DETAILED ACTION
Status of Claims
The amendments, and arguments, filed November 28, 2025, are acknowledged and have been fully considered. Claims 1, 3-8, 11-12, 14, 16-19 and 36-38 are pending and currently under consideration. Claims 1, 3, 11-12, 14, 18-19 and 36 have been amended; and claims 2, 9-10, 13, 15 and 20-35 were previously cancelled. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Office Action: Final
Withdrawn Claim Objections & Rejections
The objections to claims 3 and 36 (items A. and B. at par. 1-2 of the 05/29/2025 Office action) are withdrawn in light of applicant’s 11/28/2025 amendments. Applicant’s 11/28/2025 remarks at p. 6, par. 3-5, are acknowledged.
The rejection of claims 11-12, 14 and 18-19 under 35 U.S.C. § 112 (b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite (items A., C., D., E. and F. at par. 3-4 of the 05/29/2025 Office action), is withdrawn in light of applicant’s 11/28/2025 amendments. Applicant’s 11/28/2025 remarks at p. 6, par. 8 to p. 7, par. 1, are acknowledged.
New Claim Objections – Necessitated by Amendments
The following claims are objected to because of the following informalities:
A. Claim 11 is objected to because the claim should read:
11. ([…]) The biocompatible material according to claim 6, wherein the biocompatible material is selected from the group consisting of: organism-derived bone mineral powders, organism-derived bone mineral porous blocks, synthetic hydroxyapatite bone-packing graft materials, fine particles containing biocompatible polymers, porous scaffolds containing biocompatible polymers, titanium, three-dimensional porous scaffolds[[;]], collagen[[t]], alginic acid, polylactic acid, polyglycolic acid, poly(ε-caprolactone) (PCL), poly(3- hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), cellulose, poly(N-isopropylacrylamide), gelatin, propylene glycol, chondroitin sulfate with,[[;]] polylactic glycolic acid, poloxamer and propylene glycol.
B. Claim 14 is objected to because the claim should read:
14. ([…]) The formulation of according to claim 5, wherein said pharmaceutically acceptable excipient is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, cellulose derivatives, polycarbophil, polyacrylic acid, polymethacrylate derivatives, polyglycolic acid, polylactic acid, poly(glycolic-co-lactic) acid, polycaprolactone, alginate, carrageenan, chitosan, polysaccharide derivatives, chondroitin sulfate, hyaluronic acid, glycosaminoglycan derivatives, polyarginine, polydioxanone, xanthan gum, guar gum, starch, starch derivatives, polyoxyethylene, polypropylene oxide, polyethylene glycol, 0-alpha-tocopheryl polyethylene glycol succinate, tributyl citrate, acetyltributyl citrate, acetyltriethyl citrate, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, glycerol, propylene glycol, and polyethylene glycol.
C. Claim 12 is objected to because the claim should read:
12. ([…]) The formulation of claim 5, wherein said additional active pharmaceutical ingredient is selected from small molecule[[s]] drugs, peptides, proteins, vaccines, lymphokines, enzymes, antibodies, stem cells, secretomes, hormones, hematopoietic factors, DNA derivatives, RNA derivatives and aptamers.
Appropriate correction is required.
Maintained Claim Rejections – 35 U.S.C. § 112 - Indefiniteness
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.
Claims 11-12, 14 and 18-19 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 pre-AIA , that applicant regards as the invention.
B. Claim 11 contains the trademark/trade name, “collagent.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. § 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an antibiotic gel, and, accordingly, the identification/description is indefinite.
Further clarification is required.
New Claim Rejections – 35 U.S.C. § 102 – Necessitated by Amendments
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 3-4 are rejected under 35 U.S.C. § 102(a)(2) as being anticipated by CASTRO (Castro, M., et al., Histatin-1 counteracts the cytotoxic and antimigratory effects of zoledronic acid in endothelial and osteoblast-like cells, J. Periodontol., 90 (Mar. 7, 2019) pp. 766-774; hereinafter, “Castro”).
