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 .
DETAILED ACTION
Claims 1-22 and 24 are pending in the Claim Set filed 1/15/2026.
Claim 23 has been cancelled.
Independent Claim 10 has been amended to delete the recitation: having a pore size of between about 300 am and 1000 μm.
Claim 24 is newly added to recite: The claim scaffold 10, wherein the plurality has a pore size of between about 300 μm and 1000 μm.
This limitation: plurality have a pore size of between about 300 μm and 1000 μm, was previously recited in claim 10 in Claim Set filed 2/4/2025.
Applicants elected of Group II: claims 10-23. in the reply filed on 9/15/23. Applicant’s elected species: methacrylate monomer: 1,4-budanediol-dimethacrylate (claims 10, 11, 13, 14, 15, 19 and 20); ratio between methacrylate monomer and thiol-containing macromer is 60:40 (claim 19); bioactive agent is an Arginine-Glycine-Aspartate peptide (claims 14, 15); and formulation of scaffolding is a bone graft (claim 20). Herein, the species election for a thiol containing mercaptopropionate: pentaerythritol tetrakis (3-mercaptopropionate) is extended to include trimethylolpropane tris (3-mercaptopropionate) (i.e., 3-mercaptopropionate) (Specification: para. [0081]): extended species now applies to claim 24 (New).
Claims 1-9 of Group I remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 12, 16-18, 21 and 22 remain withdrawn as a result of Applicant’s species election filed 9/15/2023.
Herein, claims 10, 11, 13, 14, 15, 19, 20 and 24 are for examination to the extent that they read on the elected species.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/04/2025 has been considered by the examiner and an initialed copy of the IDS is included with the mailing of this office action.
Withdrawn Rejections
The rejection of claim 19 is 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the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention is withdrawn in view of the claim amendments. Applicants’ arguments are moot in view thereof.
The rejection of claims 10, 11, 13, 19 and 20 under 35 U.S.C. 103 as being unpatentable over Dikici et al (Thiolene- and Polycaprolactone Methacrylate-Based Polymerized High Internal Phase Emulsion (PolyHIPE) Scaffolds for Tissue Engineering, Biomacrolecules, p.720, 2021, Nov.) [Dikici] in view of Dhavalikar et al (Engineering Toolbox for Systematic Design of PolyHIPE Architecture, p.1479 (1-18 herein), May, 2021, of record) [Dhavalikar], Lumesky et al (Biodegradable Porous Polymers through Emulsion Templating, Macromolecules p.1627, 2009) [Lumesky], Grieber et al (WO2020/016343, IDS filed 10/20/2022) [Grieber] and Geven et al (Sulfur-based oxidation-responsive polymers. Chemistry, (chemically selective) responsiveness and biomedical applications, European Polymer Journal March, 2021, of record) [Geven], Loh et al (Three-Dimensional Scaffolds for Tissue Engineering Applications: Role of Porosity and Pore Size; Tissue Engineering, p.485. Part B, V19, #6, 2013) [Loh] and Dabrowski et al (Formulation and polymerization of foamed 1,4-BDDMA-in-water emulsions, RSC Adv., p.8717, 2020) [Dabrowski] is withdrawn in view of the claim amendments. Applicants’ arguments are moot in view thereof.
New Grounds of Rejection necessitated by Claim Amendments.
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 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(s) absent any evidence to the contrary. Applicant is advised of the obligation under 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 10, 11, 13, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Whitely et al (Prevention of Oxygen Inhibition of PolyHIPE Radical Polymerization Using a Thiol-Based Cross-Linker, ACS Biomaterials Science & Engineering, Jan. 2017, p.409) [Whitely] in view of Dhavalikar et al (Engineering Toolbox for Systematic Design of PolyHIPE Architecture, p.1479, May, 2021, of record) [Dhavalikar]
Claim Interpretation
Independent claim 10 recites the transitional term comprising, is open-ended and does not exclude additional, unrecited elements or method steps. See, e.g. Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Dependent claims 11, 13, 14, 15, 19 and 20 depend either directly or indirectly on independent claim 10. In the reply filed 2/4/2025, Applicants state that the remaining pending claims depend either directly or indirectly on the independent claim.
