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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/04/2026 has been entered.
Claims 23-44 are pending in this application, Claims 32-44 are acknowledged as withdrawn, Claims 23-31 were examined on their merits.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 05/04/2026 is sufficient to overcome the rejection of claims 23-31 based upon Mashiko et al. (2018), as set forth in the prior action.
The Declarant cites the unexpected result that ASC proliferating in the claimed scaffold sponge remain undifferentiated, as opposed to the ASC of Mashiko, citing transcriptomic analysis of the claimed ASC for markers of endothelial differentiation as compared to markers in the ASC of Mashiko (Declaration, Pg. 8, Lines 14-27 and Pg. 9, Lines 1-10). This is found to be persuasive, however the Examiner notes that the evidence presented is not commensurate in scope with the claimed invention which does not require any transcriptomic analysis. The Declarant’s arguments with regard to the Paganelli and Gundersen (Declaration, Pg. 13, Lines 17-29 and Pgs. 14-18) are the same as those provided in the Arguments/Remarks by Applicant and are not found to be persuasive for the reasoning provided below in the Response to Arguments.
The rejection of Claims 23, 29, 30 and 31 under 35 U.S.C. § 103 as being
unpatentable over Mashiko et al. (2018) in view of Petry et al. (2018), Li et al. (2018) as
evidenced by Chan et al. (2017), all of record, has been withdrawn due to the Applicant’s Declaration and arguments with regard to the differentiation status of the ASC of Mashiko being found to be persuasive.
The rejection of Claims 23, 24, 25, 29, 30 and 31 under 35 U.S.C. § 103 as
being unpatentable over Mashiko et al. (2018) in view of Petry et al. (2018), Li et al.
(2017) and as evidenced by Chan et al. (2017), all of record, and further in view of Paganelli et al. (07/01/2019), cited in the IDS, has been withdrawn due to the Applicant’s Declaration and arguments with regard to the differentiation status of the ASC of Mashiko being found to be persuasive.
The rejection of Claims 23 and 26-31 under 35 U.S.C. § 103 as being unpatentable over Mashiko et al. (2018) in view of Petry et al. (2018), Li et al. (2017) and as evidenced by Chan et al. (2017), and further in view of Mir et al. (2018) and Gundersen et al. (US 2010/0292626 A1), all of record, has been withdrawn due to the Applicant’s Declaration and arguments with regard to the differentiation status of the ASC of Mashiko being found to be persuasive.
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 23-31 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 23 now recites the limitation “tissue-like”. It is unclear what the metes and bounds of the limitation are as what tissue characteristics are present or not in the structure are not defined. Claims 24-31 are rejected as being dependent upon rejected Claim 23 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.
Claims 23, 29, 30 and 31 are rejected under 35 U.S.C. § 103 as being unpatentable over Long et al. (2017), cited in the IDS, in view of Long et al. (2009) and Corning (2015).
Long et al. (2017) teaches a method wherein a porous gelatin is loaded with about 5.0 x 104 (or 50,000 cells) Adipose-derived stem (e.g. undifferentiated) cells (ADSC) and incubating for one month (Pg. 5, Lines 8-14), wherein the cells proliferate/expand and were evenly distributed at all levels (e.g., including within) of the material (sponge) forming aggregates and cell sheets (tissue-like structures) (Pg. 9, Lines 12-20 and Pg. 10, Fig. 6 and Pg. 11, Figs. 7-8);
and wherein the sponges were and implanted and showed good biocompatibility and can be used in tissue engineering and regenerative medicine (Pg. 1, Abstract).
Long et al. (2017) indicates that the ADSC have the potential to differentiate into other cells types (Pg. 14, Lines 29-41) but does not indicate that the ADSC in the gelatin sponge are differentiated or exposed to any stimulus which would induce the cells to differentiate.