Castro is directed to:
Histatin-1 counteracts the cytotoxic and antimigratory effects of zoledronic acid in endothelial and osteoblast-like cells
Abstract
Background: Zoledronic acid, the most frequent agent associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ), has been reported as cytotoxic for bone and vascular cells. Hence, identification of novel approaches aiming to counteract its cytotoxic effects will be desirable to develop preventive therapies for BRONJ. The salivary peptide Histatin-1 was recently shown to promote oral wound healing, by acting in epithelial and endothelial cells; however, its effects on cells exposed to zoledronic acid have not been explored. This study aims to unveil the role of Histatin-1 in osteoblastic and vascular cell lineages challenged with zoledronic acid.
Methods: The effects of zoledronic acid (1–100 μM), Histatin-1 (10 μM), or their combination was evaluated in cytotoxicity (Trypan Blue exclusion) and cell migration (Boyden Chamber) assays. Caspase-3 cleavage was evaluated by Western blot. The angiogenic capacity of endothelial cells was assessed in a tubule formation assay in vitro.
Results: Zoledronic acid decreased cell viability and migration of osteosarcoma cells (SAOS-2) and preosteoblasts (MC3T3-E1), in a dose-response manner. Importantly, Histatin-1 restored both cell viability and migration in both cell lines upon challenge with zoledronic acid. These effectswere recapitulated in endothelial cells (EA.hy926), as Histatin-1 counteracted cytotoxic and antimigratory effects of zoledronic acid, and restored the angiogenic capacity in vitro.
Conclusion: We conclude that Histatin-1 counteracts the cytotoxic and antimigratory effects of zoledronic acid in osteoblast-like and endothelial cells. These observations highlight the potential use of Histatin-1, in the design of novel therapies aiming to prevent and treat BRONJ.
Castro, title & abstract. In this regard, Castro teaches “Histatin-1”:
2.1 Histatin-1 synthesis
Histatin-1 was obtained by chemical synthesis (Biomatik, Wilmington, DE), as the following sequence DpSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN, corresponding to the 38-amino acid length phosphopeptide (phospho-Serine2), as previously described.[..] The sequence SYGYKNpSPLYNHHDRFEDKYGHFEDHFSRRHKREYGHH, which contains a phosphorylation on Serine7, corresponded to the scrambled sequence of Histatin-1 and it was previously characterized.[.] Peptide stocks were prepared in ddH2O, and all experiments were performed with 10 μM Histatin-1, as this concentration is known to elicit functional effects, and is close to that reported in human saliva.[..] Importantly, all experiments involving synthetic peptides (Histatin-1, scrambled peptide) or zoledronic acid did not affect parameters, such as pH in tissue culture media.
Castro, p. 767, par. 3.
Regarding independent claim 1 and the requirements:
1. ([…]) A formulation for the treatment, repair, formation, or regeneration of bone tissue in a subject, wherein said formulation comprises:
Histatin-1 or its derivatives; or
a polynucleotide encoding Histatin-1 or its derivatives.
Castro clearly teaches “Histatin-1,” with “the following sequence DpSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN, corresponding to the 38-amino acid length phosphopeptide (phospho-Serine2)” (Castro, p. 767, par. 3), which reads on:
“Histatin-1 or its derivatives” of claim 1,
as well as “SEQ ID NO. 1” of claim 3 and a phosphorylated derivative of claim 4:
3. ([…]) The formulation according to claim 1, wherein said Histatin-1 or its derivatives comprises an amino acid sequence having at least 85%, at least 90% or at least 99% sequence identity to any of SEQ ID NO. 1 SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO.14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, or SEQ ID NO. 23.
Thus, Castro anticipates claims 1 and 3-4.
Maintained Claim Rejections – 35 U.S.C. § 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. § 103(a) 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 C.F.R. § 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.
Claims 1, 3-8, 11-12, 14, 16-19 and 36-38 are rejected under 35 U.S.C. § 103 as being unpatentable over CASTRO (Castro, M., et al., Histatin-1 counteracts the cytotoxic and antimigratory effects of zoledronic acid in endothelial and osteoblast-like cells, J. Periodontol., 90 (Mar. 7, 2019) pp. 766-774; hereinafter, “Castro”; of record), in view of HEARTLEIN (US 2016/0184458 A1, Publ. Jun. 30, 2016; hereinafter, “Heartlein”; of record).
