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
Status of the Claims
Receipt of Applicants’ Response, filed 5 August 2025, is acknowledged. No claims are amended therein. Upon finalization and entry of the Restriction/Election Requirement (see below), claims 1 – 21 will be available for substantive examination.
Response to Restriction/Election Requirement
The Examiner acknowledges Applicants’ election, without traverse, of the claims of Group I, claims 1 – 21, in the Response filed on 5 August 2025.
Response to Restriction/Election
The Examiner acknowledges Applicants’ election, without traverse, of the invention of Group I, claims 1 - 21, in the Response filed on 5 August 2025. The Examiner further acknowledges Applicants election of osteogenic glycine-histidine-lysine from the genus of peptide; tetrahydrofurfuryl methacrylate from the genus of binder; and hydroxyapatite from the genus of ceramic.
Claims 22 – 27 are hereby withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1 – 21 are available for substantive examination to the extent that osteogenic glycine-histidine-lysine is the peptide; tetrahydrofurfuryl methacrylate is the binder; and hydroxyapatite is the ceramic material.
Failure to Comply with Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d), see ¶¶[0074] and [0090]. Applicants’ cooperation is requested in reviewing the entire disclosure for additional sequences that require sequence identifiers or sequence compliance.
Required response – Applicants must provide:
an amendment to the specification inserting the required sequence identifiers, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); and
a statement that the amendment contains no new matter.
See 37CFR §1.821-1.825.
Rejections Pursuant to 35 U.S.C. § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections pursuant to this section made in this Office Action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 13 are rejected pursuant to 35 U.S.C. § 102(a)(1) as being anticipated by US 2018/0296343 A1 to Wei, G., published 18 October 2018, identified on the Information Disclosure Statement (IDS) filed 15 August 2022, cite no. 2 (USPATAPP) (“Wei ‘343”).
Wei ‘343 discloses computer implemented methods for producing a porous implant that include obtaining a 3-D image of an intended tissue repair site, generating a 3-D model of the porous implant based on the 3-D image of the intended repair site (see Abstract), wherein the implant is a layered 3-D printed porous implant, the implant comprising a first layer of implant material mixed with porogen, a second layer of implant material mixed with porogen, the second layer disposed on the first layer, a third layer of implant material mixed with porogen, the third layer disposed on the second layer, each layer repeating until the 3-D printer has completed the porous implant (see ¶[0012]), wherein the implants are used to treat bone defects in a patient in need thereof by implantation at the tissue repair site (see ¶[0013]), wherein the intended tissue repair site is a bone repair site, an osteochondral defect site, an articular cartilage defect site or a combination thereof, the tissue including soft tissue, muscle, ligaments, tendons, cartilage, and hard tissue as found in bones (see ¶[0176]), wherein the implant material comprises a carrier material and a bone material, including a natural material, a biodegradable carrier, and a growth factor (see ¶[0194]), wherein the biodegradable material comprises a biodegradable polymer (see ¶[0195]), and wherein the implant material further comprises inorganic polymers, such as hydroxyapatite, calcium HA, carbonated calcium HA, beta-tricalcium phosphate (beta-TCP), alpha-tricalcium phosphate (alpha-TCP), and other calcium phosphates (see ¶[0215]), the particles present at relative loadings of 10 – 95% wgt (see ¶[0230]), and with particle sizes in the range of 25 to about 4000 µm (see ¶[0133]), wherein the matrix of the porous implant may be seeded with harvested bone cells and/or bone tissue, such as for example, cortical bone, autogenous bone, allogenic bones and/or xenogenic bone (see ¶[0234]), wherein the carrier material constitutes an ink that dries, is cured, or reacts, to form a porous, biodegradable, biocompatible material that is osteoinductive and has a load bearing strength comparable to bone, (see ¶[0237]), and wherein the material comprises a bioerodible polymer and a synthetic ceramic (see ¶[0244]).
Consequently, Wei ‘343 discloses each and every limitation of the claims at issue, rendering them anticipated pursuant to 35 U.S.C. § 102(a)(1).
Claims 1 and 13 are rejected pursuant to 35 U.S.C. § 102(a)(1) as being anticipated by US 2003/0114936 A1 to Sherwood, J., et al., published 19 June 2003, identified on the Information Disclosure Statement (IDS) filed 15 August 2022, cite no. 1 (USPATAPP) (“Sherwood ‘936”).
