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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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.
Response to Amendment
Applicant's amendment and argument filed 05/04/2026, in response to the final rejection, are acknowledged and have been fully considered. Any previous rejection or objection not mentioned herein is withdrawn.
Claims 15, 16, and 27 have been withdrawn previously. Claims 1-5, 8-14, 29, 32-44 and are being examined on the merits.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 1-5, 10-11, 13-14, 29, 32-39 and 42-44 are rejected under 35 U.S.C. 103 as being unpatentable over Praveena Jayaraman et. al. (Controlled release of drugs in electrosprayed nanoparticles for bone tissue engineering☆, Advanced Drug Delivery Reviews, 94 (2015) 77-95) and Nishimura wt. al. (from IDS, US20030082784A1). This rejection is maintained with modifications due to the amendments filed on 05/04/2026.
Regarding claims 1-3, 34, 39, Jayaraman teaches electrospraying nanoparticles for bone tissue engineering (see abstract) and discloses PLGA nanoparticles for tissue regeneration using flow-limited field-injection electrospray. It was observed that the injection charge method inducing the ionic state of PLGA solution is highly efficient when compared to the conventional electrospray methods. Lee et al. developed anodized titanium implants layered with PLGA nanoparticles and fibroblast growth factor using electrospray to study its osseointegration in rabbit tibiae (see page 80, bottom right).
Jayaraman teaches the most extensively studied synthetic PLGA nanoparticles are applied for bone tissue regeneration in specific due to their hydrophilic surface morphology with carboxylate at the end groups. The surface properties of these nanoparticles can be modified to achieve sustained and controlled drug release rates. Choi et al. have developed a surface-functionalized tetracycline-loaded PLGA nanoparticle for bone-specific drug delivery. These nanoparticles were <200nm in size and had a hydrophilic surface layer. It has been shown that these surface-functionalized nanoparticles could be used to obtain controlled release profiles and site-specific targeted delivery [73]. In addition, these PLGA-based nanoparticles can be combined with molecules, which have a higher affinity toward CaP in bone, thus promoting their ability to reach the specific targeted bone sites [81]” (see last para. page 84 and first para. page 85).
“PLGA is generally used as a carrier in drug delivery system owing to its biocompatibility and degradability into lactic acid and glycolic acid. The surface modified carrier material improves the stability, circulation of drugs throughout the body, integration of diagnostic agents, and bio-specific targeting over the cellular ligands and ECM components. Electrospraying is considered as advantageous over other conventional methods for generating nanoparticles” (See 6. Drug delivery, 1st para., page 85).
Jayaraman teaches the bone grafts are generally made using natural or synthetic biomaterials that enhance the migration, adhesion, growth, and differentiation of cultured bone cells for bone tissue regeneration. In the autologous bone grafting method, the patient's own tissues, which are histocompatible and non-immunogenic, are used to reduce the possibility of immunoreactions of the grafted tissues (see 2nd para. Introduction).
The biodegradable PLGA nanoparticles combination with fibroblast growth factor coated on to the surface of titaniumim plants resulted in the formation of a new tissue next to the surface of the bone implant (see bottom of page 80 and top of page 81). Here the method of preparing a coated bone graft by electrospraying a PLGA polymer and a bone stimulating therapeutic agent is disclosed.
These self-dispersing charged droplets have higher deposition efficiency when compared with the uncharged spray. The size of the droplets ranges from hundred micrometers to around tens of nanometers. The droplet size can be precisely controlled by regulating both
the flow rate and applied voltage. In practice, the electrospray technique enables better control over structure, size, and composition of particles as compared to other traditional fabrication methods (see 2nd para. page 79).
Nanoparticles derived from poly(lactic-co-glycolic) acid (PLGA), polyglycolic acid (PGA), and polylactic acid (PLA) are commonly applied biomaterials for delivering osteoinductive factors, plasmid DNA (for gene therapy), or anti-inflammatory drugs to enhance bone tissue regeneration[9–11]. The size of a molecule plays a significant role in effective drug
delivery to the target site (see 3rd para. Introduction).
