DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/04/2025 has been entered.
Response to Amendment
Applicant’s response of 11/04/2025 has been received and entered into the application file. Claims 1, 5, 8, 11-15, 17-18, 20-21, 25-29, 31, 39, 40, and 54-57 are pending in this application.
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.
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.
Claims 1, 5, 8, 11-15, 17-18, 20, 21, 25-29, 31, 39, 40 and 54-57 are rejected under 35 U.S.C. 103 as being unpatentable over Liao et al (Graphene Nanomaterials. Molecular Sciences, 2018), Rostami et al. (Drug-eluting PCL/graphene oxide nanocomposite scaffolds for enhanced osteogenic differentiation of mesenchymal stem cells, Materials Science & Engineering C, 2020), Jiang et al. (Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages, Biomaterials, 2017), Ouyang et al. (Osteogenesis and Antibacterial Activity of Graphene Oxide and Dexamethasone Coatings on Porous Polyetheretherketone via Polydopamine-Assisted Chemistry, coatings, 2018), and Pacelli et al. (Fabrication of double-cross-linked IPN hydrogel surface modified with polydopamine to modulate the osteogenic differentiation of adipose-derived stem cells, Applied Materials and Interfaces, 2018).
Liao et al. teach graphene oxide has promising biomedical applications (Abstract). Carbon-based materials such as carbon or graphene possess great mechanical strength, electrical conductivity, high light transmittance. Such properties have resulted in widespread interest in the use of these materials for making drug deliveries, medical implants (page 2, 1st paragraph). Graphite is the 3D structure of graphene (page 2, 2nd paragraph). (graphites are useful for tissue engineering, drug delivery (See Figure 1). Graphene films were found to accelerate mesenchymal stem cells’ specific differentiation into bone cells (page 9, 1st paragraph).
Liao et al. do not teach graphite scaffold with dexamethasone.
Rostami et al. teach drug-eluting scaffolds that can enhance the cell differentiation through biomimicking the extracellular matrix. Polycaprolactone-based scaffolds containing synthesized graphene oxide nanosheets and drugs such as dexamethasone and simvastatin were fabricated (Abstract). Graphene oxide sheets with high surface-to-volume ratio can improve the surface and physical properties of nanofibers. Graphene oxide sheets are highly biocompatible due to the ability of surface functionalization by different groups, thus they can be used as suitable carriers for the loading and transfer of genes and drugs to regulate cellular behavior (page 2, left col, 2nd paragraph). Rostami et al. teach that graphene oxide-dexamethasone nanocomposite scaffolds had the most potential to increase both alkaline phosphatase activity, as a primary marker of osteogenic differentiation, and calcium deposition, as the final marker of differentiation into bone in mesenchymal stem cells (page 11).
Rostami et al. do not teach dexamethasone in the area of diabetes.
Jiang et al. teach pancreatic islets are susceptible to inflammatory stress following tissue engraftment. The localized delivery of dexamethasone can reduce inflammatory stress. Polydimethylsiloxane (PDMS)-based three-dimensional scaffold comprising dexamethasone was found to significantly accelerate islet engraftment in a diabetic mouse model (Abstract). Dex-PDMS scaffold provides a feasible platform to locally deliver immunomodulatory dexamethasone in a controlled manner and thereby foster a protective microenvironment for engrafted islets (page 80, Conclusion).
Ouyang et al. teach a versatile strategy with dopamine as an auxiliary for construction of dexamethasone/liposome porous coatings. The surfaces of sulfonated polyetheretherketone (SP) plates are coated with polydopamine firstly and then modified with graphene oxide (GO) and dexamethasone (Dex)-loaded liposome. The results suggest that the GO and Dex are successfully coated on the samples’ surfaces; the substrate coated with GO and Dex can significantly accelerate the proliferation and osteogenic differentiation of cells compared with the pristine sulfonated polyetheretherketone (PEEK). The results demonstrate that the modified GO- and Dex-loaded substrates are endowed with impressive biocompatibility and certain antibacterial qualities (Abstract). Graphene oxide comprises many oxygen functional groups, GO specimens are endowed with excellent hydrophilicity, which is beneficial for the cellular adhesive process and proliferation of cells. Furthermore, GO provides strong antibacterial activity (page 2, 2nd paragraph). Dopamine molecules are capable of commencing self-polymerization and create a polydopamine structure in weak alkaline conditions which can form rich catechol moieties. The groups on GO surface, such as phenol hydroxyl, epoxide groups, and carboxylic groups, bind with this catechol moieties and form strong linkages (page 5, Section 3.1.1).
