Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined pursuant to the first inventor to file provisions of the AIA .
DETAILED ACTION
Continued Examination Pursuant to 37 CFR 1.114
A request for continued examination pursuant to 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 pursuant to 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 13 July 2026 has been entered.
Status of the Claims
The Examiner acknowledges receipt of Applicants’ Response, filed 13 July 2026. Claims 16 and 22 are amended therein. Claims 19 – 21 are canceled. Claims 30 - 35 remain withdrawn as being directed to a non-elected invention. Accordingly, claims 16 - 18, and 22 - 29 remain available for substantive consideration to the extent that the biocompatible and/or resorbable polymer is collagen, and the encapsulating polymer is PLA-PGA.
REJECTIONS WITHDRAWN
Rejections Pursuant to 35 U.S.C. § 103
The obviousness rejections set forth in the Action of 12 March 2026 are hereby withdrawn in light of Applicants’ amendment of the claims, and in favor of the new grounds of rejection set forth below.
NEW GROUNDS OF REJECTION
Rejections Pursuant to 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. § 103 that 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 of this title, 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 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the Examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention absent any evidence to the contrary. Applicants are advised of the obligation pursuant to 37 CFR § 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the Examiner to consider the applicability of 35 U.S.C. § 102(b)(2)(C) for any potential 35 U.S.C. § 102(a)(2) prior art against the later invention.
Claims 16 - 18, and 22 - 27 are rejected pursuant to 35 U.S.C. § 103, as being obvious over US 2015/0010497 A1 to Bartorelli, A. and M. Gobbi, published 8 January 2015 (“Bartorelli ‘497”), in view of Gentile, P., Int. J. Mol. Sci. 15: 3640 – 3659 (2014) (“Gentile (2014)”), and US 2019/0314288 A1 to Song, H.-R., published 17 October 2019, and claiming priority to 12 August 2016 (“Song ‘288”).
The Examiner directs Applicants’ attention to the fact that the instant rejection applies the same references as applied in previous rejections of the claims pursuant to 35 U.S.C. § 103. However, the teachings of these references are applied in a manner different from how those teachings were applied in prior rejections, necessitated by Applicants’ amendment of claim 16, thus constituting a new basis of rejection.
The Invention As Claimed
Applicants claim a biomaterial comprising a three-dimensional matrix comprising collagen, and particles encapsulating a C1, or C2, or C3, or C5 complement component, or a C3 or C5 complement component, or a C3a or C5a complement active fragment, or a C5a complement active fragment, the particles dispersed in the three-dimensional collagen matrix, wherein the polymer of the microspheres is a copolymer of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA), and wherein the complement component or the complement active component is in an active form, and wherein the biomaterial further comprises a second phase of the collagen matrix that is free of particles encapsulating a complement component or complement active fragment.
The teachings of the Cited Art
Bartorelli ‘497 discloses compositions comprising various proteins, such as growth factors, cytokines, and complement proteins C3a/C4a, among others, for use in the treatment of conditions requiring tissue repair and regeneration (see Abstract), wherein the compositions comprise the complement C3a/C4a proteins at loadings from about 1 to 5 pg/mg (see ¶[0016]), wherein the disclosed compositions are used, either parenterally or topically, in the treatment of conditions requiring tissue repair and regeneration, such as for the treatment of bone traumatic and degenerative pathologies, as fillers for use in dermatology, and plastic and aesthetic surgery, in combination with biomaterials such as collagen, hyaluronic acid, matrigel, hydrocolloids, polylactides, polyglycolides, polycaprolactones, etc. (see ¶[0108]), wherein the compositions may be used to impregnate scaffolds, brackets, implants, or prostheses used in the treatment of metastatic bone lesions, atrophy of the mandibular or maxillary alveolar process, and for consolidation of bone fractures (id.), and wherein they may be coated for specific applications, for instance in controlled releases forms, preferably into microspheres (see ¶[0112]). The reference does not disclose compositions wherein the encapsulating microspheres are dispersed in a three-dimensional collagen matrix, or compositions wherein the polymeric microsphere coating of the complement component or the complement active fragment is a copolymer of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA). The teachings of Song ‘288 and Gentile (2014) remedy those deficiencies.