Castro is directed to Histatin-1 counteracting the cytotoxic and antimigratory effects of zoledronic acid in endothelial and osteoblast-like cells. Castro, title & abstract. In this regard, Castro teaches “Histatin-1”:
2.1 Histatin-1 synthesis
Histatin-1 was obtained by chemical synthesis (Biomatik, Wilmington, DE), as the following sequence DpSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN, corresponding to the 38-amino acid length phosphopeptide (phospho-Serine2), as previously described.[..] The sequence SYGYKNpSPLYNHHDRFEDKYGHFEDHFSRRHKREYGHH, which contains a phosphorylation on Serine7, corresponded to the scrambled sequence of Histatin-1 and it was previously characterized.[.] Peptide stocks were prepared in ddH2O, and all experiments were performed with 10 μM Histatin-1, as this concentration is known to elicit functional effects, and is close to that reported in human saliva.[..] Importantly, all experiments involving synthetic peptides (Histatin-1, scrambled peptide) or zoledronic acid did not affect parameters, such as pH in tissue culture media.
Castro, p. 767, par. 3.
Regarding independent claims 1 and 6 and the requirements:
1. ([…]) A formulation for the treatment, repair, formation, or regeneration of bone tissue in a subject, wherein said formulation comprises:
Histatin-1 or its derivatives; or
a polynucleotide encoding Histatin-1 or its derivatives.
[…]
6. ([…]) A biomaterial for treatment, repair, formation, or regeneration of bone tissue in a subject, wherein said material comprises Histatin-1 or its derivatives in a biocompatible material.
Castro clearly teaches “Histatin-1,” with “the following sequence DpSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN, corresponding to the 38-amino acid length phosphopeptide (phospho-Serine2)” (Castro, p. 767, par. 3), which is noted as:
“Histatin-1 or its derivatives” of claims 1 and 6,
as well as “SEQ ID NO. 1” of claims 3 and 7 and a phosphorylated derivative of claims 4 and 8:
3. ([…]) The formulation according to claim 1, wherein said Histatin-1 or its derivatives comprises an amino acid sequence having at least 85%, at least 90% or at least 99% sequence identity to any of SEQ ID NO. 1 SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO.14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, or SEQ ID NO. 23.
4. ([…]) The formulation according to claim 1, wherein said derivatives comprise a modification selected from disulfide bond formation, glycosylation, lipidation, phosphorylation, cyclization, and conjugation with a labeling component.
[…]
7. ([…]) The biomaterial according to claim 6, wherein said Histatin-1 or its derivatives comprises an amino acid sequence having at least 85%, at least 90% or at least 99% sequence identity to any of SEQ ID NO. 1 to SEQ ID NO. 2.
8. ([…]) The biomaterial according to claim 6, wherein said derivatives comprises a modification selected from disulfide bond formation, glycosylation, lipidation, phosphorylation, cyclization, and conjugation with a labeling component.
However, Castro DOES NOT TEACH:
(i) a “polynucleotide encoding Histatin-1 or its derivatives” as alternatively required by independent claim 1; or
(ii) a “biocompatible material” as required by claim 6.
Based on the state of the art, an artisan of ordinary skill would have found each of these features obvious.
Regarding (i) and (ii), Heartlein, for instance, is directed to:
MRNA THERAPEUTIC COMPOSITIONS AND USE TO TREAT DISEASES AND DISORDERS
Abstract
Disclosed are compositions and methods for producing therapeutic fusion proteins in vivo. The compositions and methods disclosed herein are capable of ameliorating diseases by providing therapeutic protein delivery.
Heartlein, title & abstract. In this regard, Heartlein discloses at least one mRNA molecule, at least a portion of which encodes a therapeutic polypeptide fused to a polypeptide capable of binding to an Fc receptor:
1. A composition comprising (a) at least one mRNA molecule, at least a portion of which encodes a therapeutic polypeptide fused to a polypeptide capable of binding to an Fc receptor; and (b) a transfer vehicle.