Above references do not explicitly teach polydopamine and dexamethasone interactions.
Pacelli et al. teach treating scaffold’s surface, such as a hydrogel, with polydopamine to create an adhesive layer for the adsorption of the osteo-inductive drug dexamethasone. The presence of the pDA coating enhanced Dex adsorption and retention over 21 days (Abstract). Pacelli et al. also teach that polydopamine layer can be virtually adsorbed on any surface irrespective of their composition, size, and shape (pg 24955).
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Pacelli et al. teach biocompatibility of the pDA coating and dexamethasone adsorption and schematic indicating the main physical interactions between the pDA layer and dexamethasone (Figure 2).
Liao et al. teach that graphite is useful in tissue engineering and drug delivery. Rostami et al. teach that graphene with dexamethasone is particularly useful for mesenchymal stem cell differentiation. Jiang et al. teach that dexamethasone can significantly accelerate islet engraftment in a diabetic mouse model. Ouyang et al. teach many advantages of incorporating polydopamine nanolayers on the surface of the graphene matrix, wherein the nanolayer is functionalized with the dexamethasone. Pacelli et al. teach that polydopamine coating can be applied to bioscaffolds for adsorption of dexamethasone onto polydopamine coating.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have created three-dimensional graphene matrix comprising polydopamine layer with embedded dexamethasone for tissue engraftment or drug delivery as taught by above references. This is combining prior art elements according to known methods to yield predictable results such as a bio-scaffold comprising graphene matrix with dexamethasone coating.
Regarding claim 5, Rostami et al. teach that the SEM images showed the random alignment of the nanofibers and the presence of Graphene Oxide (GO) nanosheets (medium size: 2-5 micrometer, thickness: 1 nm) on the surface of PCL nanofibers with the average diameter of 166 +/- 46 nm. The scaffolds attained uniform distribution of porosity, which is essential for adhesion and penetration of mesenchymal stem cells, along with non-agglomerated and well dispersed GO nanosheets (page 6, Section 3.2). Furthermore, one of ordinary skill in the art would, through routine experimentation, experiment with various diameters of pores and thickness of the bioscaffold. Such experiments would help to yield scaffolds with uniform distribution of porosity which is essential for cell adhesion and penetration as discussed above.
Regarding claims 8 and 54, Jiang et al. teach that the macroporous scaffolds were loaded with dexamethasone from about 0.5% to 1% (Abstract). Jiang et al. also teach that decreasing the Dex loading to 0.5% resulted in reversal of diabetes in 3 out of 4 recipients (pg 74, right col, last paragraph).
Regarding claim 11, Rostami et al. teach a combination of drug-eluting PCL/graphene oxide with mesenchymal stem cells (Abstract).
Regarding claim 12, Rostami et al. teach that mesenchymal stem cells are well dispersed throughout GO nanosheets as discussed above in claim 5.
Regarding claims 13-15, mesenchymal stem cells are discussed above.
Regarding claims 17-18, Jiang et al. teach that donor pancreatic islets were isolated and loaded onto scaffolds. The syngeneic islets were collected in a syringe and pipetted on the top of the scaffold, where they distributed into the pores via gravity-driven fluid flow (page 72, Section 2.2).
Regarding claims 20-21, Jiang et al. teach the use of bioscaffolds comprising insulin-secreting cells as discussed above.
