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 .
Applicants’ arguments, filed 09/16/2025, have been fully considered. Rejections and/or objections not reiterated from previous office action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 – Maintained
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1) Claims 1-3 and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Garg et al. (WO 2018/183846, publication date 10/04/2018) and Zha et al. (Macromolecular Bioscience, 2021, 21(3):e2000361).
Regarding instant claims 1-3, Garg "relates to electrospun fibrous scaffolds of decellularized muscle tissue and methods of making fibers and fiber scaffolds by electrospinning" [abstract]. The decellularized-extracellular muscle matrix (D-ECM matrix) scaffold comprises an electrospun D-ECM matrix fiber and a polymer, such as polycaprolactone [0034-35]. In one example Garg discloses an electrospun scaffold of PCL:D-ECM (i.e., polycaprolactone:decellularized-extracellular muscle matrix) at a 50:50 ratio [0069]. Garg also discloses the scaffolds can be used for tissue engineering in wound healing [0040].
Garg does not disclose usnic acid.
Zha discloses a nanofiber scaffold for wound healing comprising usnic acid as an antibacterial and wound-healing agent [abstract]. The usnic acid is mixed into the spinning solution before the scaffold in electrospun [p. 11, right col, para. 2].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the usnic acid wound healing agent of Zha with the electrospun scaffolds of Garg with a reasonable expectation of success. One would have had an expectation of success because each prior art element would have merely performed the same function as it did separately. Additionally, this combination would have yielded predicable results because the prior art discloses usnic acid is a wound healing additive for nanofiber scaffolds. See MPEP 2143 I, Rational A.
With respect to the mass ratio of polycaprolactone (PCL) to decellularized extracellular matrix (dECM); in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the instant case the prior art (i.e., PCL:dECM of 50:50 or 2:2) overlaps with the instantly claimed range of 8:2 to 2:8 and a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have achieved a nanofiber scaffold, prepared by electrospinning and comprising polycaprolactone (PCL), decellularized extracellular matrix (dECM), and usnic acid, wherein the PCL and dECM are present within the claimed ratios.
Regarding instant claims 8-10, Garg discloses “[t]he D-ECM matrix scaffolds can be used as tissue engineering scaffolds for wound healing, skeletal, cardiac or smooth muscle repair following ischemia or traumatic injury, and drug delivery” [0040]. In other words, Garg discloses the scaffold can be used to dress wounds (tissue engineering scaffolds for wound healing). Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have achieved a wound dressing comprising the nanofiber scaffold taught by Garg and Zha because Garg desires it.
Response to arguments
In the second full paragraph on page 7 of their remarks, applicant asserts Garg does not provide any teaching or suggestion that a small molecule such as UA can be successfully incorporated into such hybrid scaffolds while maintaining scaffold integrity.
This argument is not persuasive. In response to applicant's arguments against the references 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 the present case, while Garg does not discloses usnic acid, Zha does teach usnic acid can be incorporated into a nanofiber mesh scaffold for wound healing, via electrospinning [abstract].
In the paragraph spanning pages 7 and 8 of their remarks, applicant asserts that one skilled in the art would not have had reasonable expectation that UA, which is known to be a hydrophobic lichen metabolite, could be compatibly incorporated into a PCL/dECM electrospun matrix.
This argument is not persuasive. Both Garg and Zha disclose electrospinning a nanofiber matrix for wound healing. Garg discloses “that the description of specific embodiments is not intended to limit the disclosure to cover all modifications, equivalents and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims” [0021]. Zha further discloses including an anti-bacterial and wound healing agent during the electrospinning process [abstract]. That is to say, Garg discloses the scaffolds may be modified within the spirit and scope of the invention (i.e., wound healing) and Zha discloses a wound healing agent, usnic acid, can be incorporated into a wound healing scaffold, and both Garg and Zha disclose electrospinning. Thus even though the scaffolds of Garg and Zha are not exactly the same, one still would have had a reasonable expectation of success in combining the usnic acid of Zha with the scaffold of Garg because both are electrospun scaffolds for the same purpose.