(Heartlein, claim 1), wherein the mRNA molecule “encod[es] a therapeutic protein fused to a polypeptide that is capable of binding to an Fc receptor (“Therapeutic Fusion Protein”), for delivery to one or more target cells for production of therapeutic levels of functional protein”:
SUMMARY OF THE INVENTION
[0005] The invention provides improved mRNA therapy that has increased mRNA stability and prolonged half-life, among other things. In particular, the invention is based on mRNA encoding a therapeutic protein fused to a polypeptide that is capable of binding to an Fc receptor (“Therapeutic Fusion Protein”), for delivery to one or more target cells for production of therapeutic levels of functional protein. Without wishing to be bound by any theory, it is contemplated that such therapeutic fusion protein is readily transported from the target cell into systemic circulation via an Fc receptor and/or secreted from the cell, recaptured by an Fc receptor and then transcytosed into the systemic circulation. In certain embodiments, the therapeutic protein encoded is naturally secreted and thus naturally associated with an appropriate signal sequence. In other embodiments mRNA encoding a protein that is not normally secreted may be operatively linked to an appropriate signal sequence that results in the secretion of the translated protein.
(Heartlein, par. [0005]). Heartlein also teaches suitable “Therapeutic Fusion Protein[s],” inter alia, “Histatin-1”:
[0068] In some embodiments, the therapeutic protein in the Therapeutic Fusion Protein is chosen from the secreted proteins listed in Table 1; thus, compositions of the invention may comprise an mRNA encoding a protein listed in Table 1 (or a homolog thereof, as discussed below) along with other components set out herein, and methods of the invention may comprise preparing and/or administering a composition comprising an mRNA encoding a protein listed in Table 1 (or a homolog thereof, as discussed below) along with other components set out herein.
[0069] TABLE 1
Secreted Proteins
Uniprot ID Protein Name Gene Name
[…]
P15515 Histatin-1 HTN1
[…]
The Uniprot IDs set forth in Table 1 refer to the human versions of the listed proteins and the sequences of each are available from the Uniprot database. Sequences of the listed proteins are also generally available for various animals, including various mammals and animals of veterinary or industrial interest. Accordingly, in some embodiments, compositions and methods of the invention provide for the delivery of one or more mRNAs encoding a Therapeutic Fusion Protein, wherein the encoded therapeutic protein is chosen from mammalian homologs or homologs from an animal of veterinary or industrial interest of the secreted proteins listed in Table 1. In some embodiments, mammalian homologs are chosen from mouse, rat, hamster, gerbil, horse, pig, cow, llama, alpaca, mink, dog, cat, ferret, sheep, goat, or camel homologs. In some embodiments, the animal of veterinary or industrial interest is chosen from the mammals listed above and/or chicken, duck, turkey, salmon, catfish, or tilapia.
(Heartlein, par. [0068]-[0069]), wherein “(a) at least one mRNA molecule” (Heartlein, claim 1) is: “a polynucleotide encoding Histatin-1 or its derivatives” of claim 1, as well as an “RNA molecule” of claim 19:
19. ([…]) The formulation according to claim 1, wherein said polynucleotide is selected from DNA molecule, RNA molecule, aptamers, genetic construct, virus, adenovirus, adeno-associated virus, lentivirus, plasmid, artificial chromosome, natural vectors, and synthetic vectors, among others.
Hearlein also teaches suitable “Target Cells” (Heartlein, par. [0115]-[0117]) inter alia, “bone cells” (Heartlein, par. [0117]);
[0115] Target Cells
[0116] As used herein, the term “target cell” refers to a cell or tissue to which a composition of the invention is to be directed or targeted. In some embodiments, the target cells are epithelial cells found e.g., in the lung, intestine, renal proximal tubes, nasal passages, vaginal surfaces, and bilary tree surfaces, which contain the Fc neonatal receptor.
[0117] In some embodiments, the target cells are deficient in a protein or enzyme of interest. For example, where it is desired to deliver a nucleic acid to a hepatocyte, the hepatocyte represents the target cell. In some embodiments, the compositions of the invention transfect the target cells on a discriminatory basis (i.e., do not transfect non-target cells). The compositions of the invention may be prepared to preferentially target a variety of target cells, which include, but are not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells (e.g., meninges, astrocytes, motor neurons, cells of the dorsal root ganglia and anterior horn motor neurons), photoreceptor cells (e.g., rods and cones), retinal pigmented epithelial cells, secretory cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes and tumor cells.