Regarding claims 10, 11, 13, 19 and 20,
Whiteley teaches polymerized high internal phase emulsions (polyHIPEs) are highly porous constructs currently under investigation as tissue engineered scaffolds. We previously reported on the potential of redox-initiated polyHIPEs as injectable bone grafts that space fill irregular defects with improved integration and rapid cure. Upon subsequent investigation, the radical-initiated cure of these systems rendered them susceptible to oxygen inhibition with an associated increase in uncured macromer in the clinical setting. In the current study, polyHIPEs with increased resistance to oxygen inhibition were fabricated utilizing a tetrafunctional thiol, pentaerythritol tetrakis(3-mercaptoproprionate) (elected species: thiol-containing monomer), and the biodegradable macromer, propylene fumarate dimethacrylate (methacrylate monomer) increased concentrations of the tetrathiol additive provided improved oxygen resistance as confirmed by polyHIPE gel fraction while retaining the requisite rapid cure rate, compressive properties, and pore architecture for use as an injectable bone graft. Additionally, thiol-methacrylate polyHIPEs exhibited increased degradation under accelerated conditions and supported critical markers of human mesenchymal stem cell activity. In summary, we have improved upon current methods of fabricating injectable polyHIPE grafts to meet translational design goals of improved polymerization kinetics under clinically relevant conditions without sacrificing key scaffold properties (Abstract; Fig. 1, p.410; also See chemical structures below (Abstract; Fig. 1, p.410)).
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Whiteley teaches the utilization of radical mediated chain-growth polymerization of methacrylate-capped macromers in our scaffold design renders susceptible to oxygen inhibition (i.e., polymeric scaffold comprises sulfide linkages configured to sequester reactive oxygen species molecules). Under oxygen-rich conditions, high levels of initiating and propagating radicals are scavenged and converted to peroxy radicals. To evaluate the potential of our system in orthopedic applications, we assessed the effects of tetrathiol concentration on pore architecture, compressive modulus, and yield strength (left col., p.410; p.411: Scaffold Chraterization; Compressive testing; Accelearted Degradation in Vitro; See entire document). Whiteley teaches this work aims to highlight the strong potential of thiol-methacrylate polyHIPEs to serve as rapid-curing injectable bone grafts that retain desirable properties when applied under physiological conditions (top right col., p.410). Further, Whiteley teaches PFDMA/tetrathiol polyHIPE compressive modulus and yield strength were assessed to ensure that these polyHIPEs retained appropriate compressive mechanical properties for use as bone grafting materials (p.414, right col.; Fig. 6). Conclusions at p.417): This study demonstrates the potential of thiol-methacrylate polyHIPEs to serve as an injectable bone graft with improved resistance to oxygen inhibition. Incorporation of tetrathiol monomer (i.e., (thiol-containing monomer) provided more rapid and complete network formation in the presence of oxygen with minimal impact on compressive modulus, yield strength, and pore architecture.
Whiteley differs from the claims in that the document does not teach that the methacrylate monomer is 1, 4-butanediol dimethacrylate (elected species: recited in claim 11); wherein said scaffold has a degradation rate which is complementary to the rate of bone healing.
However, Dhavalikar cures the deficiencies.
Dhavalikar teaches the objective of this study was to generate a framework for the rational design of polyHIPE architectures using a systematic study of the relative effects of emulsion variables on pore architecture. Dhavalikar teaches different macromers were chosen to provide a design space for this evaluation that include: 1,4 butanediol dimethacrylate (BDMA) and propylene fumarate dimethacrylate (PFDMA) (described above). The effect of surfactant oncentration (5–20%), mixing speed (500–2000 RPM), macromer molecular hydrophobicity (logP, 1.9–4.4) and macromer viscosity (~6–170 cP) on the resulting polyHIPE architecture was characterized, including emulsion rheology, stability studies, cure time and polyHipe architecture.