In paragraph 1 on page 8 of their remarks, applicant argues the invention provides unexpected release characteristics. Specifically applicant states “PCLU scaffolds (PCL+UA, without dECM) demonstrated poor release characteristics, with only 23% cumulative UA release even after 14 days (the pre-grant publication of the instant application at paragraph [0072]; F of Fig. 3). In sharp contrast, PEU scaffolds (PCL+dECM+UA) exhibited controlled, sustained release over 14 days with no burst release (the pre-grant publication of the instant application at paragraph [0072]; F of Fig. 3).”
This argument is not persuasive. The results are not compared to the PCL:D-ECM scaffold of Garg nor are the results compared to the Usnic-Acid-Functionalized Silk Fibroin Composite Scaffolds of Zha. As such, the results have not been compared to the closest prior art, and so this argument of unexpected results is not persuasive. MPEP 716.02(e).
On pages 8-9, applicant argues the allegedly unexpected antibacterial efficacy in PCL+dECM+UA scaffolds distinguishes the present invention over the cited art. Specifically, applicant asserts “UA-loaded PEU scaffolds formed large inhibition zones against Cutibacterium acnes (33.60 ± 1.9 mm) and Streptococcus mutans (25.47 ± 0.3 mm) (the pre-grant publication of the instant application at paragraph at [0073]). By contrast, PCL scaffolds without UA produced no inhibition zones, and PCLU scaffolds (PCL+UA without dECM) showed significantly inferior results” [p. 8-9].
This argument is not persuasive. Figure 4 (as originally filed) does not compare the allegedly unexpected results to the closest prior art (i.e., PCL:D-ECM scaffold or Usnic-Acid-Functionalized Silk Fibroin Composite Scaffolds). Additionally, paragraphs 73-75 of the PG-Pub US 2024/0189475 which applicant cites (i.e., [01111] to [00114] instant specification as originally filed) do not make such a comparison either. As such, it is unclear if the allegedly unexpected results are truly unexpected over the closest prior art, and this argument of unexpected results is not persuasive. MPEP 716.02(e).
Furthermore, this argument is not persuasive because the cited paragraph (i.e., [01111] to [00114] instant specification as originally filed) do not appear to indicate that the incorporation of usnic acid provides any unexpected results at all. In fact they appear to concern the effect of dECM content on the antibacterial activity: “Based on the above results [See Figure 4], it was concluded that the increased concentration of dECM showed a higher antibacterial effect against pathogens compared to the control group. The high antibacterial effect by high content of dECM suggests that the high content of dECM in nanofiber scaffolds results in high release properties accompanied by increased swelling, surface erosion and degradation. However, the antibacterial effect of PCLU clarifies the antibacterial effect of UA despite the minimal release and fiber degradation. Previous studies have shown that UA-loaded nanofibers, DA-encapsulated nanomaterials and hydrogels show antibacterial effects similar to those of the present disclosure” (Instant specification, p. 26, paragraph 114).
On page 9 of their remarks, applicant asserts the instant invention provides unexpected wound healing results and cites Figure 8.
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Figure 8 (A) and (B) are provided below:
This argument is not persuasive. Garg discloses PCL:D-ECM scaffolds at a 50:50 ratio, not 4:6 (applicant refers to PCL:D-ECM scaffolds as “PE” scaffolds). Accordingly, the results are not compared to the closest prior art. MPEP 716.02(e).
Additionally, the specification does not appear to actually indicate the PEU (i.e., PCL:D-ECM scaffold further comprising usnic acid) provides unexpected results when compared to the PCL:D-ECM (PE) scaffold alone. Applicant indicates that usnic acid improves wound healing, but provides no support that this improvement is unexpected. For example, the instant specification discloses “[w]hen comparing UA-integrated nanofibers and non-integrated nanofibers, PEU 4:6 nanofibers showed faster wound closure, suggesting that UA increases wound healing as a marine-derived compound with excellent biological activity and antibacterial and wound healing properties” (p. 29-30, [00121). This appears to suggest that the results of adding usnic acid, which has wound healing properties, was not unexpected. Furthermore, the specification appears to indicate the differences between PE (PCL:D-ECM) and PEU (PCL:D-ECM further comprising usnic acid) are not statistically significant: “Compared to the control group (60.8% ± 10.0%, 19.8% ± 1.70%, and 9.9% ± 5.0%), the wound area of the PEU4:6-treated group at 7, 14, and 21 days was reduced by 20 42.1 % ± 13.8%, 7.2% ± 3.4%, and 1.3% ± 1.0%, and the wound area of the PE4:6-treated group was reduced by 51.3% ± 8.2%, 11.6% ± 1.4%, and 2.7% ± 2.0%” (p. 29, [00121]).
