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Claims 1, 2, 5, 8, 10 and 11-14 are pending in this application, Claims 11-14 are acknowledged as withdrawn, Claims 1, 2, 5, 8 and 10 were examined on their merits.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 objection to the Drawings as failing to comply with 37 CFR 1.84(p)(5)
because they include reference character(s) not mentioned in the description has been withdrawn due to the Applicant’s amendments to the Specification filed 03/12/2026.
The objection to Claim 2 because of minor punctuation informalities has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claims 1-10 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inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the Applicant), regards as the invention, has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claim 2 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inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the Applicant), regards as the invention, has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claims 1, 2 and 10 under 35 U.S.C. § 102(a)(1) as being anticipated by Bell (US 4,485,096), of record, has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claims 1-3 and 8-10 under 35 U.S.C. § 102(a)(1) as being anticipated by Eisenberg (WO 91/16010), has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claim(s) 1-3, 4 and 8-10 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 (2016), cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claim(s) 1-3, 5 and 7-10 under 35 U.S.C. § 103 as being
unpatentable over Eisenberg (WO 91/16010) in view of Viswanathan et al. (2016), has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
The rejection of Claim(s) 1-3, 6 and 8-10 under 35 U.S.C. § 103 as being
unpatentable over Eisenberg (WO91/16010) in view of Kaira et al. (2016), has been withdrawn due to the Applicant’s amendments to the claims filed 03/12/2026.
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 newly rejected under 35 U.S.C. § 103 as being
unpatentable over Eisenberg (WO91/16010) in view of Newton et al. (2016), cited in the
IDS, Viswanathan et al. (2016) and Kaira et al. (2016), both of record, as necessitated by Applicant’s amendments to the claims filed 03/12/2026.
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 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.
There was 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 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, as now 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).
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.
Response to Arguments
Applicant’s arguments, see Remarks, filed 03/12/2026, with respect to the above withdrawn objections/rejections have been fully considered and are persuasive.
The remaining arguments have been considered only insofar as they apply to the new rejections set forth above.
The Applicant argues that Eisenberg performs a different series of method steps than claimed (Remarks, Pg. 13, Lines 3-24).
In response to Applicant's arguments against the Eisenberg reference individually, one cannot show nonobviousness 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 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.
Applicant argues that the claimed invention differs from Eisenberg in that the technology described in Eisenberg does not control the reticular ridge structure for specific age groups (Remarks, Pg. 14, Lines 4-8).
This is not found to be persuasive for the following reasons, as discussed above, 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.
The Applicant argues that Kaira is drawn to research that Young’s modulus varies with age and gender, but does not disclose any means of implementing the height of peaks and valleys of skin or how to implement the Young’s modulus according to the age of a real person into artificial skin (Remarks, Pg. 14, Lines 16-21 and Pg. 15, Lines 1-5).
In response to applicant's arguments against the Kaira reference individually, one cannot show nonobviousness 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 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. 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.
The Applicant argues that Newton merely examines general skin characteristics and does not disclose a means for implementing the height of the peaks and valleys of (artificial) skin according the age of a person while Viswanathan does not teach or suggest forming a dermal layer using a shape changing hydrogel mold that controls concave-convex structure to implement age-specific structural and mechanical characteristics, e.g. controlling peak-to-valley height and spacing to correspond with defined age groups or associated elasticity (Remarks, Pg. 15, Lines 8-19).
This is not found to be persuasive for the reasoning provided in the new rejections above, that is 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 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. As discussed above, 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). 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.
Conclusion
No claims are 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 PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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, 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.
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.
/PAUL C MARTIN/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653