Song ‘288 discloses compositions for preventing or treating soft tissue diseases comprising porous polymer microspheres and a biodegradable polymer scaffold having a three-dimensional network structure (see Abstract), wherein the compositions further comprises a drug for treating soft tissue diseases that is incorporated in the network structure of the biodegradable polymer scaffold (see ¶[0010]), wherein the drug is a protein drug that is effective for treating soft tissue diseases, wherein the polymer of the biocompatible scaffold is collagen (see ¶[0016]), wherein the porous polymer microspheres enable drugs effective for regeneration of damaged tissues to be directly applied to diseased sites in need of treatment, and, because the drug is slowly released, a desired amount of drug can be delivered to the diseased site for a prolonged time, excellent regeneration effects can be directly expressed in soft tissues, and side-effects can be prevented because the microspheres are made of a biodegradable material (see ¶[0020]), wherein drug release is carried out through pores of the porous polymer microspheres, or is carried out when the biodegradable polymer scaffold is degraded in vivo (see ¶[0042]), wherein the polymer scaffold comprises a drug for treating soft tissue diseases incorporated in the network structure of the biodegradable polymer scaffold (see ¶[0041]), wherein release conditions, such as amount or rate, of the drug can be controlled depending on the type of polymer constituting the polymer scaffold, the density of network structure, porosity and pore size (see ¶[0043]), wherein the porous polymer microspheres may contain the drug in an amount of 2 to 30 parts by weight, with respect to 10 parts by weight of the biocompatible polymer (see ¶[0044]), wherein the microspheres have a porosity of 10 to 90%, a pore size of 5 to 100 µm, and a particle size of 200 to 1,000 µm (see ¶[0067]), wherein the porous polymer microspheres can be manufactured using pharmaceutically suitable and physiologically available adjuvants, in addition to the effective ingredients, and examples of the adjuvant include vitamins, colorants, thickening agents, pectic acid, electrolytes, alginic acid, organic acids, carbonating agents, excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, glidants, lubricants, or flavors (see ¶[0070]), wherein the porous polymer microspheres further include one or more pharmaceutically available carriers, apart from the aforementioned active ingredient, and are thus preferably prepared as a pharmaceutical composition for administration (see ¶[0071]), wherein the concentration of drug present in the porous polymer microspheres is preferably 1 ng/ml to 500 mg/ml and can be varied depending on type of contained drug, such that, for example, and when the application of the drug is for regenerating cartilage or bones, the concentration of drug is preferably 1 pg/mL to 3 mg/mL (see ¶[0073]).
Gentile (2014) discloses that poly(lactic-co-glycolide) (PLGA) copolymers are among the most commonly used biodegradable synthetic polymers for scaffolds in tissue engineering (see p. 3641, 2nd para.), wherein PLGA is preferred over other synthetic biodegradable polymers because it offers superior control compared with degradation properties by varying the ratio between its monomers, with a wide range of degradation rates, governed by the composition of chains, both hydrophobic/hydrophilic balance and crystallinity (id.), wherein, unlike pure PLA and pure PGA with limited solubilities, PLGA can be dissolved by a wide range of common solvents, including chlorinated solvents, tetrahydrofuran, acetone or ethyl acetate and can be processed into any shape and size, and can encapsulate biomolecules of any size (see p. 3643, 2nd para.), and wherein the degradation rates of PLGA can be influenced by different parameters, such as the molecular weight (increasing the molecular weight of conventional PLGAs from 10 – 20 to 100 kDa, degradation rates were reported to range from several weeks to several months, the ratio of GA to LA (PLGA’s with a higher content of LA are less hydrophilic, absorb less water, and subsequently degrade more slowly, as a consequence of the presence of methyl side groups in PLA making it more hydrophobic than PGA), with the exception being the 50:50 (LA:GA) copolymer that exhibits the faster degradation (see p. 3645, 1st para.).
