisenberg and Viswanathan references are reasonably drawn to the same field of endeavor, that is artificial skin constructs.
While the references listed above do not specifically teach the limitation of Claim 1, that the modulus of elasticity is 20 to 30 kPa, in the case of artificial skin at the age of 20 or more to less than 40, wherein the modulus of elasticity is 10 to 20 kPa, in the case of artificial skin at the age of 40 or more to less than 60, and wherein the modulus of elasticity is 10 kPa or less, in the case of artificial skin at the age of 60 or more, one of ordinary skill in the art would recognize that the elastic modulus of the artificial skin would vary with the intended age of the artificial skin, and is therefore a result-effective optimizable variable.
Kaira et al. teaches there is a measurable difference in the natural elastic modulus between aged and young natural skin. This is motivation for someone of ordinary skill in the art to practice or test the artificial skin elastic modulus parameter values widely to find those that are functional or optimal to sufficiently mimic the age of the skin they are intended for, which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the differences in elastic modulus in artificial skin intended to mimic a certain age, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B).
Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a more physiologically relevant age-matched artificial skin. There would have been a reasonable expectation of success in making these modifications because all of the references are reasonably drawn to the same field of endeavor, that is, the characteristics of skin.
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of preparing a composite living skin comprising collagen hydrogel of Eisenberg, Newton and Viswanathan with the addition of alginate methacrylate, as taught by Shoseyov because this would alter the mechanical properties of the collagen hydrogel. Those of ordinary skill in the art would have been motivated to make this modification in order to reinforce the collagen hydrogel’s fibrous network, if a more durable hydrogel is desired. There would have been a reasonable expectation of success in making this modification because at least the Eisenberg, Viswanathan and Shoseyov references are reasonably drawn to the same field of endeavor, that is collagen hydrogels.
With regard to Claim 1, the limitation, “wherein the dermis layer is manufactured in a shape-changing hydrogel mold prepared by at least one-method selected from the group consisting of a shape-changing ductility technique, a three-dimensional lithography technique and a 3D printing technique, wherein the shape-changing hydrogel changes shape depending on temperature to control a concave-convex structure of the dermis layer”, as discussed above, for purposes of application of prior art, the product has been evaluated to assess whether it is the same as or obvious from a product of the prior art. In this instance, the claimed dermis layer comprising a concave-convex structure on the surface appears to be the same as, or obvious over the dermis layer comprising a concave-convex structure on the surface of Viswanathan et al. above. The claimed dermis layer does not appear to be structurally distinct from the dermis layer of the prior art, absent any evidence to the contrary, and therefore the limitation is made obvious.
Response to Arguments
Applicant's arguments filed 06/29/2026 have been fully considered but they are not persuasive.
The Applicant argues that the cited prior art does not teach or suggest the newly added limitations to Claim 1 (Remarks, Pg. 6, Lines 1-22).
This is not found to be persuasive for the reasoning provided in the above rejections.
The Applicant argues that Eisenberg performs a different series of method steps
than claimed (Remarks, Pg. 6, Lines 23-31 and Pg. 7).
In response to Applicant's arguments against the Eisenberg reference
individually, one cannot show non-obviousness by attacking references individually
where the rejections are based on combinations of references. See In re Keller, 642
F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231
USPQ 375 (Fed. Cir. 1986). In this instance the combination of references as set forth above in the new rejections, makes obvious the instant invention as now claimed.
The Applicant argues that Eisenberg does not describe a method in which a
dermal layer having controlled mechanical strength is formed on a shape-changing hydrogel mold having a specific concave-convex structure, thereby implementing the mechanical properties of skin characteristics specific to each age group (Remarks, Pg. 8, Lines 1-8 and Lines 30-34 and Pg. 9, Lines 13-25).
This is not found to be persuasive for the following reasons, as discussed above, the claimed dermis layer comprising a concave-convex structure on the surface appears to be the same as, or obvious over the dermis layer comprising a concave-convex structure on the surface of Viswanathan et al. above, even if prepared by a different method. The claimed dermis layer does not appear to be structurally distinct from the dermis layer of the prior art, absent any evidence to the contrary and therefore the limitation is made obvious. Shoseyov makes obvious the addition of alginate methacrylate to a collagen hydrogel to change its’ mechanical properties, such as if a more durable hydrogel is desired.
The Applicant argues that Newton and Kaira are research articles that merely characterize general skin characteristics observed in actual human skin but do not disclose how to implement those characteristics according to actual human age in artificial skin with a reasonable expectation of success (Remarks, Pg. 9, Lines 8-13).
In response to Applicant's arguments against the Newton and Kaira reference individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this instance, as set forth above, one of ordinary skill in the art would recognize that the height of the rete ridges (concave-convex structure with peaks and valleys) of an artificial skin (such as that of Eisenberg) would decrease with the intended age of the artificial skin and vice versa, and is therefore a result-effective optimizable variable. Newton teaches there is a measurable difference in the natural rete ridge height between aged and young natural skin. This is motivation for someone of ordinary skill in the art to practice or test the artificial skin rete ridge parameter values
widely to find those that are functional or optimal to sufficiently mimic the age of the skin
they are intended for (such as a graft) which then would be inclusive or cover the
instantly claimed values. One of ordinary skill in the art would also recognize that the
elastic modulus of the artificial skin would vary with the intended age of the artificial
skin, and is therefore a result-effective optimizable variable. Kaira teaches there is a measurable difference in the natural elastic modulus between aged and young natural skin. This is motivation for someone of ordinary skill in the art to practice or test the artificial skin elastic modulus parameter values widely to find those that are functional or optimal to sufficiently mimic the age of the skin they are intended for, which then would be inclusive or cover the instantly claimed values.
Further, Viswanathan teaches an artificial skin with a patterned substrate which mimics the topographical features of the epidermal-dermal interface (Pg. 21, Abstract) wherein substrates have a concave-convex structure wherein the distance between a valley to adjacent valleys is 250 µm or less (Pg. 25, Fig. 2), wherein the concave-convex structure of the dermis layer is prepared by 3D photolithography coated with collagen (hydrogel) which conforms to the shape on which it is applied (Pg. 26, Fig. 3 and Pg. 23, Column 1, Lines 33-35) while Newton teaches a method of characterizing age-related remodeling of the dermal-epidermal junction (Title) wherein the peaks and valleys of the concave-convex structure (rete ridges) in young (18-30 years, median 24 ± 3 years) and old (65 years and older, median 71 ± 4 years) (Pg. 133, Column 1, Lines 3-6) were measured and the average rete ridge height in the buttock of the young group was 61.7 ± 13.2 µm and 46.0 ± 15.3 µm in the buttock of the old group (Pg. 135, Column 1, Lines 6-13). Thus, it would have been obvious to those of ordinary skill in the art to modify the method of preparing an age-matched composite living skin of Eisenberg and Newton to use the substrate of Viswanathan because this would provide an artificial skin which mimics the topographical features of the epidermal-dermal interface in vivo.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653
08/03/3036
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