Regarding claims 4 and 29, Jayaraman discloses that “among the growth factors, BMP-2 and BMP-7 are most effective in inducing complete bone morphogenesis. Yilgor et al. synthesized PLGA and PHBV nanoparticles consisting of BMP-2 and BMP-7 proteins and incorporated them in PCL scaffolds for developing 3D tissue-engineered constructs. These nanoparticles incorporated in PCL scaffolds delivered both BMP-2 and BMP-7 in a successive manner by improving the differentiation of bone marrow MSCs into osteogenic lineage (see page 87, right column).
Regarding claim 11, Jayaraman teaches “the size of the droplets ranges from hundred micrometers to around tens of nanometers. The droplet size can be precisely controlled by regulating both the flowrate and applied voltage” (see page 79, para. 2).
Regarding claims 38-39 and 44, Jayaraman teaches wherein the surface properties of these nanoparticles can be modified to achieve sustained and controlled drug release rates. Choi et al. have developed a surface-functionalized tetracycline-loaded PLGA nanoparticle for bone-specific drug delivery. These nanoparticles were <200 nm in size and had a hydrophilic surface layer (see 5. Nanoparticles in bone tissue engineering, at bottom). Also see table 1, particle size for references of the various sizes for creating nanoparticles to be electrosprayed.
Jayaraman teaches methods of preparing a coated bone graft with BMP-2, however is silent on the BMP-2 fragment comprises the SEQ ID NO:1.
Nishimura’s general disclosure is to a novel peptide having osteogenic activity (see abstract).
Nishimura teaches a bone stimulating agent being BMP-2 (see 0048 and 0051).
Regarding claim 5, Nishimura teaches a peptide having an amino acid sequence represented by SEQ ID NO:1 of the instant application (see Test example, 0063, (Lys Ile Pro Lys Ala Ser Ser Val Pro Thr Glu Leu Ser Ala Ile Ser Thr Leu Tyr Leu)) and having osteogenic activity (see claim 1).
Therefore it would have been obvious given the prior art and before the effective filling date to use BMP-2 or a fragment thereof with SEQ ID NO:1 of the instant invention because Nishimura teaches that this fragment has osteogenic activity and using this for material as a bone stimulating agent for coating of a bone graft would have been prima facie obvious. It would have also been obvious to electrospray a second composition comprising the PLGA and a therapeutic agent onto the first electrosprayed composition because adding another layer of the same material would only reinforce the activities which have already been described. It would have also been obvious to mineralize the synthesized bone graft in order to promote nucleation and growth as described by Jayaraman. It would have further been obvious to optimize the lactide and glycolide monomers to be within the claimed ratios because those are the active polymers useful for regenerating bone tissues and thus optimizing those monomers is well within the purview of any skilled artisan.
Regarding claims 35-36 and 42-43, pertaining to the coated bone graft being uniform and being 97% of the exposed bone graft, or the entire bone graft being coated is something a person having ordinary skill in the art would have known to do since the coating is what is assisting to create the ECM to improve the bone graft. Also creating similar sized nanoparticles is obvious given that the art recognizes the benefits of size selection for creating more stable delivery to tissues as can be appreciated from the above rejection and prior art (see, page 78, 2nd to final para. “ The size of a molecule plays a significant role in effective drug delivery to the target site.). It would have also been obvious to make the bone graft an autograft as this would require using the patient’s own tissues which would help with the patient’s immune system rejecting the graft. Finally, it would have been obvious to make the coating of the bone graft from about 1 um to about 1 mm thick and uniform because persons having ordinary skill in the art would want to create a scaffold of evenly distributed molecules which are helping heal the native tissues and would definitely create a thickness within the 1000-fold difference of about 1 um to about 1mm being claimed, depending on where in the body the bone is being treated. Not all treated surfaces would be the same and this optimization is well within the purview of a skilled artisan for creating a bone graft electrospray material, especially given the prior art.