Regarding claims 25-26, Rostami et al. teach that the mesenchymal stem cells are utilized on drug-eluting scaffolds to differentiate into specific cells and tissues, the cell-scaffold interaction is a combination of messenger response, cell-cell and, cell-bioactive agents interactions (page 1, right column). One of ordinary skill in the art would be motivated to use mesenchymal stem cells as extracellular vesicles as taught by Rostami et al.
Regarding claims 27-28, Jiang et al. teach that the mice receiving 0.25% Dex-PDMS scaffolds exhibited stable normoglycemia in 13 of the 13 (100%) grafts, with an average reversal time significantly superior to control scaffold implants at 12 +/- 16 days post-transplant. Once normoglycemia was established, all recipients remained stable until elective graft removal. Prompt restoration to the diabetic state was observed following elective explantation of the islet-loaded EFP, verifying that the observed euglycemia was due to the transplanted islets (page 75, left col, 1st paragraph). Jiang et al. teach that bioscaffolds comprising dexamethasone resulted in decrease of blood sugar levels in recipients and the effect persisted for 12 +/- 16 days as discussed above.
Regarding claim 29, insulin-secreting cells are discussed above.
Regarding claim 31, Jiang et al. teach that the mouse epididymal fat pad (EFP) was used as the islet transplant site, as it is an appropriate murine surrogate to the clinically relevant omentum (page 74, Section 3.2). Furthermore, one of ordinary skill in the art would immediately envisage that in order to treat diabetes, one would certainly consider implantation sites such as kidney, liver, omentum, peritoneum, abdomen, and other tissues.
Regarding claim 39, Regarding claim 39, Liao et al. teach fabrication of graphene-based nanomaterials include chemical vapor deposition (pages 3-4). Ouyang et al. teach coating GO with polydopamine as discussed above. Furthermore, Pacelli et al. disclose that in order to create an osteo-inductive hydrogel coating, the hydrogel presenting a polydopamine layer was treated with Dex (dexamethasone), which is a model drug to induce osteogenic differentiation. Dex can interact with polydopamine by pi-pi interactions and establish hydrogen bonding with the oxidized layer of dopamine (pg 24960, left col, 2nd paragraph).
Regarding claim 40, Ouyang et al. disclose SEM images showing the morphologies of MC3T3 cells adhering to the bioscaffolds (See Figure 6).
Regarding claim 55, one of ordinary skill in the art would, through routine experimentation, experiment with various particle sizes of dexamethasone when interacting dexamethasone with polydopamine layer. And it would have been obvious to do so in this case.
Regarding claims 56-57, mesenchymal stem cells are discussed above.
Response to Arguments
Applicant’s arguments filed 11/04/2025 have been fully considered but they are not persuasive.
On page 7 of remarks, applicant argues that none of the references teach the criticality of 0.5 to 1 w/v% in the bioscaffold. Applicant states that concentrations of dexamethasone from 0.25 w/v% to 1 w/v% in the bioscaffold led to improved cell viability compared to the control group. The greatest islet functionality was seen with a concentration of 0.5 w/v% dexamethasone in the bioscaffold.
On page 7 of remarks, applicant states that Jiang does not teach or suggest using a concentration of about 0.5 to about 1 w/v% dexamethasone. However, Jiang does teach that dexamethasone dosage must be carefully tailored to prevent overloading at the implant site, as elevated glucocorticoids can severely impair cell mobility, resulting in compromised engraftment and vascularization. Furthermore, evaluation of kinetic release of dexamethasone from the 3-D scaffold permitted tailoring of drug loading to desired doses. Following optimization, the impact of this drug-release platform on the efficiency of islet engraftment and subsequent host cell responses were investigated (pg 72, left col, last paragraph). Jiang seems to emphasize the importance of dexamethasone-releasing kinetics as well as dexamethasone dosage.