As such, applicant has not provided an explanation of why the results are unexpected and has not established that the results are in fact really unexpected and of statistical and practical significance. See MPEP See MPEP § 716.01 (c)(Il) and Ex parte Gelles, 22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992). See also MPEP § 716.02.
Finally, this argument is not persuasive because the claims are not commensurate in scope with the results. Unlike the allegedly unexpected results, the claims do not recite a ratio of PCL to dECM, and applicant has not provided a reason why the 4:6 ratio of Fig. 8 reasonably represents all possible ratios of PCL to dECM. MPEP 716.02(b) I-II.
2) Claims 4 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Garg et al. (WO 2018/183846, publication date 10/04/2018) and Zha et al. (Macromolecular Bioscience, 2021, 21(3):e2000361) as applied to claims 1-3 and 8-10 above, and further in view of Chen et al. (International Journal of Nanomedicine, 2019, 14, p. 2127-2144).
Garg and Zha, which are taught above, differ from the instant claims insofar as they do not teach a nanofiber scaffold that is crosslinked. Garg does, however, disclose the D-ECM is primarily collagen by describing it as a “complex three-dimensional network of connective tissue that is primarily composed of collagen" [0024].
Regarding instant claim 4, Chen discloses a synthetic/natural (polycaprolactone/collagen) nanofiber scaffold useful for tissue regeneration [p. 2127, Purpose and Materials]. Chen discloses that the structural and mechanical properties may be enhanced by crosslinking the scaffold [2142, left col.].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have crosslinked the nanofiber scaffold disclosed by Garg and Zha because Chen discloses it enhances the mechanical and structural properties of similar scaffolds. One would have had an expectation of success because in both cases the nanofiber scaffolds are intended for tissue regeneration and comprise polycaprolactone and collagen. Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have to have reach a nanofiber scaffold, as taught be Garg and Zha, wherein the scaffold was crosslinked.
Regarding instant claims 11, Garg discloses “[t]he D-ECM matrix scaffolds can be used as tissue engineering scaffolds for wound healing, skeletal, cardiac or smooth muscle repair following ischemia or traumatic injury, and drug delivery” [0040]. In other words, Garg discloses the scaffold can be used to dress wounds (tissue engineering scaffolds for wound healing). Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have achieved a wound dressing comprising the nanofiber scaffold taught by Garg, Zha and Chen because Garg teaches it.
Response to Arguments
Applicant asserts Chen fails to cure the noted deficiencies of Garg and Zha set forth above.
These arguments are not persuasive. The claims stand rejected for the same reasons above and of record.
3) Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Garg et al. (WO 2018/183846, publication date 10/04/2018) and Zha et al. (Macromolecular Bioscience, 2021, 21(3):e2000361) in view of Chen et al. (International Journal of Nanomedicine, 2019, 14, p. 2127-2144) as applied to claims 1-4 and 8-11 above, and further in view of Reddy et al. (WO2019217765A1, publication date 11/14/2019).
Garg, Zha and Chen, which are taught above, differ from the instant claims insofar as they do not teach freeze-drying the nanofiber mat.
Garg discloses a method of preparing a decellularized-extracellular muscle matrix (D-ECM matrix) scaffold comprising electrospinning the D-ECM matrix to prepare a D-ECM matrix scaffold [p. 15, claim 12]. The D-ECM matrix scaffold may further comprise a polymer, such as polycaprolactone [p. 15, claims 12 and 14]. Garg further discloses that polymer may be mixed with the solubilized D-ECM matrix (i.e., mixing polycaprolactone and decellularized extracellular matrix) [0036]. Garg also disclose one example of an electrospun scaffold comprising PCL:D-ECM (i.e., polycaprolactone:decellularized-extracellular muscle matrix) at a 50:50 ratio [0069].
Garg does not disclose mixing usnic acid with the polycaprolactone and D-ECM, crosslinking the scaffold or lyophilizing the scaffold.
Zha discloses the usnic acid is mixed into the spinning solution before the scaffold in electrospun [p. 11, right col, para. 2].