Sherwood ‘936 discloses composite implantable devices that can be used to select or promote attachment of specific cell types on and in the devices prior to and/or after implantation, wherein the devices are made using solid free form processes, especially three-dimensional printing processes (see ¶[0019]), wherein the resulting device is a fully resorbable synthetic scaffold in a cell-scaffold-based tissue engineering approach to repair articular defects, the devices being built one thin layer at a time (see ¶[0020]), wherein solid free-form fabrication methods are used to manufacture devices for tissue regeneration and for seeding and implanting cells to form organ and structural components, which can additionally provide controlled release of bioactive agents, and can be used with a variety of polymeric, inorganic and composite materials to create structures with defined compositions, strengths, and densities, using computer aided design (CAD) (see ¶[0033]), wherein the printer “ink” comprises polycaprolactone (PCL) with 45 – 75 µm particle sizes (see ¶[0051]), wherein the device matrix can comprise biologically active materials, including osteoconductive materials such as hydroxyapatite (HA) (see ¶[0104]; see also, ¶[0136]), wherein resorbable polymers of the polyester family, such as (poly(Ɛ-caprolactone) (PCL), are preferred, largely because their degradation rates can be tailored to match the rate of new tissue formation (see ¶[0139]), and wherein either exogenously added cells or exogenously added factors may be added to the implant before or after its placement in the body, including autograft cells derived from the patient's tissue (see ¶[0147]).
Consequently, Sherwood ‘936 discloses each and every limitation of the claims at issue, rendering them anticipated pursuant to 35 U.S.C. § 102(a)(1).
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 1 – 7 and 9 - 11 are rejected pursuant to 35 U.S.C. § 103, as being obvious over Sherwood ‘936, in view of Guo, J., et al., J Biomed Mater Res. 108A: 684 – 693 (2019) (“Guo (2019)”), Chen, T., et al., e-Polymers 15(1): 3 – 13 (2015) (“Chen (2015)”), Boren, B., et al., J. AM. CHEM. SOC. 130: 8923 – 8930 (2008) (“Boren (2008)”), and US 2019/0359766 A1 to Becker, M., et al., published 28 November 2019, identified on the IDS filed 15 August 2022, cite no. 3 (USPATAPP) (“Becker ‘766”).
The Invention As Claimed
Applicants claim a method of making a biocompatible article comprising the steps of preparing a 3D-printable mixture, and depositing successive layers of the mixture in a predetermined pattern to form a porous biocompatible article, wherein the predetermined pattern comprises a porosity suitable for a bone or cartilage scaffold, wherein the step of preparing a 3D-printable mixture comprises conjugating an alkyne-terminated polymer to an osteogenic glycine-histidine-lysine peptide to form a peptide-containing composite, wherein the conjugating comprises mixing the alkyne-terminated polymer, the peptide, and a catalyst in an aqueous medium at a temperature of from 20 to 70 °C for a time of from 12 to 48 hours, wherein the alkyne-terminated polymer is alkyne-terminated poly(Ɛ-caprolactone), wherein the alkyne-terminated poly(Ɛ-caprolactone) has a molecular weight of from 4 to 50 kDa, wherein the catalyst is chloro(pentamethylcyclopentadienyI)(cycloocta-diene)ruthenium(II), wherein the method further comprises cell seeding of the biocompatible article, wherein the porosity of the article is from 60 to 85%, and wherein the article comprises pores with an average pore size of from 300 to 600 µm.
The Teachings of the Cited Art
Sherwood ‘936 discloses composite implantable devices having a gradient of materials, macroarchitecture, microarchitecture, or mechanical properties, that can be used to select or promote attachment of specific cell types on and in the devices prior to and/or after implantation, the gradient forming a transition zone in the device from a region composed of materials or having properties best suited for one type of tissue to a region composed of materials or having properties suited for a different type of tissue (see Abstract), wherein, in order to encourage cellular attachment and growth, the overall porosity of the device is important, with the individual pore diameter, or size, being an important factor in determining the ability of cells to migrate into, colonize, and differentiate while in the device, wherein pore sizes above 150 µm and a porosity of 50 to 90% are necessary for cell invasion of the carrier by bone forming cells (see ¶[0009]), wherein the devices are made using solid free form processes, especially three-dimensional printing processes (see ¶[0019]), wherein the resulting device is a fully resorbable synthetic scaffold, containing a cartilage-appropriate region and a bone-appropriate region, in a cell-scaffold-based tissue engineering approach to repair articular defects, the devices being built one thin layer at a time, which process allows for the production