Applicant argues that the claimed invention demonstrates a synergistic effect between the graphene scaffold and the dexamethasone. In particular, the claimed scaffold includes the dexamethasone microparticles immobilized and distributed substantially uniformly on a surface of the graphene matrix. The instant specification states “using SEM, Dex particles were found attached onto the surface of graphene bioscaffolds, and uniformly distributed, with increases in the concentration of Dex from 0.25 to 1 w/v% resulting in more Dex particles seen (FIG. 2A)” ([0125]). The examiner cannot determine the uniformity shown by FIG. 2A. Additionally, the specification does not disclose how this uniformity is achieved. Is it achieved with only a specific concentration of dexamethasone? Is the synergistic relationship between the graphene scaffold and the dexamethasone only possible within certain parameters? The examiner cannot determine how the achieved synergism is critical and particular to this invention. Additionally, Rostami discloses that the GO scaffolds attained uniform distribution of porosity, which is essential for adhesion and penetration of MSCs (Section 3.2). Likewise, a graphene oxide sheet with uniform porosity would house whatever active ingredients within its’ pores, uniformly.
Continued on page 7 of remarks, applicant argues that higher loading levels were capable with the claimed combination. However, Jiang clearly teaches that evaluation of kinetic release of Dex from the 3-D scaffold permitted tailoring of drug loading to desired doses. Following optimization, the impact of this drug-release platform on the efficiency of islet engraftment and subsequent host cell responses were investigated (pg 72). One of ordinary skill in the art would routinely experiment with different kinetic release profiles for a 3-D scaffold housing dexamethasone. Additionally, higher loading levels and specific initial burst amounts are not claimed in claim 1.
Applicant argues that Jiang suggests only using dexamethasone at concentrations ranging from 0.1 to 0.25 w/v %. The Applicant’s release rates of dexamethasone for 0.25 w/v%, 0.5 wv/%, and 1 w/v% were 3.96 ng/mL/h, 4.53 ng/mL/h, and 10.2 ng/mL/h, respectively. Jiang teaches that the total dexamethasone release averaged from a maximum of 518 ng/day for 1% Dex-PDMS scaffolds to a minimum of 6.5 ng/day for 0.1% Dex-PDMS scaffolds during the subsequent plateau phase, after the initial burst phase (See pg 74, right col, 1st paragraph). Dexamethasone release of 518 ng/day would equal to roughly 21.5 ng/hr; 6.5 ng/day would equal to roughly 0.27 ng/hr. In conclusion, the dexamethasone-releasing profile disclosed in Jiang encompasses the dexamethasone-releasing profile disclosed in this instant application. Jiang encompasses the critical concentration or critical dexamethasone-release profile of Applicant’s bioscaffolds. And as discussed above, one of ordinary skill in the art would routinely optimize kinetic release profiles.
Furthermore, per MPEP 716.02(d) (II), to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). The applicant only tested concentration of Dex from 0.25 to 1 w/v % and no concentration outside this range. A sufficient number of tests at various concentrations above 1 w/v % or below 0.25 w/v % would need to be presented to clearly show the criticality of the range at which the unobvious results were obtained.
On page 8 of remarks, applicant argues that Rostami does not disclose an amount of drug loading or a specific release profile. As mentioned above, claim 1 is not commensurate in scope with these kinetic profiles. Additionally, the applicants have not shown if their claimed, critical kinetic profile is specific to only 0.5% or 1% dexamethasone. Per MPEP 2145 (IV), One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references.
Continued on page 8 of remarks, applicant argues that the inventors have found and demonstrated in the examples of the application a synergy between the graphene matrix and dexamethasone. As mentioned above, one of ordinary skill in the art would routinely optimize the release profiles as they see fit for a safe, effective therapy for patients. Applicant argues that live cell percentage was significantly greater in the graphene-Dex bioscaffolds as compared to control cell culture plates. This would be expected as Jiang discloses Dex-PDMS scaffold provides a protective microenvironment for engrafted islets (page 80).
Therefore, rejections of 1, 5, 8, 11-15, 17-18, 20, 21, 25-29, 31, 39, 40 and 54-57 are maintained.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615