Application of the Cited Art to the Claims
It would have been prima facie obvious before the filing date of the claimed invention to prepare compositions comprising various proteins, such as complement component proteins, or complement active fragments, such as C3a or C4a, among others, for use in the treatment of conditions requiring tissue repair and regeneration, such as the treatment of traumatic and degenerative bone pathologies, in combination with biomaterials such as collagen, wherein the compositions may be used to impregnate scaffolds used in the treatment of conditions such as metastatic bone lesions, and wherein they may be coated for controlled release forms, into microspheres, as taught by Bartorelli ‘497, wherein microspheres are formed from poly(lactic-co-glycolide) (PLGA) that are considered to be among the most commonly used biodegradable synthetic polymers for scaffolds in tissue engineering, wherein PLGA offers superior control over degradation properties by varying the ratio between its monomers, providing a wide range of degradation rates, wherein degradation rates can range from several weeks to several months, based on ratios of GA to LA (PLGA’s with a higher content of LA are less hydrophilic, absorb less water, and subsequently degrade more slowly, as a consequence of the presence of methyl side groups in PLA making it more hydrophobic than PGA), with the exception being the 50:50 (LA:GA) copolymer that exhibits the faster degradation, and wherein PLGA can be dissolved by a wide range of common solvents, and can, therefore, be processed into any shape and size, and can encapsulate biomolecules of any size, as taught by Gentile (2014), wherein compositions comprising porous PLGA microspheres used for preventing or treating soft tissue diseases include a biodegradable polymer scaffold having a three-dimensional network structure, wherein the scaffold comprises collagen, wherein the microspheres comprise a protein drug that is effective for treating soft tissue diseases, such as, for example, transforming growth factor (TGF), platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin like growth factor (IGF), bone morphogenetic protein-7 (BMP-7), or anti-inflammatory peptide, wherein the PLGA microspheres enable drugs effective for regeneration of damaged soft tissues to be directly applied to diseased sites in need of treatment, and, because the drug is slowly released, a desired amount of drug can be delivered to the diseased site for a prolonged time, resulting in excellent regeneration effects in soft tissues, while side-effects can be minimized because the microspheres are made of a biodegradable material, wherein drug release is carried out through pores of the porous polymer microspheres, or is carried out when the biodegradable polymer scaffold is degraded in vivo, and wherein release conditions, such as the amount or rate, of the drug can be controlled depending on the type of polymer constituting the polymer scaffold, the density of network structure, porosity and pore size, as taught by Song ‘288.
One of skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the teachings of Gentile (2014) to the effect that use of PLGA to encapsulate drugs to provide controlled release rates offers superior control over degradation properties by varying the ratio between its monomers, and by the teachings of Song ‘288 to the effect that encapsulation of protein drugs in PLGA microcapsules enables drugs that are effective for regeneration of damaged tissues to be directly applied to diseased sites in need of treatment, wherein, because the drug is slowly released, a desired amount of drug can be delivered to the diseased site for a prolonged time, resulting in excellent regeneration effects, while side-effects can be minimized because the microspheres are made of a biodegradable material.
The Examiner notes that claim 27 recites a limitation directed to the biomaterial of the invention further comprising a second phase of the three-dimensional polymer matrix that is free of particles encapsulating a complement active fragment. The Examiner acknowledges that the cited references do not explicitly disclose that the collagen matrix has a phase that is free of microspheres. However, the Examiner further notes that Song ‘288 discloses an embodiment that is reasonably read to include at least a portion of the collagen matrix comprising the active drug species that is not encapsulated within the PLGA microspheres. See, for example, ¶[0010]: (“including a biodegradable polymer scaffold having a three-dimensional network structure . . . and a drug for treating soft tissue diseases incorporated in the network structure of the biodegradable polymer scaffold”); ¶[0042]: (“Drug release . . . is carried out when the biodegradable polymer scaffold (hereinafter referred to as "polymer scaffold") is degraded in vivo”); and ¶[0043]: (“release conditions, such as amount or rate, of the drug can be controlled depending on the type of polymer constituting the polymer scaffold, the density of network structure, porosity and pore size”).
Thus, it is the Examiner’s position that those portions of the bioresorbable polymer scaffold that contain an active drug species that is not encapsulated within the PLGA microspheres would read on the limitation in question, rendering it obvious.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by claims 16 -18 and 22 – 27 would have been obvious within the meaning of 35 USC § 103.
