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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed May 20, 2025.
Claims 1, 10, and 22 are independent. No new claims are added, canceled or amended.
Therefore, claims 1-7, 9-16, and 18-25 are pending in the application and examined on the merits
Priority
Applicant’s claim for the benefit of a prior-filed parent provisional application 62/444,468 filed 01/10/2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is January 10, 2017.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 1-7, 10-16, and 18-25 remain rejected under 35 U.S.C. 103 as being unpatentable over Jabbari (U.S. Patent No 9,314,549) in view of Deng et al. (2016. Journal of Orthopedic Research 34(3): 386-94; previously cited), Lin et al. (2014. PNAS 111(28): 10137–10142; previously cited), Vunjak-Novakovic et al. (US 2016/0199450), and Li (2014. Sci. Rep. 4, 5600, pg. 1-7). The rejection has been modified as necessitated by amendment of the claims in the responses filed May 20, 2025.
Regarding claims 1, 6-7, 10, 11, 14, and 18-25, Jabbari teaches a biomimetic scaffold comprising an electrospun porous synthetic substrate (Col. 1, lines 38-50). Jabbari aims for said biomimetic scaffolds to be utilized to develop bone graft materials that can exhibit strength and osteoconductivity similar to the native bone and that exhibit uniform distribution of nutrients in the scaffolds (Abstract).
Jabbari does not teach seeding and culturing mesenchymal stem cells which are devitalized via lyophilization.
Deng et al. teaches a method of culturing and devitalizing mesenchymal stem cells via freeze drying (i.e. lyophilization) on tissue engineered constructs for tissue engineering purposes such as repairing bone defects (Abstract, p. 387). Deng et al. further discloses that the freeze drying is important to immobilize cytokines which are critical for host cell recruitment and tissue regeneration created from culturing the stem cells on the scaffold and make the constructs suitable for long term storage and transportation (p. 392).
It would be obvious to one of ordinary skill in the art to modify Jabbari’s biomimetic scaffold by seeding the mesenchymal stem cells of Deng et al. on the scaffold and devitalizing them with a reasonable expectation of success. An artisan would be motivated to utilize mesenchymal stem cells which are devitalized via freeze drying as the freeze drying is important to immobilize cytokines which are critical for host cell recruitment and tissue regeneration created from culturing the stem cells on the scaffold and make the constructs suitable for long term storage and transportation (Deng et al; p. 392).
Jabbari in combination with Deng et al. does not teach seeding devitalized endothelial colony forming cells (ECFCs) on the scaffold in addition to the devitalized MSCs of Deng et al.
Lin et al. teaches that ECFCs provide trophic support to MSCs before the onset of neovascularization (p. 10137). MSCs retrieved at day 7 from implants coseeded with ECFCs maintained significantly more CFU-F activity (42 ± 3 colonies) than those from implants without ECFCs (p. 10138). ECFC-lined microvessels has been shown to be similar to that of normal microvessels in several respects, including nonthrombogenicity, blood flow, regulation of macromolecule permeability, and capacity to induce leukocyte-endothelial interactions in response to cytokine activation (p. 10138). Moreover, Lin states “transplanted MSCs displayed fate-restricted potential in vivo, with adipose tissue-derived and bone marrow-derived MSCs contributing exclusive differentiation along adipogenic and osteogenic lineages, respectively.” (abstract).
It would be obvious to one of ordinary skill in the art to incorporate ECFCs described by Lin et al. into the biomimetic scaffold comprising devitalized MSCs as taught by Jabbari and Deng et al. and then devitalize the cells as taught by Deng et al. with a reasonable expectation of success. One would be motivated to have both mesenchymal stem cells and endothelial colony forming cells on the same scaffold as cotransplanting ECFCs has been shown to significantly enhance MSC engraftment by reducing early apoptosis and preserving stemness-related properties via a trophic support that proceeds neovascularization. Thus, they serve as paracrine mediators which greatly improves engraftment (Lin et al.; Abstract, p. 10137-10138) and facilitate transplanted MSC engraftment, wherein bone marrow-derived MSCs differentiated along osteogenic lineages (Lin abstract) . An artisan would be motivated to devitalize ECFCs in the same way as MSCs in Deng et al. as Deng et al. teaches that devitalization enables constructs to be stored for a long period of time (p. 392). Additionally, claim 24 concerning devitalizing differentiated ECFCs would be obvious as it would additionally make these cells suitable for storage.
The combination of Jabbari et al., Deng et al., and Lin et al. do not teach the seeding of living macrophages onto the cell.