Long et al. (2017) did not teach a method wherein ASC loaded gelatin sponge is placed onto a semipermeable membrane floating over an ASC culture medium and incubating to grow and expand the ASC, while remaining undifferentiated and removing the ASC containing sponge from the semipermeable membrane to obtain an ASC-containing sponge, as required by Claim 23;
wherein the gelatin sponge is loaded with about 100,000 to 50 million autologous or heterologous ADSC, as required by Claim 29;
wherein the semipermeable membrane is made of polytetrafluoroethylene, polycarbonate or polyethylene terephthalate, as required by Claim 30;
or wherein the floating ADSC sponge is incubated for about 5-20 days under ASC culture conditions, as required by Claim 31.
Long et al. (2009) teaches a method wherein 2 x 106 (or 2,000,000) ADSC (encompassed within the claimed range of about 100,000 to 50 million cells) are combined with a 3D fibrin scaffold/matrix which is applied to a semi-permeable membrane (transwell insert) suspended over an ASC culture medium and incubated for 8 and 14 days (encompassed within the claimed about 5-30 days),
before removal/harvest of the construct (Pg. 126, Columns 2-3, Paragraph “Fibrin-ASC Construct Formation”);
the reference hypothesized that ASC require both an air interface and specific growth factors for epithelial differentiation (Pg. 125, Column 2, Lines 39-41);
wherein ASC cultured with an air-liquid interface but not growth factor rarely expressed cytokeratin 8 and showed no E-cadherin (Pg. 128, Fig. 4C and Fig. 5C) and wherein epithelial cell phenotype differentiated ASC express both cytokeratin 8 and e-cadherin (Pg. 130, Column 1, Lines 20-22). This is indicative of ADSC cultured within a matrix/scaffold exposed to an air-liquid interface without external growth factors not being differentiated.
Corning (2015) teaches that transwell permeable inserts may be polycarbonate, polyethylene terephthalate or polytetrafluoroethylene (Pg. 7/C15, Lines 21-30).
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 undifferentiated, expanded ASC
comprising gelatin sponge of Long et al. (2017) by culturing the construct under the ALI conditions as taught by Long et al. (2009) because this would allow the cells in the undifferentiated cells in the construct to expand under culture conditions which can later my minimally altered to induce differentiation when required, such as by addition of medium containing growth factors.
Those of ordinary skill in the art would have been motivated to make this modification because this would allow preparation of an implant/graft under conditions wherein the cells remain undifferentiated until specifically required. There would have been a reasonable expectation of success in making this modification because both references are reasonably drawn to the same field of endeavor, that is, the 3D culture of ASC.
It would have been further obvious to those of ordinary skill in the art to use either autologous or heterologous ADSC as these are the only two possibilities for ADSC to be. See the MPEP citing KSR at 2143, I., E. Those of ordinary skill in the art would have been motivated to make this modification in order to prepare a construct with the desired cells therein. There would have been a reasonable expectation of success in making this modification because neither Long reference specifies whether the ADSC are autologous or heterologous and ADSC may be only one or the other.
It would have been further obvious to those of ordinary skill in the art before the
effective filing date of the claimed invention to modify the gelatin sponge expansion of
undifferentiated, ASC comprising gelatin sponge under ALI conditions of Long et al. (2017) and Long et al. (2009), which uses a transwell insert, to select a polycarbonate, polyethylene terephthalate or polytetrafluoroethylene insert as taught by Corning because Long et al. (2009) does not indicate what material is used to construct the transwell insert and Corning provides common material used to construct permeable transwell inserts.
Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a transwell insert suitable for the desired application. There would have been a reasonable expectation of success in making this modification because Long et al. (2009) does not indicate the material used in its’ transwell insert and Corning provides specific materials which can be used to construct a transwell insert.
Claims 23, 24, 25, 29, 30 and 31 are rejected under 35 U.S.C. § 103 as being unpatentable over Long et al. (2017), cited in the IDS, in view of Long et al. (2009) and Corning (2015), as applied to Claims 23, 29, 30 and 31 above, and further in view of Paganelli et al. (07/01/2019), cited in the IDS.
The teachings of Long et al. (2017), Long et al. (2009) and Corning were
discussed above.