Results And Discussion: PFDMA had a substantially higher viscosity (171.2 cp) as compared to BDMA (5.9 cP); Pore size decreased with increasing surfactant: PFDMA pore size displayed a greater reduction in pore size than BDMA *Section 3.1, pp.6-7); BDMA and PFDMA maintained similar trend in decreasing pore with increased mixing speed (Section 3.2, p8); molecular hydrophobicity for BDMA and PFDMA provided a similar range with LogP in the range of 2-4; Diluent effects on PolyHIPE Archictecture (Section 3.5, p.12): increased dilution with toluene resulted in a greater than 10-fold decrease in viscosity of PFDMA which had the highest macromer viscosity, wheres BDMA had a with a lower starting viscosity had had a less pronounced effect on dilution: (at 30 wt% Toluene) PFDMA provide a pore size of about 18 um, whereas BDMA had a pore size at about 142 um (Table 2, p.13; Figure 9), thus, the average pore size for PFDMA remained small compared to BDMA; Effect of architecture of polyHIPE formation with reactive diluent: 1,4-butanedithiol (BDT): Fumarate thiol-base reactivity was greater for fumarate than methacrylate, but PFDMA lacked spherical structure, whereas BDMA maintained its spherical structure. Moreover, PFDA provides a significantly higher viscosity about 149 cP (at 20 mol% reactive diluent) than BDMA of about 4.3 cP (See Table 3, p.15).
Accordingly, Dhavalikar teaches polymerization of high internal phase emulsions (polyHIPEs) for the production of high porosity materials using 1.4- butanediol dimethacrylate (BDMA) (Abstract; p.3, 2nd para.; Table 1, p.6; See entire document). Dhavalikar teaches that low viscosity macromers, e.g., DBMA, demonstrated an increase in pore size and distribution with increased time to cure (p.9, Section 3.4; Figure 7). Dhavalikar teaches polyHIPE pore size can be tuned by varying surfactant concentration and emulsification speed to control initial droplet size, wherein at 500 RPM, BDMA produced pore sizes comprising 200 µm (p.8, middle; Figure 5). Moreover, Dhavalikar teaches that 1,4- butanediol dimethacrylate (BDMA) (reactive methacrylate monomer at about 30% molar ratio) when reacted with butanediol dithiol (Thiol) maintained spherical pore structure as the reactivity of the thiol with the methacrylate ends group are slow to react slow, whereas PFDMA lacked spherical structure (p.3, middle; p.6, Table 1; Figure 2; p.15, bottom; See entire document).
One skilled in the art would have recognized that 1.4- butanediol dimethacrylate (BDMA) (methacrylate monomer) when reacted with butanediol dithiol (reactive Thiol) maintained its spherical pore structure, whereas PFDMA lacked spherical structure after reacting with reactive thiol macromer. Moreover, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention that 1.4- butanediol dimethacrylate (BDMA) was suitable for use in polyHIPEs to produce high porosity materials. Thus, one skilled in the art would have recognized the benefit of using 1.4- butanediol dimethacrylate (BDMA) in place of PFDMA because especially because it maintains it spherical structure when reacted with a reactive thiol monomer, has low viscosity and can be tuned to provide increased porosity by increasing mixing speed for fabrication, whereas mixing speed has little effect on the pore size of PFDMA (Table 2). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Furthermore, Dhavalikar teaches polymerization that the thiol monomer was used at about 30% molar ratio (p.14, middle). Thus, it would have been well within the purview of one of ordinary skill in art to optimize the molar ratio of 1.4- butanediol dimethacrylate (BDMA) (methacryl monomer) to pentaerythritol tetrakis(3-mercaptoproprionate) (thiol containing monomer) to about molar ratio 70:30 having a reasonable expectation of success. The normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine the optimal molar ratio needed to achieve a desired result. Optimization of parameters is a routine practice that would be obvious to a person of ordinary skill in the art to employ and reasonably expect success. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955) & MPEP 2144.05.
Moreover, the oxidatively responsive polymeric scaffold as taught by Whiteley and Dhavalikar is structurally and chemically indistinguishable from the claimed scaffold, so that it would necessarily follow that polymeric scaffold as taught by the Whiteley and Dhavalikar, as a whole, would be a scaffold having a degradation rate which is complementary to the rate of bone healing. This property would be the natural result of the combination of the prior art elements. PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (quoting In re Oelrich, 666 F.2d 578,581 (CCPA 1981) (when the limitation at issue is the 'natural result' of the combination of prior art elements).
A recitation of the intended use, as recited in claim 10: for promoting bone fusion, must result in a structural difference between the claimed invention and the prior art to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Moreover, the preamble is generally not accorded any patentable weight where it merely recites the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the 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). If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction (MPEP 2111.02 II). Since the prior art teaches an oxidatively responsive polymeric scaffold that is structurally the same as those claimed, it must be at least capable of performing the intended use.