Claims 8-9 and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Praveena Jayaraman et. al. (Controlled release of drugs in electrosprayed nanoparticles for bone tissue engineering☆, Advanced Drug Delivery Reviews, 94 (2015) 77-95) and Nishimura wt. al. (from IDS, US20030082784A1) as applied to claims 1-5, 10-11, 13-14, 29, 32-39 and 42-44 above, and further in view of Fan Yang et. al. (Anti-Schistosomiasis Liver Fibrosis Effect of Corilagin Through Interacting the IL-13/miR-21/smads Signaling Pathway in Vitro and in Vivo, The Lancet, Sept 17, 2018) and Ying Huang et. al. (MicroRNA-21: A Central Regualtor of Fibrotic Diseases Via Various Targets, Current Pharmaceutical Design, 2015, 21, 2236-2242). This rejection is maintained with modifications due to the amendments filed on 05/04/2026.
Jayaraman teaches methods of preparing a coated bone graft with BMP-2, however is silent on the composition comprising a fibrotic agent or a fibrotic agent being that of corilagin.
Yang teaches “no matter in normal, miR-21 up- or down-regulated LX2 cells, corilagin could inhibit the mRNA level of miR-21 and CTGF and promote smad7 mRNA level (P < 0.01 or 0.05). Meanwhile, corilagin could significantly reduce the protein level of CTGF, p-smad1, p-smad2, psmad2/3, smad4, TβR Ⅰ and α-SMA，and promote smad7 protein level (P <0.05 or 0.01). Corilagin could decrease serum IL-13 and SCAg level (P < 0.01 or 0.05), and also reduce the degree of liver fibrosis in pathological manifestations. Interpretation: Corilagin could inhibit schistosomiasis-induced hepatic fibrosis through the potential drug intervention targets in IL13/miR21/smads pathway, which might serve as an anti-fibrosis agent…” (see abstract).
Although Yang teaches that corilagin can inhibit fibrosis in hepatic cell lines, Huang’s disclosure is relied upon to show how the same mir-21/smad pathways discussed by Yang are beneficial for control over fibrosis.
Huang’s article discusses miR-21 as a regulator of fibrotic disease (see abstract).
Huang teaches that “MicroRNAs (miRNAs) are small non-coding RNA molecules that diversely regulate physiological and pathophysiological processes by specifically binding to different regions of targeting messenger RNAs (mRNAs). Fibrosis is characterized by the abnormal proliferation of fibroblasts and the deposition of the extracellular matrix (ECM). Both clinical and experimental animal studies have revealed that aberrant expression of miRNAs is closely associated with the development of fibrotic diseases. microRNA-21 (miR-21) is a ubiquitously expressed miRNA that is traditionally considered to be an oncogenic miRNA (oncomiR). Recent studies have demonstrated that elevated expression of miR-21 may play a vital role in the development of fibrosis by promoting the proliferation of interstitial fibroblasts and increasing the abnormal deposition of the ECM. In this review, we comprehensively summarize the role of miR-21 in tissue fibrosis. Furthermore, we highlight miR-21 as a potential diagnostic and prognostic marker and therapeutic target for fibrosis diseases” (see abstract).
Additionally, “miR-21 is a ubiquitously expressed miRNA in human tissues. The important role of miR-21 in the pathogenesis of fibrotic diseases has been generally demonstrated by both clinical and basic evidences. The accumulated data suggest a promising idea that sequence-specific inhibition of miR-21 may provide a novel therapeutic implication in fibrotic disease” (see conclusion and perspectives, page 2240).
Therefore it would have been obvious given the prior art and before the effective filling date to persons having ordinary skill in the art to use anti-fibrotic agent such as corilagin in the invention taught by Jayaraman because corilagin is known as an anti-fibrotic agent which can inhibit miR-21 levels thus helping to reduce fibrosis of interstitial tissues and decreasing abnormal deposition of the ECM as discussed by Huang and Yang.
There would have been a reasonable expectation of success in using corilagin as an anti-fibrotic agent for the invention taught by Huang because both Yang and Huang teach how it can inhibit miR-21 which in turn would decrease fibrosis.