None of the above cited references teach coating the cultured ASC comprising
sponge with keratinocytes in keratinocyte culture media to allow the formation of a
stratified epidermis over the surface of the covered ASC-containing sponge, as required
by Claims 24;
or covering the ASC-containing sponge with keratinocytes in keratinocyte culture
medium to form a keratinocyte-covered ASC-containing sponge within the said cell
culture insert;
incubating the keratinocyte-covered ASC-containing sponge under keratinocyte
culture conditions thereby defining air interface conditions over the keratinocyte layer
and allowing a stratified epidermis to grow on the surface of the ASC-containing sponge
under said air interface conditions; and
removing the keratinocyte-covered ASC-containing sponge from the cell culture
insert and obtaining an ASC-containing sponge covered with a stratified epidermis as a
tissue substitute material, as required by Claim 25.
Paganelli et al. teaches covering an ASC-derived matrix on a semipermeable membrane (polycarbonate membrane) floating on keratinocyte growth medium (ALI interface) with keratinocytes and incubating (Pg. 48, Column 1, Lines 33-40 and 51-56), wherein the obtained scaffolding is already colonized by MSCs (Pg. 55, Column 1, Line 31) is easily obtained from patients and is 100% biocompatible and represents a possible therapeutic tool since it appears to potentially grafted with keratinocyte layers, thus bypassing the classical two-step grafting procedure (Pg. 46, Column 2, Lines 8- 13).
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 culturing of an ASC loaded gelatin sponge on a semipermeable membrane floating (air-liquid interface/ALI conditions) over an ASC culture medium which are implantable and suggested for tissue engineering and regenerative medicine, as taught by Long et al. (2017), Long et al. (2009) and Corning with the overlaying of the ASC sponge with keratinocytes and culturing under ALI conditions as taught by Paganelli et al. because this would provide a suitable skin bioscaffold for transplant/grafting. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a biocompatible undifferentiated ASC comprising, keratinocyte coated bioscaffold which is easily obtainable from patients, comprises MSC (ASC are a type of MSC) and is suitable for implantation. There would have been a reasonable expectation of success in making these modifications because both references are reasonably drawn to the same field of endeavor, that is, the generation of implantable cell scaffolds.
With regard to the limitation of Claim 24, "to allow the formation of a stratified epidermis over the surface of the covered ASC-containing sponge";
and the limitations of Claim 25, "allowing a stratified epidermis to grow on the surface of the ASC-containing sponge under said air interface conditions" and "obtaining an ASC-containing sponge covered with a stratified epidermis as a tissue substitute material", these are no more than the expected results from covering the ASC-containing sponge of Long et al. (2017) with the keratinocytes of Paganelli and culturing under the conditions described by Paganelli above.
With regard to the limitation of Claim 25 of, "removing the keratinocyte-covered ASC-containing sponge from the hemi-permeable membrane", Long et al. (2017) teaches wherein the ASC cultured gelatin sponge scaffolds were removed and wherein sponge scaffolds alone were implanted into rats, which accelerated wound healing while Paganelli et al. teaches covering an ASC-derived matrix on a semipermeable membrane (polycarbonate membrane) floating on keratinocyte growth medium (ALI interface) with keratinocytes and incubating. Thus it would have been obvious to the ordinary artisan to remove the keratinocyte covered ASC-containing gelatin sponge from a non-biological/biocompatible semipermeable membrane (such as the polycarbonate membrane of Paganelli) prior to implantation or grafting. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a keratinocyte-covered ASC-containing sponge which would be suitable for implantation/grafting.
Claims 23, 26, 27, 28, 29, 30 and 31 are rejected under 35 U.S.C. § 103 as being unpatentable over Long et al. (2017), cited in the IDS, in view of Long et al. (2009) and Corning (2015), as applied to Claims 23, 29, 30 and 31 above, and further in view of Mir et al. (2018) and Gundersen et al. (US 2010/0292626 A1), both of record.
The teachings of Long et al. (2017), Long et al. (2009) and Corning were
discussed above.