All the claimed elements herein are known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention, where there is no unobvious distinction between the structural and functional characteristics of the claimed polymeric scaffold and the polymeric scaffold of the prior art.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to provide instantly claimed oxidatively responsive polymeric scaffold and one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the claimed invention, as a whole, would have been obvious to one of ordinary skill as evidenced by the Whiteley and Dhavalikar, as a whole.
Claims 14 and 15 are rejected under pre-AIA 35 U.S.C. 103 as being unpatentable over Whitely et al (Prevention of Oxygen Inhibition of PolyHIPE Radical Polymerization Using a Thiol-Based Cross-Linker, ACS Biomaterials Science & Engineering, Jan. 2017, p.409) [Whitely] in view of Dhavalikar et al (Engineering Toolbox for Systematic Design of PolyHIPE Architecture, p.1479, May, 2021, of record) [Dhavalikar] as applied to claims 10, 11, 13, 19 and 20 above and further in view of Liska et al (WO2013052328, of record).
The teachings of Whiteley and Dhavalikar, as a whole, are described above.
Whiteley and Dhavalikar differ from the claims in that the documents do not teach Arginine-Glycine-Aspartate (RGD) peptide (bioactive agent) is coupled to a thiolated group. Although, Grieber generally teaches that thiol functional group is coupled to a peptide by formation of disulfide bonds (p.33).
However, Liska cures the deficiency.
Liska teaches biodegradable, biocompatible, cross-linked polymers [0007], wherein vinyl ester monomers and/or vinylcarbonate monomers are polymerized with multifunctional thiols, e.g., pentaerythritol tetrakis (3-mercaptopropionate [0010]. Further, Liska teaches that natural and synthetic biological cell coupling agents such as RGD peptides (i.e., Arginine-Glycine-Aspartate) are attached to the surface of the polymer structure to provide desired properties [0072].
One of ordinary skill in the art would have recognized the benefit of attaching a biologically active coupling agent to an oxidatively responsive polymeric scaffold and would have been motivated to do so to impart additional physiologically beneficial properties such as targeting selective cells having a reasonable expectation of success.
Thus, it would have been obvious for one of ordinary skill in the art to provide instantly claimed invention and one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the Whiteley, Dhavalikar and Liska, as a whole.
Response to Arguments
Applicants argue that, in view of the amendments submitted herewith, Applicant's claim 10 is entitled to the earliest available priority date of May 5, 2021. As the Examiner concedes in the Office Action, paragraph [0026] of U.S. Provisional Application No. 63/184,740, filed May 5, 2021, states that the scaffold disclosed therein "is porous with homogenous pores ranging from 100 to 500 microns." As such, the May 5, 2021 filing provides support for a "polymeric scaffold for promoting bone fusion, comprising ... a plurality of pores," as recited in Applicant's amended claim 10. Because claim 10 as amended is entitled to a priority date of May 5, 2021, Dikici is not prior art to Applicant's claimed invention and cannot be applied to reject Applicant's claims 10-22 under 35 U.S.C. § 103. The earliest publication date of Dikici is the online publication made available on November 3, 2021, which is nearly six months after Applicant's earliest priority date. Dikici therefore cannot be used to support a rejection under 35 U.S.C. § 103, because it was published after the earliest priority date to which Applicant's claims are entitled. Moreover, Dhavalikar, Lumesky, Grieber, Geven, Loh, and/or Dabrowski alone, (i.e., without Dikici) are sufficient to support a rejection of Applicant's claim 10, at least because neither reference discloses or suggests a polymeric scaffold comprising an effective amount of a methacrylate monomer and an effective amount of a thiol-containing macromer as recited in Applicant's claims.
For at least these reasons, Applicant's independent claim 10, and the claims dependent thereon, are nonobvious over Dhavalikar, Lumesky, Grieber, Geven, Loh, and Dabrowski.