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Praveena Jayaraman et. al. (Controlled release of drugs in electrosprayed nanoparticles for bone tissue engineering☆, Advanced Drug Delivery Reviews, 94 (2015) 77-95) and Nishimura wt. al. (from IDS, US20030082784A1) as applied to claims 1-5, 10-11, 13-14, 29, 32-39 and 42-44 above, and further in view of Jingwei Xie and Sunil Kumar Boda (from IDS, WO2019209762A1), hereinafter Xie. This rejection is maintained with modifications due to the amendments filed on 05/04/2026.
Jayaraman teaches methods of preparing a coated bone graft, however is silent on the freeze drying, lyophilized or mineralized of the synthesized coated bone graft.
Xie’s general disclosure is to the use of Nanofiber segments and nanofiber microspheres as injectable scaffolds for biomedical engineering (see background of the invention).
Xie teaches of electrospray(ed) nanofibers (see claims 1-2), wherein the nanofibers (coating) are mineralized, comprise of bone morphogenetic protein (see claim 25), freeze-dried and/or lyophilized (see claim 28), and for the purpose of periodontal bone loss (see claims 34 and 37).
Xie teaches “The nanofiber segments and nanofiber microspheres of the instant invention may comprise a material that enhances water absorption; may be crosslinked and/or thermally treated; may be mineralized; may comprise one or more agents or compounds such as therapeutic agents; and/or may comprise cells and/or tissue, or any combination of any one, two, three, four, or five of these features”
“For example, the nanofiber structures may be used to enhance wound healing, build tissue constructs, promote tissue regeneration (e.g., bone regeneration)..” (see summary of the invention, first and second para.).
Xie teaches that “mineralization, for example, with hydroxyapatite, can enhance the adhesion of osteogenic precursor cells in vitro and in vivo”
Therefore it would have been obvious given the prior art and before the effective filling date to mineralize lyophilize and/or freeze-dry the coating in the invention taught by Jayaraman, because these components are taught in the art. It would have been obvious to freeze-dry/lyophilize the coating because this would help preserve the coating components and it would have been useful to mineralize the coating especially given that it is for the purpose for a bone graft as mineralization is needed for bone deposition.
Response to Arguments
Applicant's arguments filed 05/04/2026 have been fully considered but they are not persuasive. The applicant’s arguments appear to rely on the fact that Jayaraman teaches of electrospraying onto titanium implants rather than electrospraying onto bone. The applicant claims electrospraying onto a bone graft and does not recite electrospraying onto “bone”. As recognized by the art above and generally speaking, a bone graft can be made using natural or synthetic biomaterials that enhance the migration, adhesion, growth, and differentiation of cultured bone cells for bone tissue regeneration. Thus the bone graft of the prior art does not have to be bone as argued because that is not a limitation being claimed and the bone graft of the prior art is indeed a bone graft when so broadly claimed especially given the broadest reasonable interpretation. Additionally, the applicant does not define a “bone graft” in their specifications. Jayaraman indeed teaches electrospraying onto the surface of a bone graft as required. Additionally, the prior art recognizes the many benefits of utilizing PLGA in bone grafts through electrospray technology as is recognized by Jayaraman. PLGA is a known biodegradable material which is commonly used in bone grafts for effective tissue regeneration and drug delivery. Using this with electrospray technology which is also known to assist with dispersion of particles, control of particle size, for enhancing cell adhesion and creating scaffolds for tissue regeneration is recognized in the prior art and by Jayaraman. Optimizing the bone graft thickness to be within the claimed range is well within the purview of any skilled artisan and making sure the surface is uniformly coated would have been prima facie obvious and does not make the instant application patentably distinct over the prior art. Indeed, small or fine-gained bone grafts are often 1 mm thick and since the grafts being taught are made of nanoparticles which range from hundreds of micrometers to around tens of nanometers in diameter it would naturally flow that layering a scaffold with nanoparticles of that size would create thicknesses from about 1um to about 1mm in thickness.
Conclusion
Currently no claims are allowed.
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JACOB A BOECKELMANExaminer, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
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