(Heartlein, par. [0115]-[0117]), and further discloses suitable routes of administration including local administration:
[0128] Suitable routes of administration include, for example, oral, rectal, vaginal, transmucosal, pulmonary including intratracheal or inhaled, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Pulmonary administration by aerosolization or nebulization is particularly preferred for its noninvasive features and because of the ability of the Therapeutic Fusion Protein to be easily transported across the lung epithelium into the circulatory system.
[0129] Alternately, the compositions of the invention may be administered in a local rather than systemic manner, for example, via injection of the pharmaceutical composition directly into a targeted tissue, preferably in a sustained release formulation. Local delivery can be affected in various ways, depending on the tissue to be targeted. […].
(Heartlein, par. [0128]-[0129]). With respect to a “(b) a transfer vehicle” (Heartlein, claim 1), Heartlein teaches suitable carrier such as “a polymeric carrier alone or in combination with other carriers,” inter alia, chitosan:
[0089] In certain embodiments, the carriers employed in the compositions of the invention may comprise a liposomal vesicle, or other means to facilitate the transfer of a mRNA to target cells and/or tissues. Preferred embodiments include compositions with high transfection efficacies and in particular those compositions that minimize adverse effects which are mediated by transfection of non-target cells. The compositions of the present invention that demonstrate high transfection efficacies improve the likelihood that appropriate dosages of the mRNA will be delivered to the target cell, while minimizing potential systemic adverse effects. […].
[0090] The mRNA can be formulated with one or more acceptable reagents, which provide a vehicle for delivering such mRNA to target cells. Appropriate reagents are generally selected with regard to a number of factors, which include, among other things, the biological or chemical properties of the mRNA, the intended route of administration, the anticipated biological environment to which such mRNA will be exposed and the specific properties of the intended target cells. In some embodiments, transfer vehicles, such as liposomes, encapsulate the mRNA without compromising biological activity. In some embodiments, the transfer vehicle demonstrates preferential and/or substantial binding to a target cell relative to non-target cells. In a preferred embodiment, the transfer vehicle delivers its contents to the target cell such that the mRNA is delivered to the appropriate subcellular compartment, such as the cytoplasm.
[0091] In some embodiments, the compositions of the invention employ a polymeric carrier alone or in combination with other carriers. Suitable polymers may include, for example, polyacrylates, polyalkycyanoacrylates, polylactide, polylactide-polyglycolide copolymers, polycaprolactones, dextran, albumin, gelatin, alginate, collagen, chitosan, cyclodextrins, protamine, PEGylated protamine, PLL, PEGylated PLL, polyethylenimine (PEI), including, but not limited to branched PEI (25 kDa) and multi-domain-block polymers. Alternatively, suitable carriers include, but are not limited to, lipid nanoparticles and liposomes, nanoliposomes, ceramide-containing nanoliposomes, proteoliposomes, both natural and synthetically-derived exosomes, natural, synthetic and semi-synthetic lamellar bodies, nanoparticulates, calcium phosphor-silicate nanoparticulates, calcium phosphate nanoparticulates, silicon dioxide nanoparticulates, nanocrystalline particulates, semiconductor nanoparticulates, dry powders, nanodendrimers, starch-based delivery systems, micelles, emulsions, sol-gels, niosomes, plasmids, viruses, calcium phosphate nucleotides, aptamers, peptides, peptide conjugates, small-molecule targeted conjugates, and other vectorial tags. Also contemplated is the use of bionanocapsules and other viral capsid proteins assemblies as a suitable carrier. (Hum. Gene Ther. 2008 September; 19(9):887-95).
(Heartlein, par. [0089]-[0091]), which is noted as “chitosan” of claims 11 and 14, a “pharmaceutically acceptable excipient” of claims 5 and 14, encompassed by “natural polymers” of claim 37, being “dispersed” or “embedded into” of claim 36, and a “biocompatible material” of claims 11 and 36-37.
5. ([…]) The formulation according to claim 1, wherein said formulation further comprises an additional active pharmaceutical ingredient, a pharmaceutically acceptable excipient or a combination thereof.