Applicant’s arguments have been fully considered and are persuasive, the rejection of claims 10, 11, 13, 19 and 20 under 35 U.S.C. 103 as being unpatentable over Dikici et al (Thiolene- and Polycaprolactone Methacrylate-Based Polymerized High Internal Phase Emulsion (PolyHIPE) Scaffolds for Tissue Engineering, Biomacrolecules, p.720, 2021, Nov.) [Dikici] in view of Dhavalikar et al (Engineering Toolbox for Systematic Design of PolyHIPE Architecture, p.1479 (1-18 herein), May, 2021, of record) [Dhavalikar], Lumesky et al (Biodegradable Porous Polymers through Emulsion Templating, Macromolecules p.1627, 2009) [Lumesky], Grieber et al (WO2020/016343, IDS filed 10/20/2022) [Grieber] and Geven et al (Sulfur-based oxidation-responsive polymers. Chemistry, (chemically selective) responsiveness and biomedical applications, European Polymer Journal March, 2021, of record) [Geven], Loh et al (Three-Dimensional Scaffolds for Tissue Engineering Applications: Role of Porosity and Pore Size; Tissue Engineering, p.485. Part B, V19, #6, 2013) [Loh] and Dabrowski et al (Formulation and polymerization of foamed 1,4-BDDMA-in-water emulsions, RSC Adv., p.8717, 2020) [Dabrowski] is withdrawn in view of the claim amendments. Applicants’ arguments are moot in view thereof.
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Regarding claim 24 (New):
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e)as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure of the prior-filed applications, Application No. 63/184,740 and 63/303,208, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In particular, the disclosure of these provisional applications fails to describe the full scope as instantly claimed. For instance, provisional applications: 63/184,740 and 63/303,208, fail to provide for the following: pore size of between about 300 µm and 1000 µm, as recited in Claim 24 (New). Provisional Application 63/184,740 states: para. [0026]: pores ranging from 100 to 500 microns (100 to 500 µm) and Provisional Application 63/302,208 states: para. [0027]: pores ranging from 100 to 500 microns (100 to 500 µm). The claimed range of a pore size of between 300 µm -1000 µm encompasses pore sizes outside the range provided by the provisional applications because the provisional applications stop at 500 microns (500 µm). Accordingly, claim 24 is not afforded the prior art date(s): 63/184,740 filing date 05/05/2021; 63/302,208 filing date 01/20/2022. Therefore, the effective filing date of claim 24 for the purpose of prior art is the filing date of instant invention 05/04/2022.
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 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(s) absent any evidence to the contrary. Applicant is advised of the obligation under 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
Claim 24 (New) is rejected under 35 U.S.C. 103 as being unpatentable over Dikici et al (Thiolene- and Polycaprolactone Methacrylate-Based Polymerized High Internal Phase Emulsion (PolyHIPE) Scaffolds for Tissue Engineering, Biomacrolecules, p.720, 2021, Nov., of record) [Dikici] in view of Dhavalikar et al (Engineering Toolbox for Systematic Design of PolyHIPE Architecture, p.1479 (1-18 herein), May, 2021, of record) [Dhavalikar], Lumesky et al (Biodegradable Porous Polymers through Emulsion Templating, Macromolecules p.1627, 2009, of record) [Lumesky], Grieber et al (WO2020/016343, IDS filed 10/20/2022) [Grieber] and Geven et al (Sulfur-based oxidation-responsive polymers. Chemistry, (chemically selective) responsiveness and biomedical applications, European Polymer Journal March, 2021, of record) [Geven], Loh et al (Three-Dimensional Scaffolds for Tissue Engineering Applications: Role of Porosity and Pore Size; Tissue Engineering, p.485. Part B, V19, #6, 2013, of record) [Loh] and Dabrowski et al (Formulation and polymerization of foamed 1,4-BDDMA-in-water emulsions, RSC Adv., p.8717, 2020, of record) [Dabrowski].
Claim Interpretation
Independent claim 10 recites the transitional term comprising, is open-ended and does not exclude additional, unrecited elements or method steps. See, e.g. Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Dependent claims 11, 13, 14, 15, 19 and 20 depend either directly or indirectly on independent claim 10. In the reply filed 2/4/2025, Applicants state that the remaining pending claims depend either directly or indirectly on the independent claim. Specification at page 31 states: as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more").