Claims 28 and 29 are rejected pursuant to 35 U.S.C. § 103, as being obvious over Bartorelli ‘497, in view of Gentile (2014), and Song ‘288, as applied in the above rejection of claims 16 – 18 and 22 - 27, and further in view of US 2015/0374694 A1 to Boden, S. and S. Sangdala, published 31 December 2015 (“Boden ‘694”).
The Invention As Claimed
The invention with respect to claim 16 is described above. In addition, Applicants claim a biomaterial comprising a three-dimensional matrix of a biocompatible/resorbable polymer, and polymeric particles encapsulating a complement active fragment distributed in the matrix, wherein the three-dimensional matrix is porous, and wherein the three-dimensional matrix is in the form of a hydrogel.
The Teachings of the Cited Art
The disclosures of Bartorelli ‘497, Gentile (2014), and Song ‘288 are relied upon as applied in the above rejection of claims 16 - 18 and 22 – 27. The references do not disclose a biomaterial wherein the matrix is porous, or the matrix is in the form of a hydrogel. The teachings of Boden ‘694 remedy those deficiencies.
Boden ‘694 discloses compounds and compositions for cartilage repair and methods related thereto, the methods comprising implanting a cartilage matrix comprising an active compound in a subject (see Abstract), wherein the cartilage matrix, comprising collagen, is implanted in an area of lesions where it is desired to induce collagen growth or regeneration, and releases a compound to the subject from the matrix, the cartilage matrix comprising compounds and materials such as progenitor cells, autologous mesenchymal stem cells, autologous peripheral blood progenitor cells, autologous chondrocytic cells, a TGF-β protein, hyaluronic acid, proteoglycans, growth factors, or combinations thereof (see ¶[0012]; see also, ¶[0016]), wherein
The matrix is in the form of hydrogels, sponges, or meshes, and can contain cells and growth factors (see ¶[0130]), wherein the matrix is made up of a hydrogel polymer and is biodegradable (see ¶[0133]), wherein a collagen matrix is implanted at a site of exposed underlying bone in a subject in order to improve chondrogenic differentiation of mesenchymal stem cells at the site (see ¶[0143]), and wherein microspheres of poly(lactide-co-glycolide) may be used to form sustained-release protein delivery systems where the proteins may be entrapped in the poly(lactide-co-glycolide) microsphere depot by a number of methods, including formation of a water-in-oil emulsion with water-borne protein and an organic solvent-borne polymer (an emulsion method) (see ¶[0165]).
Application of the Cited Art to the Claims
It would have been prima facie obvious before the filing date of the claimed invention to prepare compositions comprising various proteins, such as complement proteins, C3a/C4a, among others, for use in the treatment of conditions requiring tissue repair and regeneration, wherein the proteins are encapsulated within PLGA microspheres, according to the teachings of Bartorelli ‘497, Taluja (2007), and Song ‘288, and wherein compositions suitable for cartilage repair comprise a collagen matrix comprising one or more proteins for implantation in a subject, wherein the matrix is implanted in an area of lesions where it is desired to induce collagen growth or regeneration, and releases one or more proteins to the subject from the matrix, wherein the matrix is in the form of hydrogels, sponges, or meshes, wherein the matrix is made up of a hydrogel polymer and is biodegradable, and wherein microspheres of poly(lactide-co-glycolide) are used to form sustained-release protein delivery systems where the proteins may be entrapped in the poly(lactide-co-glycolide) microsphere depot by a number of methods, including formation of a water-in-oil emulsion with water-borne protein and an organic solvent-borne polymer (an emulsion method). One of skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the teachings of Boden ‘694 to the effect that collagen scaffolds can be produced in a variety of forms, such as “hydrogels, sponges, or meshes, and can contain cells and growth factors” (see ¶[0130]), thus providing the skilled artisan with considerable flexibility in preparing implantable scaffold compositions, particularly those scaffolds designed to include cells.
With respect to claim 28, which claim recites a limitation directed to the collagen matrix being porous, the Examiner notes that collagen scaffolds in the form of sponges or meshes would necessarily be porous.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by claims 28 and 29 would have been obvious within the meaning of 35 USC § 103.