[…]
11. ([…]) The biocompatible material according to claim 6, wherein the biocompatible material is selected from the group consisting of: organism-derived bone mineral powders, organism-derived bone mineral porous blocks, synthe tichydroxyapatite powders, synthetic hydroxyapatite porous blocks, tricalcium phosphate powders, tricalcium phosphate porous blocks, monocalcium phosphate powders, monocalcium phosphate porous blocks, bone graft materials containing silicon dioxide (silica), bone graft biomaterial[[ ]], bone-packing graft materials, fine particles containing biocompatible polymers, porous scaffolds containing biocompatible polymers, titanium, three-dimensional porous scaffolds; collagent, alginic acid, polylactic acid, polyglycolic acid, poly(ε-caprolactone) (PCL), poly(3- hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), cellulose, poly(N-isopropylacrylamide), gelatin, propylene glycol, chondroitin sulfate, and chitosan; polylactic glycolic acid, poloxamer and propylene glycol.
[…]
14. ([…]) The formulation of according to claim 5, wherein said pharmaceutically acceptable excipient is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, cellulose derivatives, polycarbophil, carbopol, polyacrylate, polyacrylate derivatives, polymethacrylate, polymethacrylate derivatives, polyglycolic acid, polylactic acid, poly(glycolic-co-lactic) acid, polycaprolactone, alginate, carrageenan, chitosan, polysaccharide derivatives, chondroitin sulfate, hyaluronic acid, glycosaminoglycan derivatives, polyarginine, polydioxanone, xanthan gum, guar gum, starch, starch derivatives, polyoxyethylene, polypropylene oxide, polyethylene glycol, 0-alpha-tocopheryl polyethylene glycol succinate, tributyl citrate, acetyltributyl citrate, acetyltriethyl citrate, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, glycerol, propylene glycol, and polyethylene glycol.
[…]
36. ([…]) The biomaterial according to claim 6, wherein said Histatin-1 or its derivatives are dispersed, coated, or embedded into the biocompatible material.
37. ([…]) The biomaterial according to claim 36, wherein said biocompatible material is selected from bone mineral, metals, natural polymers, and synthetic polymers.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine Castro’s “Histatin-1” (Castro, p. 767, par. 3) with Heratlein’s (i) “(a) at least one mRNA molecule, at least a portion of which encodes a therapeutic polypeptide fused to a polypeptide capable of binding to an Fc receptor,” wherein the therapeutic polypeptide is histatin-1 (Heartlein, claim 1 & Heartlein, par. [0069], Table 1) into (ii) a chitosan carrier (Heartlein, par. [0089]-[0091]). One would have been motivated to do so with a reasonable expectation of success since both Castro and Ellies are concerned with similar problems in the art, namely gene products for treating conditions such as osteonecrosis (Castro, abstract) or bone cells (Heartlein, par. [0117]). Further, it is well within the skill of the ordinary artisan to select suitable forms of histatin-1 known in the art. Doing so amounts to no more than combining prior art elements according to known methods to yield predictable results, namely:
(i) combining Castro’s “Histatin-1” (Castro, p. 767, par. 3) with Heratlein’s “(a) at least one mRNA molecule, at least a portion of which encodes a therapeutic polypeptide fused to a polypeptide capable of binding to an Fc receptor” (Heartlein, claim 1) wherein the therapeutic polypeptide is histatin-1 (Heartlein, par. [0069], Table 1) in order to obtain the advantage of “a therapeutic protein fused to a polypeptide that is capable of binding to an Fc receptor (“Therapeutic Fusion Protein”), for delivery to one or more target cells for production of therapeutic levels of functional protein” (Heartlein, par. [0005]); AND
(ii) a chitosan polymeric carrier in order to obtain the advantage of a suitable carrier for therapeutic polypeptides such as “Histatin-1” (Heartlein, par. [0069], Table 1) suitable for local administration (Heartlein, par. [0128]-[0129]) to “bone cells” (Heartlein, par. [0115]-[0117]);
thereby rendering (i) and (ii), as noted above, obvious. It is further noted that the requirements of independent claims 1 and 6 for “treatment, repair, formation, or regeneration of bone tissue in a subject,” as well as the requirements of claims 16-18 and 38 for:
16. ([…]) The formulation according to claim 1, wherein said formulation is administered systemically, transmucosally or locally to the subject.