Regarding claim 24,
Dikici teaches PolyHIPE Scaffolds. Dikici teaches highly porous emulsion templated polymers (PolyHIPEs) provide a number of potential advantages in the fabrication of scaffolds for tissue engineering and regenerative medicine. Porosity enables cell ingrowth and nutrient diffusion within, as well as waste removal from, the scaffold. The properties offered by emulsion templating alone include the provision of high interconnected porosity, and, in combination with additive manufacturing, the opportunity to introduce controlled multiscale porosity to complex or custom structures. Dikici teaches fibroblasts sit on the pores and spread over the walls of the PolyHIPE scaffold (Abstract; p.722, left col.; p.727, left col.; Figures 6-7; See entire document). Dikici teaches thiol-ene chemistry is a promising route to produce biodegradable photocurable PolyHIPEs for the fabrication of scaffolds using conventional or additive manufacturing methods. Dikici teaches three-arm PCL methacrylate (3PCLMA) was used in a PolyHIPE formulation. Biocompatibility of the PolyHIPEs was investigated using human osteosarcoma (bone cancer) cell line (MG-63) by DNA quantification assay, and developed PolyHIPEs were shown to be capable of supporting cell attachment and viability (Abstract). Particularly, Dikici teaches timethylolpropane tris (3-mercaptopropionate) (i.e., thiol containing macromer) and polycaprolactone (PCL) methacrylate (3PCLMA) (i.e., methacrylate monomer) based PolyHIPE materials are provided using photoinitiated thiolene click reaction (Abstract; Figure 1; Figure 2 (A); Section(s) 2.1 Materials and Methods; 2.2 Synthesis of 3PCLMA; 2.6 Preparation of PolyHIPE Scaffolds; Figure 2: 3-arm PCLMA). Particularly, Dikici teaches timethylolpropane tris (3-mercaptopropionate) and polycaprolactone (PCL) methacrylate (3PCLMA) having pore size between 100 µm and 500 µm (See Figure 5: (B; p.725): shown below,
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Thus, the pore size between 100 µm and 500 µm of the polymeric scaffold as taught by Dikici overlaps with the claimed scaffold having a pore size between about 300 µm and 1000 µm. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257,191 USPQ 90 (CCPA 1976); In re Woodruff, 91 9 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05.
Dikici teaches that ratio of the methacrylate monomer 3PLCMA to the thiol containing macromer: timethylolpropane tris (3-mercaptopropionate), was about 50:50 by weight (See Figure 5, p.725), which overlaps with the claimed ratio. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257,191 USPQ 90 (CCPA 1976); In re Woodruff, 91 9 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05. Moreover, Dikici teaches that the degrees of methacrylation of 3PCLMA can be controlled using various parameters such as the ratio of methacrylation agents and prepolymer (PCL) and the reaction time of methacrylation. Particularly, Dikici explicitly teaches that the degree of methacrylation can be increased up to 100% for specific applications, such as bone tissue-engineering scaffolds (p.724). It would have been well within the purview of one of ordinary skill in art to optimize the ratio of methacrylate monomer to the thiol-containing macromer, e.g., 60:40 (recited in claim 19), to best achieve a desired goal wherein the polymer scaffold comprises sulfide linkages configured to sequester reactive oxygen species (ROS) in view of the teachings of the cited prior art references having a reasonable expectation of success. Optimization of parameters is a routine practice that would be obvious to a person of ordinary skill in the art to employ and reasonably expect success. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955) & MPEP 2144.05. It would have been customary for an artisan of ordinary skill to determine the optimal ratio of methacrylate to thiol to best achieve a desired result.
Dikici differs from the claims in that the document does not teach that the methacrylate monomer is 1, 4-butanediol dimethacrylate (elected species: recited in claim 11); wherein said polymeric scaffold comprises sulfide linkages configured to sequester reactive oxygen species molecules; and wherein said scaffold has a degradation rate which is complementary to the rate of bone healing.
However, Dhavalikar, Lumesky, Grieber, Geven, Loh and Dabrowski, as a whole.
Dhavalikar teaches polymerization of high internal phase emulsions (polyHIPEs) for the production of high porosity materials using 1.4- butanediol dimethacrylate (BDMA) (Abstract; p.3, middle; Table 1, p.6; See entire document). Dhavalikar teaches that low viscosity macromers, e.g., DBMA, demonstrated an increase in pore size and distribution with increased time to cure (p.9, Section 3.4; Figure 7). Dhavalikar teaches polyHIPE pore size can be tuned by varying surfactant concentration and emulsification speed to control initial droplet size, wherein at 500 RPM, BDMA produced pore sizes comprising 200 µm (p.8, middle; Figure 5). Moreover, Dhavalikar teaches that 1,4- butanediol dimethacrylate (BDMA) (methacrylate monomer) when reacted with butanediol dithiol (Thiol) maintained spherical pore structure as the reactivity of the thiol with the methacrylate ends group are slow to react slow (p.3, middle; p.6, Table 1; Figure 2; p.15, bottom).