Vunjak-Novakovic et al. teaches a biocompatible scaffold which promotes M1 and M2 macrophage phenotypes (Abstract). Macrophages are seeded onto the scaffold and then stimulating polarization is administered to the macrophages on the scaffold in order to produce the M1 and M2 phenotypes (para. 0027-0028). Vunjak-Novakovic et al. discloses M1 macrophages recruit endothelial cells and initiate angiogenesis via secretion of VEGF and M2 macrophages secrete PDGF that recruit pericytes to stabilize the growing vasculature both of which increase vascularization or healing (Vunjak-Novakovic et al.; para. 0019, 0064, 0254). Furthermore Vunjak-Novakovic et al. teach that the biocompatible scaffold may further comprise mesenchymal cells, MSC-derived cells (i.e. differentiated mesenchymal stem cells), endothelial progenitor cells (i.e. endothelial colony forming cells), and various endothelial cells which may be derived from endothelial progenitor cells (para. 0010, 0162).
It would have been obvious to one of ordinary skill in the art to incorporate living macrophages as taught by Vunjak-Novakovic et al. and additional cells onto the scaffold once it was devitalized comprising undifferentiated ECFCs and undifferentiated MSCs thus making it suitable for storage An artisan would be motivated to seed living macrophages that show either the M1 or M2 phenotype because M1 macrophages recruit endothelial cells and initiate angiogenesis via secretion of VEGF and M2 macrophages secrete PDGF that recruit pericytes to stabilize the growing vasculature both of which increase vascularization or healing (Vunjak-Novakovic et al.; para. 0019, 0064, 0254). The seeding of additional living cells (i.e. mesenchymal cells, endothelial progenitor cells) as recited in the limitations of claim 18 would also be obvious to one of ordinary skill in the art due to known treatment methods involving biomimetic scaffolds (Vunjak-Novakovic et al.; para. 0157, 0173-186, Claims 18-19). Furthermore, one would want to seed living macrophages as sequential promotion of an M1 macrophage phenotype followed by promotion of an M2 macrophage phenotype can increase vascularization of a scaffold. For example, a controlled release composition for promoting M1 macrophage or M2 macrophage phenotypes can be introduced into or onto a scaffold. As another example, a controlled release composition (i.e. a devitalized cell with immobilized cytokines) for promoting an M1 or M2 macrophage phenotype can be introduced into or onto a scaffold (para. 0145). Therefore, it would be obvious to control the cytokines by immobilizing them by devitalization as in Deng et al. in order to promote the sequential controlled release to promote vascularization.
However, these references do not teach wherein the living cells such as macrophages or ECFCs in the above discussed method are autogenic.
Li teaches living autogenic cells seeded on a scaffold to create a living cell-scaffold (p. 5-6, bridging paragraph). Autogenic materials are still the sources of choice in current medical applications, because autologous materials are free of biocompatibility and immunocompatibility concerns (p. 1, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to seed living cells which are autogenic as taught by Li in place of the allogenic cells utilized in the combined references of Jabbari, Deng et al., Vunjak-Novakovic et al. and Lin et al. including autogenic macrophages to be seeded on the scaffold of the combined references with a reasonable expectation of success. An artisan would have been motivated to do so as Li teaches autogenic materials are still the sources of choice in current medical applications, because autologous materials are free of biocompatibility and immunocompatibility concerns (p. 1, 2nd paragraph).
Regarding Claims 2-4, Jabbari teaches a porous synthetic substrate (Col. 1, lines 38-50) made by electrospinning fibrous sheets and layering those sheets into multi-layered structures (Col. 11, lines 24-40).
Regarding Claim 5, Jabbari discloses calcium phosphate contents within the nanofibers of the synthetic substrate (Col. 10, lines 6-12).
Regarding Claims 12 and 13, Jabbari teaches seeding a biomimetic structure with stem cells (Col. 12, lines 63-67) and differentiating the stem cells (Col 2, lines 35-40).
Regarding Claim 15, Jabbari discloses methods for forming a bone tissue biomimetic structure that can include “wrapping the fibrous sheet around a mold” (Col 2, 59-64).
Regarding Claim 16, Jabbari discloses that “constructs can be utilized for bone regeneration. For instance, the constructs can be seeded with cells and utilized as a cellular scaffold for either in vivo or in vitro applications” thereby teaching that the scaffold materials can be configured for implantation in a living being (Col. 13, lines 1-9)
Therefore, the invention as a whole would be prima facie obvious to a person of ordinary skill in the art.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Jabbari (supra) in view of Deng et al. (supra), Lin et al. (supra), Vunjak-Novakovic et al. (supra), and Li (supra) as applied to claim 1 above, and in further view of OrthoReBirth’s ReBOSISS® (http://orthorebirth.com/orthorebirth/wp-content/uploads/2015/07/Composition_of_ReBOSSIS_Porous_Structure_of_ReBOSSIS.pdf; herein OrthoReBirth)
Regarding claim 9, as discussed in the above 103 rejection of claims 1, 10, 22, and incorporated here in its entirety, Jabbari et al., Deng et al., Lin et al. Vunjak-Novakovic et al., and Li provide teachings which illustrate a biomimetic scaffold with devitalized mesenchymal stem cells and endothelial colony forming cells and additionally living macrophages seeded onto a porous synthetic substrate made of electrospun fibers. These references do not teach scaffolds being used as bone filler or bone chips.