17. ([…]) The formulation according to claim 1, wherein said subject is a mammalian subject selected from human, horse, cat, and dog.
18. ([…]) The formulation according to claim 1, wherein said subject suffers from bone defect, bone fracture, bone resection, craniofacial cleft, musculoskeletal injury, arthrosis, pseudo-arthrosis, osteoporosis, osteomyelitis, osteonecrosis, spondylitis ankylosans, rickets, osteomalacia, osteogenesis imperfecta, marble bone disease (osteopetrosis), Paget disease of bone, fibrous dysplasia, and combination thereof.
[…]
38. ([…]) The biomaterial according to claim 6, wherein said biomaterial is applied, attached, grafted, or implanted to a subject in need of bone treatment, repair, formation, or regeneration.
are recitations of intended use. In this respect, it is noted that a recitation of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it reads on the claim, see MPEP § 2103 (I)(C). In the instant case, Castro per Heartlein teaches the structural requirements of instant claims 1 and 6, as discussed above. It is further noted that:
Castro teaches “Histatin-1” for treating osteonecrosis of the jaw (Heartlein, abstract), and the references teach a human-derived sequence (Castro, p. 767, par. 3; Heartlein, par. [0069]), which relates to “osteonecrosis” of claim 18, as well as a human subject of claim 17,
while Heartlein teaches local administration (Heartlein, par. [0128]-[0129]) and treatment of “bone cells” (Heartlein, par. [0115]-[0117]), which relates to local administration of claim 16, “bone treatment, repair, formation, or regeneration” of claim 3,
whereby it reasonably follows that a composition meeting the above noted structural requirements of Castro per Heratlein, as discussed above would be capable of performing the intended uses recited in claims 1, 6, 16-18 and 38.
Thus, the prior art renders claims 1, 3-8, 11, 14, 16-19 and 36-38 obvious.
Regarding claim 12 and the requirements:
12. ([…]) The formulation of claim 5, wherein said additional active pharmaceutical ingredient is selected from small molecules drugs, peptides, proteins, vaccines, lymphokines, enzymes, antibodies, stem cells, secretomes, hormones, hematopoietic factors, DNA derivatives, RNA derivatives and aptamers.
Castro teaches: “The effects of zoledronic acid (1–100 μM), Histatin-1 (10 μM), or their combination was evaluated in cytotoxicity (Trypan Blue exclusion) and cell migration (Boyden Chamber) assays” (Castro, abstract), wherein “zoledronic acid” is encompassed by “small drug molecules” as well as an “additional active pharmaceutical ingredient” of claims 5 and 12.
Thus, the prior art renders claim 12 obvious.
Response to Arguments
Applicants’ arguments, filed on November 28, 2025 (hereinafter, referred to as “Remarks”), have been fully considered, but they are not persuasive.
Applicant argues that “the document of Castro, while demonstrating the osteoconductive potential of Histatin-1 (i.e., providing a scaffold for pre-existing bone growth), neither teaches nor suggests the essential osteoinductive potential of the peptide.” (Remarks, p. 7, par. 4), which “is evidenced by multiple mechanistic markers: Histatin-1 promotes the expression and activity of Alkaline Phosphatase (ALP), a key enzyme for bone re-mineralization; it promotes the stabilization and activation of ~-catenin, which is associated with inducing osteogenesis; and, crucially, the alizarin red test confirmed the secretion of a greater number of mineral nucleation centers and the formation of calcium deposits by stem cells exposed to the peptide, unequivocally indicating cellular differentiation into bone lineage cells (see [0023]-[0026] and accompanying Figures)” (Remarks, p. 7, par. 6, cont. on p. 8).