Thus, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention that 1.4- butanediol dimethacrylate (BDMA) was suitable for use in polyHIPEs to produce high porosity materials. Moreover, one skilled in the art would have recognized that 1.4- butanediol dimethacrylate (BDMA) (methacrylate monomer) when reacted with butanediol dithiol (Thiol) maintained spherical pore structure as the reactivity of the thiol because of the methacrylate ends group are slow to react slow in view of the teachings of Dhavalikar.
On the other hand, Lumesky teaches that when polycaprolactone (PCL) is added to highly porous, emulsion polymers, polyHIPE, polycaprolactone destabilizes the HIPE because the PCL polymer content is reduced by degradation of the polymer ((Abstract; p.1632, right col.). Lumesky teaches the addition of PCL destabilizes the HIPE, yielding a partial collapse of the porous structure (Abstract); See entire document). Lumesky teaches PCL is a hydrolytically degradable polyester (p.1630, right col.)
Thus, one skilled in the art would have recognized the disadvantages of providing a scaffold for promoting bone fusion that comprises polycaprolactone (PCL) methacrylate because it is a hydrolytically degradable polyester that is susceptible to degradation by hydrolysis as taught by Lumesky teaches.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to replace the 3PCLMA methacryl monomer with 1,4-butanediol dimethacrylate (BDMA) (methacrylate monomer) to avoid hydrolytic degradation of the polymeric scaffold having a reasonable expectation of success. BDMA and BDMA has been shown to maintain its spherical pore structure when reacted with butanediol dithiol (Thiol).
The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See MPEP 2144.07.
Grieber teaches that after polymerization of terminal thiol functional groups with a monomer comprising carbon-carbon double bonds (in terminal alkene functional groups) some of thiol functional groups (e.g., -S-, sulfur atoms of thioether) remain in the polymer after completion of the thiol-alkene reaction, in particular, on the surface of the polymer, and, that reaction conditions can be adjusted to provide thiol groups on the surface of the polymer (pp.25-26; 29; 59; claims 12-14; See entire document).
Geven teaches low-oxidation-state sulfur groups (thioethers, bis(alkylthio) alkenes, sulfoxides, thioketals, oligosulfides) to provide macromolecules (i.e., polymers) with responsivity to oxidizing conditions. Geven teaches that reactive oxygen species (ROS) (i.e., biologically relevant oxidants, ROS) at sufficiently low concentrations are essential for the healthy functioning of biological systems, but their overproduction is associated to a broad range of pathologies. Geven teaches providing thioethers in polymer structures to scavenge ROS in biomedical applications (Abstract; Section 3, pages 3-4; See entire document).
Along these lines, Loh teaches scaffolds to provide a suitable microenvironment for the incorporation of cells or growth factors to regenerate damaged tissues or organs (Abstract). Loh teaches that the porosity and pore size of 3D scaffolds have direct implications on their functionality during biomedical applications, wherein the network structure of the pores assists in guiding and promoting new tissue formation (p.485, left col.). Loh teaches the importance of having pore sizes greater than 300 mm for osteogenesis (i.e., bone formation) to occur (p.494). Accordingly, one skilled on the art would have been motivated to provide a scaffold for bone fusion having a pore size of about 300 µm.
Dabrowski teaches highly porous poly(1,4-BDDA) polymer foam provided using the monomer 1,4- butanediol dimethacrylate using emulsion templating, wherein the polymeric materials formed have pore diameters of 366 µm ± 91 µm (Abstract; p.6918, left col.). Dabrowski teaches polymer foams are used as scaffolds for the seeding and growing of cells (p.8917, left col.).
Moreover, the oxidatively responsive polymeric scaffold as taught by the cited references, as a whole, is structurally and chemically indistinguishable from the claimed scaffold, so that it would necessarily follow that polymeric scaffold as taught by the cited references, as a whole, would be a scaffold having a degradation rate which is complementary to the rate of bone healing. This property would be the natural result of the combination of the prior art elements. PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (quoting In re Oelrich, 666 F.2d 578,581 (CCPA 1981) (when the limitation at issue is the 'natural result' of the combination of prior art elements).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to provide an oxidatively responsive polymeric scaffold comprising a methacrylate monomer (1.4- butanediol dimethacrylate) and a thiol-containing macromer (timethylolpropane tris (3-mercaptopropionate) in a 60:40 ratio to promote bone fusion (i.e., intended use) in view of the teachings of the cited references. One skilled in the art would have been motivated to so in order to provide polymeric scaffold having a pore size in in the range between 100 µm and 500 µm since it is known in the prior art that scaffolds having large pore sizes is important for osteogenesis (bone formation).