Zha does not disclose polycaprolactone or D-ECM, crosslinking the scaffold or lyophilizing the scaffold.
Chen discloses that the structural and mechanical properties may be enhanced by crosslinking the scaffold with EDC/NHS cross linking technologies [2142, left col.]. Specifically, the scaffold was crosslinked with EDC, NHS and ethanol [2129, left col., para. 2].
Chen does not disclose usnic acid or lyophilizing the scaffold.
Reddy discloses a soft tissue device useful for healing soft tissue which comprises a nanostructure [abstract], tissue [p. 97, claim 6]. The nanostructure of the soft tissue device comprises electrospun polycaprolactone nanofibers [p. 100, claims 25 and 26]. Reddy discloses that lyophilization (freeze-drying) prior to storage of the complex (i.e., soft tissue device) “allows for storage of the product at room temperature for extended periods of time without loss of function” [p. 29, line 17-20].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the methods of Garg, Zha, Chen and Reddy with a reasonable expectation of success because each method was disclosed for an electrospun nanofiber scaffold of wound healing. One would have been motivated to do so to obtain the advantages of each as discussed in the rejections of claims 1-4 (i.e., usnic acid wound healing of Zha and improved structural properties of Chen) and the improved storage stability disclosed by Reddy. One would have expected predictable results because in combing the prior art elements each element would have served the same function as it did separately. See MPEP 2143 I, Rational A.
With respect to the mass ratio of polycaprolactone (PCL) to decellularized extracellular matrix (dECM); in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the instant case the prior art (i.e., PCL:dECM of 50:50 or 2:2) overlaps with the instant claimed range of 8:2 to 2:8 and a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have prepared a nanofiber scaffold by mixing polycaprolactone, decellularized extracellular matrix and usnic acid, electrospinning the mixed components, cross-linking the resultant nanofiber mat with EDC/NHS dissolved in ethanol and finally freeze-drying the cross-linked nanofiber matt. Wherein the polycaprolactone and decellularized extracellular matrix would have been present within the claimed ratio.
Response to Arguments
In the last paragraph on page 9 of their remarks, applicant argues the Chen and Reddy do not provide any reasonable expectation that combining EDC/NHS crosslinking with freeze-drying would result in sustained release of UA and enhanced antibacterial efficacy.
This argument is not persuasive. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the present case Chen discloses crosslinking enhances the mechanical and structural properties of similar scaffolds and Reddy discloses freeze-drying improves storge stability (see rejection above).
On pages 10-11 of their remarks, applicant argues the specific sequence of method steps, including EDC/NHS crosslinking and freeze drying, are essential to achieve the observed stability and release characteristics. Applicant cites Fig. 3 and paragraphs 56-58 and 72 of the PGPub US 2024/0189475 which corresponds to Fig. 3 and paragraphs 75-81 and 110 of the instant specification as originally filed.
This argument is not persuasive. The examiner is unable to find mention of the method sequence or crosslinking affecting the release or stability characteristics in the cited paragraphs. Paragraphs 56-58 (i.e., 75-81 of the instant specification) appear to recite conditions for testing the antibacterial and antifungal activity as well as an anti-biofilm assay. Paragraph 72 (i.e., 110 of the instant specification) concerns the effect of dECM (D-ECM) on release kinetics and does not disclose crosslinking.
It appears applicant is interpreting the PCL scaffold comprising usnic acid and not comprising dECM (D-ECM) to represent an non-crosslinked scaffold. See, for example the first two lines on page 11 of their remarks “PCLU scaffolds (PCL+UA without dECM and without cross-linking) exhibited poor release”. Therefore, this argument is not persuasive because it is unclear if the release characteristics are due to the presence of dECM or crosslinking as applicant asserts. This is further evidenced on pages 24-25, paragraph 110, of the instant specification as originally filed: “As can be seen in (F) of FIG. 3, the PCLU scaffold was observed to have the lowest release property, reaching 23.0 ± 0.7% even on day 14, because the PCL had a dense crystalline structure and held the UA firmly. However, it was found that the PEU scaffold had a controlled release behavior due to the amount of dECM contained” (emphasis added).
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/C.T.W./ Examiner, Art Unit 1612
/WALTER E WEBB/ Primary Examiner, Art Unit 1612