Response to Applicants’ Arguments
The Examiner has considered the Arguments of Applicants submitted with Response filed 13 July 2026, but does not find them persuasive. Applicants argue that, in Song '288, a secondary obviousness reference, “the scaffold is the material of the microspheres. There is no other scaffold in which the microspheres could be dispersed ( emphasis in original).” However, it is the Examiner’s position that Applicants’ argument misconstrues, or misapplies, the logic of the obviousness rejections of record. The rejections apply Song '288, as a secondary reference, to address an admitted deficiency of the primary obviousness reference, Bartorelli '497, namely that the reference does not discloses complement components and/or complement active fragments encapsulated in particles. However, this deficiency is remedied by the disclosures of Song '288 directed to the use of porous polymer microcapsules for delivery of an encapsulated active component, wherein the polymer is PLGA, as taught by Gentile (2014). As for motivation to so modify the teachings of the primary reference, Song '288 explicitly discloses that the porous polymer microspheres enable drugs to be slowly released, and that a desired amount of drug can be delivered to a diseased site for a prolonged time, and excellent regeneration effects can be directly expressed in soft tissues, and side-effects can be prevented because the microspheres are made of a biodegradable material (see ¶[0020]). Gentile (2014) discloses the desirable properties of PLGA in that the degradation rates of PLGA can be influenced by a number different parameters, including molecular weight (by increasing the molecular weight of conventional PLGA's from 10 - 20 to 100 kDa, degradation rates were extended to a range of from several weeks to several months), and by the ratio of GA to LA (PLGA's with a higher content of LA degrade more slowly, allowing for optimized control of degradation rates (see p. 3645, 1st para.). Thus, Song ‘288 provides the motivation to encapsulate the active components in porous polymer microcapsules, and Gentile (2014) provides the motivation to use PLGA as the encapsulating polymer, the microcapsules dispersed throughout the collagen matrix of Bartorelli ‘497.
The Examiner further notes that Applicants’ argument with respect to Song ‘288 ignores the disclosures of Bartorelli ‘497 that teach complement components and/or complement active fragments dispersed in a porous polymer [collagen] scaffold. Why would one of ordinary skill in the relevant art abandon the teachings of the primary reference (or, at least, ignore its teachings related to a collagen matrix in which the active components are dispersed), to adopt an isolated teaching of one of the secondary references rather than using that teaching to effectively modify the primary reference. In this manner, Applicants are, in effect, arguing against the references taken individually, and not to what the cited references, taken as a whole, would teach or suggest to one of ordinary skill in the art. In this regard, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this regard, Applicants further argue that “none of Bartorelli, Gentile, or Song discloses nor suggests particles which are dispersed in a three-dimensional matrix.” Applicants err in that the rejection rests, not on what each (“none of”) reference teaches, but on what the cited references, taken as a whole, would teach or suggest to one of ordinary skill in the art in combination. Thus, these teachings of the cited references lead one of ordinary skill in the art to complement active fragments dispersed in a collagen matrix (Bartorelli ‘497), where the complement active fragments are encapsulated in polymer microspheres (Song ‘288), and the polymer of the microspheres is PLGA (Gentile (2014).
Applicants argue that “the technical effect of encapsulating complement component and/or a complement active fragment in particles is that the release of the complement component and/or complement active fragment is more controlled over time and still under an active form: the complement component and/or the complement active fragment remains active longer (especially, for 7 days) despite its short half-life in vivo,” citing to disclosure in their specification for support. However, it is clear from the teachings of Gentile (2014) that selection of PLGA as the encapsulating polymer is motivated by the desire to control the rate of degradation of the microspheres in order to effectively tailor release of the active from the microspheres.
Consequently, based on the above discussion, Applicants’ arguments are unpersuasive, and claims 16 - 18 and 22 - 29 stand rejected pursuant to 35 U.S.C. § 103.
NO CLAIM IS ALLOWED.
CONCLUSION
Any inquiry concerning this communication or any other communications from the examiner should be directed to Daniel F. Coughlin whose telephone number is (571)270-3748. The examiner can normally be reached on M-F 8:30 am - 5:30 pm.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, David J Blanchard, can be reached on (571)272-0827. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/-interviewpractice.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANIEL F COUGHLIN/
Examiner, Art Unit 1619
/DAVID J BLANCHARD/ Supervisory Patent Examiner, Art Unit 1619
Prosecution Insights