None of the above cited references teach covering the ASC-containing sponge
with a silicone-polyurethane composite layer, as required by Claims 26-28.
Mir et al. teaches that polymer films are used in semi-permeable dressings
because of their impermeability to bacteria and liquid and permeability to moisture vapor
and air (Pg. 4, Column 2, Lines 22-26).
Gundersen et al. teaches a composite layer wound dressing comprising a skin-
contacting layer of silicone adhesive and a support layer in the form of a polyurethane
film (Pg. 4, Paragraph [0088] and Fig. 1).
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 gelatin sponge expansion of
undifferentiated, ASC under ALI conditions of Long et al. (2017), Long et al. (2009) and Corning by coating the ASC-containing sponge with a silicone-polyurethane composite layer as taught by Mir et al. and Gundersen et al. because this would provide a barrier which is impermeable to bacteria, while being permeable to air and moisture and is suitable for application to a wound, such as when the ASC-sponge is grafted/implanted into a surface wound. Those of ordinary skill in the art would have been motivated to make these modifications in order to obtain an ASC comprising bioscaffold which is sterile and capable of grafting into a surface wound in vivo.
There would have been a reasonable expectation of success in making these modifications because at least the Long (2017) reference is drawn to an implantable bioscaffold suggested for tissue engineering and regenerative medicine and Mir and Gundersen are drawn to coverings suitable for wound covering.
Response to Arguments
Applicant’s arguments filed 05/04/2026, see Pages 2-16 and Pg. 18, Lines 20-30, Pg. 19, with respect to claim(s) 1-9 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. The remaining arguments have been considered only insofar as they apply to the pending rejections herein.
The Applicant argues that Paganelli is drawn to an overgrown 2D culture in the presence of vitamin C allowing the differentiation of ADSC into cell producing a dermal matrix. Applicant asserts that the reference does not indicate if undifferentiated ADSC remain in the matrix and there would have been no motivation to modify the method of the other prior art with the method of Paganelli with a reasonable expectation of success (Remarks, Pg. 17, Lines 17-30 and Pg. 18, Lines 1-19).
In response to Applicant's arguments against the Paganelli 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). As stated above, Long et al. (2017) teaches collagen sponge (which is a 3D
structure) seeded/loaded with (therefore embedded within) undifferentiated, ADSC. Further, Paganelli was not cited for its’ teaching of an ASC derived matrix, but for the covering thereof with keratinocytes while floating on a semipermeable membrane in keratinocyte growth medium. Applicant has provided no evidence on the record that such a covering necessarily requires the presence of differentiated ADSC.
The Applicant argues that the instant invention degrades over a period of time in vivo and the ASC within remain undifferentiated prior to transplantation. Applicant notes that the differentiated ASC of Paganelli produce a matrix having a dermis-like structure which has a secretome profile similar to fibroblasts and notes the instant invention provides a higher level of regenerative and angiogenic factors not found in Paganelli due to the secretome of the undifferentiated ADSC in the scaffold sponge (Remarks, Pg. 20 and Pg. 21, Lines 1-21).
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., transplantation of the construct, the period of time to degrade in vivo, the secretome of the ADSC) are not recited in the rejected claim(s).
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The Applicant argues that Mir does not suggest a method for the preparation of a tissue substitute as claimed. Applicant further notes that Gundersen teaches an absorbent dressing not designed for cell culture and does not teach or suggest the claimed invention (Remarks, Pg. 21, Lines 27-30 and Pg. 22 and Pg. 23, Lines 1-7).
In response to Applicant's arguments against the Mir and Gundersen references 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). The Examiner maintains the cited prior art makes obvious the claimed invention for reasons of record set forth above and in the prior action, noting that Mir was cited only for its’ teaching that polymer films are used in semipermeable dressings because of their impermeability to bacteria and liquid and permeability to moisture vapor and air and Gundersen was cited only for its’ teaching of a composite layer wound dressing comprising a skin-contacting layer of silicone adhesive and a support layer in the form of a polyurethane film.
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 07/17/2026
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