In response: Castro clearly teaches “Histatin-1,” with “the following sequence DpSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN, corresponding to the 38-amino acid length phosphopeptide (phospho-Serine2)” (Castro, p. 767, par. 3), which is noted as: “Histatin-1 or its derivatives” of claims 1 and 6, as well as “SEQ ID NO. 1” of claims 3 and 7 and a phosphorylated derivative of claims 4 and 8. It is further noted that the limitation, “for treatment, repair, formation, or regeneration of bone tissue in a subject” (claims 1 and 6),” has not been given patentable weight because the recitation occurs in the preamble. A preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Further, the instant claims are not commensurate in scope with the alleged unexpected results. According to MPEP § 716.02, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In this regard, examiner suggests amending claim 1 to recite the particular effects evidenced at par [0023]-[0026] and Fig.’s 2-4 of the instant published application, US 2023/0010110 A1 in a more particular compositional form:
6. ([…]) A biomaterial for treatment, repair, formation, or regeneration of bone tissue in a subject, wherein said biomaterial comprises:
Histatin-1 or its derivatives, or a polynucleotide encoding Histatin-1 or its derivatives; and
a biocompatible material;
wherein the biomaterial provides Histatin-1 in an amount effective for the formation of crystal nucleation centers for osteoinductivity and bone matrix synthesis in the treatment, repair, formation or regeneration of bone tissue in a subject; and
wherein the biocompatible material is selected from the group consisting of: organism-derived bone mineral powders, organism-derived bone mineral porous blocks, synthetic hydroxyapatite powders, synthetic hydroxyapatite porous blocks, tricalcium phosphate powders, tricalcium phosphate porous blocks, monocalcium phosphate powders, monocalcium phosphate porous blocks, bone graft materials containing silicon dioxide (silica), bone graft biomaterial, bone-packing graft materials, fine particles containing biocompatible polymers, porous scaffolds containing biocompatible polymers, titanium, three-dimensional porous scaffolds, collagen, alginic acid, polylactic acid, polyglycolic acid, poly(ε-caprolactone) (PCL), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), cellulose, poly(N-isopropylacrylamide), gelatin, propylene glycol, chondroitin sulfate, chitosan, polylactic glycolic acid, poloxamer, propylene glycol, and combinations thereof.
Applicant also argues that “Heartlein provides no functional description, working examples, or specific motivation for using Histatin-1 in bone regeneration applications” (Remarks, p. 8, par. 2), and per the combination with Castro, “[w]hile Heartlein teaches generic vehicles, excipients, and biomaterials, this general knowledge on formulation does not provide a reasonable expectation of success for the claims” (Remarks, p. 8, par. 3). Further in this regard, applicant argues that there is no “technical basis to expect that the mere incorporation of Histatin-1 into the known vehicles of Heartlein would result in the active differentiation of stem cells and subsequent bone regeneration” (Remarks, p. 8, par. 4) because “the configuration defined in the claims is much more precise than the generic functional difference articulated by the Examiner in the rejection” (Remarks, p. 9, par. 1).
In response: it would ha be obvious to combine Castro’s “Histatin-1” (Castro, p. 767, par. 3) with Heratlein’s (i) “(a) at least one mRNA molecule, at least a portion of which encodes a therapeutic polypeptide fused to a polypeptide capable of binding to an Fc receptor,” wherein the therapeutic polypeptide is histatin-1 (Heartlein, claim 1 & Heartlein, par. [0069], Table 1) into (ii) a chitosan carrier (Heartlein, par. [0089]-[0091]). One would have been motivated to do so with a reasonable expectation of success since both Castro and Ellies are concerned with similar problems in the art, namely gene products for treating conditions such as osteonecrosis (Castro, abstract) or bone cells (Heartlein, par. [0117]). Further, it is well within the skill of the ordinary artisan to select suitable forms of histatin-1 known in the art. Doing so amounts to no more than combining prior art elements according to known methods to yield predictable results, namely (ii) a chitosan polymeric carrier in order to obtain the advantage of a suitable carrier for therapeutic polypeptides such as “Histatin-1” (Heartlein, par. [0069], Table 1) suitable for local administration (Heartlein, par. [0128]-[0129]) to “bone cells” (Heartlein, par. [0115]-[0117]). In this regard, it is noted that MPEP § 2144 (IV) states: “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) [...]; In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) [...].
Summary/Conclusion
Claims 1, 3-8, 11-12, 14, 16-19 and 36-38 are rejected. No claims are allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOMINIC LAZARO whose telephone number is (571)272-2845. The examiner can normally be reached on Monday through Friday, 8:30am to 5:00pm EST; alternating Fridays out.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, BETHANY BARHAM can be reached on (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DOMINIC LAZARO/Primary Examiner, Art Unit 1611