OrthoReBirth teaches its invention ReBOSISS® which is an electrospun bioresorbable bone void filler.
It would have been obvious to a person skilled in the art before the effective filling date of the claimed invention to use the synthetic scaffolds taught by Jabbari et al., Deng et al., Vunjak-Novakovic et al., Lin et al. and Li as the bone filler taught by OrthoReBirth. OrthoReBirth teaches that the interconnected structure provided by the electrospun material allows for the growth of capillary blood vessels throughout the network of interconnecting pores and the fiber overall promotes bone formation.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filling date of the claimed invention.
Response to Applicants’ Arguments as they apply to rejection of claims 1-7, 9-16, and 18-25 under 35 USC § 103 in relation to the teachings of Jabbari, Deng, Vunjak-Novakovic and Lin
Applicant’s arguments filed 09/15/2025 have been considered, however they are not persuasive.
First, Applicant argues that the rejection is based on hindsight bias and that there is no reason to combine to arrive at the claimed invention.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Second, Applicant argues each reference individually in order to highlight nonobviousness. Particularly, Applicant argues:
A skilled artisan would not be motivated to modify Jabbari in view of Li because Jabbari's goal is to develop alternatives to auto- and allografts and points to Jabbari, col. 2, lines 16-23
A skilled artisan would not have been motivated to modify autogenic materials taught in Li in place of the allogenic MSCs utilized in Deng because Deng's goal is to preserve hWJMSC-derived proteins on scaffolds by devitalization
Vunjak-Novakovic teaches that progenitor cells can be derived from the same or different species as an intended transplant recipient (para. [0161]). In other words, in Vunjak-Novakovic, progenitor cells are not derived from the same subject/person in which the cells are to be implanted,
Lin teaches that living ECFC or ECFC-conditioned media can prevent apoptosis of living MSC and ECFCs modulates MSC engraftment and regenerative capacity in vivo, which does not read on the biomimetic scaffold of the present invention.
The examiner disagrees. 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). Moreover, as detailed in the 103 rejection above there is motivation to combine.
Jabbari’s goal is to improve/develop alternatives to allo and auto bone grafts which are harvested with engineered grafts by “a method for developing composites that are more accurate bone tissue biomimetics” and the interest in these procedures “has rapidly been growing in an attempt to develop engineered bone grafts that can mimic the bone microstructure” (Jabbari, col. 2, lines 10-15 and 20-23). This does not teach away from the combination of references. Additionally, Jabbari does not need to provide a motivation to combine as it is the primary reference modified by Li. Therefore, Li contributes to the teachings of utilizing autologous materials to make a biomimetic scaffold.
A skilled artisan would have been motivated to modify autogenic materials taught in Li in place of the allogenic MSCs utilized in Deng, regardless of Deng’s goal, as Li teaches autogenic materials are still the sources of choice in current medical applications, because autologous materials are free of biocompatibility and immunocompatibility concerns (p. 1, 2nd paragraph). Furthermore, Li is not modifying solely Deng, the motivation is to have a wholly autologous material based scaffold. Deng is combined with Jabbari as the freeze drying of MSCs and other cells to devitalize is important to immobilize cytokines which are critical for host cell recruitment and tissue regeneration created from culturing the stem cells on the scaffold and make the constructs suitable for long term storage and transportation (Deng et al; p. 392).
While Vunjak-Novakovic teaches that progenitor cells can be derived from the same or different species as an intended transplant recipient (para. [0161]), this would also encompass autogenic or autologous materials as they would be the same species. Moreover, as discussed above, Li provides motivation for autologous materials.
While Lin teaches that living ECFC or ECFC-conditioned media can prevent apoptosis of living MSC and ECFCs modulates MSC engraftment and regenerative capacity in vivo, Lin is utilized to demonstate cotransplanting ECFCs has been shown to significantly enhance MSC engraftment by reducing early apoptosis and preserving stemness-related properties via a trophic support that proceeds neovascularization. Moreover, as the overall goal of the scaffold is to be transplanted in vivo, it does not teach away by discussing in vivo effects.
The examiner reminds Applicant that this combination of references and reasoning was upheld and affirmed by the PTAB decision set forth on 03/25/2025.
Claim objections
Claims 19 and 20 are objected to because they appear to be missing the phrase “further comprising” before the word “stimulating”. Appropriate correction is requested.
Regarding the claim objections previously set forth in the Office Action dated 06/16/2025,
Applicant has not addressed this objection in their arguments, nor amended the claims. Therefore, the objection is maintained.
Conclusion
No claims are allowed.
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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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634