All the claimed elements herein are known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention, where there is no unobvious distinction between the structural and functional characteristics of the claimed polymeric scaffold and the polymeric scaffold of the prior art.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to provide instantly claimed oxidatively responsive polymeric scaffold and one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the claimed invention as a whole would have been obvious to one of ordinary skill as evidenced by the cited references, as a whole.
Response to Arguments
Applicants argue that, in view of the amendments submitted herewith, Applicant's claim 10 is entitled to the earliest available priority date of May 5, 2021. As the Examiner concedes in the Office Action, paragraph [0026] of U.S. Provisional Application No. 63/184,740, filed May 5, 2021, states that the scaffold disclosed therein "is porous with homogenous pores ranging from 100 to 500 microns." As such, the May 5, 2021 filing provides support for a "polymeric scaffold for promoting bone fusion, comprising ... a plurality of pores," as recited in Applicant's amended claim 10. Because claim 10 as amended is entitled to a priority date of May 5, 2021, Dikici is not prior art to Applicant's claimed invention and cannot be applied to reject Applicant's claims 10-22 under 35 U.S.C. § 103. The earliest publication date of Dikici is the online publication made available on November 3, 2021, which is nearly six months after Applicant's earliest priority date. Dikici therefore cannot be used to support a rejection under 35 U.S.C. § 103, because it was published after the earliest priority date to which Applicant's claims are entitled. Moreover, Dhavalikar, Lumesky, Grieber, Geven, Loh, and/or Dabrowski alone, (i.e., without Dikici) are sufficient to support a rejection of Applicant's claim 10, at least because neither reference discloses or suggests a polymeric scaffold comprising an effective amount of a methacrylate monomer and an effective amount of a thiol-containing macromer as recited in Applicant's claims.
For at least these reasons, Applicant's independent claim 10, and the claims dependent thereon, are nonobvious over Dhavalikar, Lumesky, Grieber, Geven, Loh, and Dabrowski.
Regarding claim 24:
Applicant’s arguments have been fully considered but they are not persuasive, because the claimed range of a pore size of between 300 µm -1000 µm encompasses pore sizes as recited in claim 24 (New) are outside the range provided by the provisional applications because the provisional applications stop at 500 microns (500 µm). Accordingly, claim 24 is not afforded the prior art date(s): 63/184,740 filing date 05/05/2021; 63/302,208 filing date 01/20/2022.
Therefore, the effective filing date of claim 24 for the purpose of prior art is the filing date of instant invention 05/04/2022.
For a claim in a nonprovisional application to get the earlier filing date of a provisional application, the provisional application must provide adequate written description support for that claim. Therefore, claim 24 loses its entitlement to the provisional priority date. Its effective filing is the actual filing date of the nonprovisional application (Instant Application).
Further, Applicants state that new claim 24 is added. Applicants argue that support for this amendment (newly filed claim 24) can be found throughout Applicant's specification as originally filed. No new matter has been added.
Applicants are reminded that although the PTO has the initial burden of presenting evidence or reasons why a person skilled in the art would not recognize in the disclosure a description of the invention defined by the claims, when filing an amendment an applicant should show support in the disclosure for new or amended claims (Newly filed claim 24). See MPEP 714.02 and 2163.06 ("Applicant should therefore specifically point out the support for any amendments made to the disclosure.").
Applicants fail to provide arguments directed specifically to claim 24. Because Applicant did not distinctly and specifically point out the supposed errors in the Rejections and Response to Arguments made by the Office in Non-Final Rejection filed 10/17/2025, the Rejections are herein made again in regards to Instant claim 24 (New) and the arguments are maintained in their entirety.
Conclusions
No claim is allowed.
Applicants’ amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicants are reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/T.W./Examiner, Art Unit 1619
/SARAH ALAWADI/ Primary Examiner, Art Unit 1619