of devices having almost arbitrary spatial distribution of composition and geometric features, and provides the capability to fabricate devices with biologically and anatomically relevant features (see ¶[0020]), wherein the device contains geometry, pores, and fluid communication channels that are conducive to cell migration, attachment, growth, and differentiation (see ¶[0029]), wherein solid free-form fabrication methods are used to manufacture devices for tissue regeneration and for seeding and implanting cells to form organ and structural components, which can additionally provide controlled release of bioactive agents, and can be used with a variety of polymeric, inorganic and composite materials to create structures with defined compositions, strengths, and densities, using computer aided design (CAD) (see ¶[0033]), wherein instructions for each layer of the devices are derived directly from a computer-aided design (CAD) representation of the component with the individual slices segments being joined to form a three-dimensional structure (see ¶[0048]), wherein, while the layers become hardened, or at least partially hardened, as each of the layers is laid down, once the desired final part configuration is achieved and the layering process is complete, it can be desirable that the form and its contents be heated or cured at a suitably selected temperature to further promote binding of the particles (see ¶[0053]), wherein manipulation of the printing parameters and component characteristics allow the design and fabrication of macroarchitecture, microarchitecture, and internal and surface characteristics (see ¶[0057]), wherein the printer “ink” comprises polycaprolactone (PCL) with 45 – 75 µm particle sizes (see ¶[0051]), wherein there is no limit as to the number of layers that can be constructed due to the material forming each layer being deposited by one or more depositors that can deposit specific compositions in specific places, with the individual compositions at specific locations within a layer having individual chemical compositions, such as different polymers, with different contents or concentrations of a porogen such as sodium chloride so that, when the porogen is eventually leached out, different porosities remain in the different locations, resulting in layers having compositional variation within the layers, and different porosities at different locations within an individual layer of the 3DP process (see ¶[0088]; see also, ¶[0115]), wherein the materials used in the manufacture of the devices are biocompatible, bioresorbable over periods of weeks or longer, and generally encourage cell attachment (see ¶[0096]), wherein the device matrix can comprise biologically active materials, including osteoconductive materials such as hydroxyapatite (HA) (see ¶[0104]; see also, ¶[0136]), wherein resorbable polymers of the polyester family, such as (poly(Ɛ-caprolactone) (PCL), are preferred, largely because their degradation rates can be tailored to match the rate of new tissue formation (see ¶[0139]), and wherein either exogenously added cells or exogenously added factors, including genes, may be added to the implant before or after its placement in the body, including autograft cells derived from the patient's tissue and have (optionally) been expanded in number by culturing ex vivo for a period of time before being reintroduced into the device (see ¶[0147]). The reference does not explicitly disclose a method of making a biocompatible article by 3D printing a mixture comprising an osteogenic peptide conjugated to an alkyne-terminated polymer, wherein the alkyne-terminated polymer is alkyne-terminated poly(Ɛ-caprolactone), the peptide is a GHK peptide, the method using chloro(pentamethylcyclopentadienyI)(cycloocta-diene)ruthenium(II) as a catalyst, or a method that uses an alkyne-terminated polymer with a molecular weight in the range of 4 to 50 kDa, or a method wherein the conjugation reaction is conducted at a temperature range of 20 to 70° C for a time from 12 to 4 hours, or a method wherein the printing step comprises extrusion of the mixture at a temperature of from 70 - 100° C. The teachings of Guo (2019), Chen (2015), Boren (2008), and Becker ‘766 remedy those deficiencies.
Guo (2019) discloses biofunctionalized, mesenchymal stem cell-laden hydrogels that can present in situ biochemical cues for either chondrogenesis or osteogenesis by simple click modification of a crosslinker with either cartilage-specific biomolecules or bone-specific biomolecules, such as a glycine-histidine-lysine (GHK) peptide, to selectively promote the desired bone- or cartilage-like matrix synthesis and tissue-specific gene expression, with effects that are dependent on both biomolecule selection and concentration (see Abstract), wherein bioconjugation strategies, which can utilize highly specific click chemistry, have emerged as a means of directly tethering biomolecules of interest to hydrogels for tissue engineering (see p. 684, 2nd col, 1st para.), wherein the hydrogels are functionalized with N-terminal azides of GHK peptides, with the sequence GGGGHKSP, prepared by solid phase peptide synthesis, the functionalization accomplished with click chemistry involving a simple mixing process of peptide and polymer in water at ambient temperature for 6 hours using a cytocompatible Cp*RuCl(cod) catalyst (see p. 686, 1st col., 2nd para.), wherein, for GHK-functionalized hydrogels, a low concentration peptide formulation failed to produce significant improvements in mineralization until day 35, while a high concentration peptide formulation promoted significant early mineralization starting at day 3, as well as continued enhancement of mineralization up to day 35 (see p. 690, 1st col., 2nd para.; see also, p. 691, 2nd col., 2nd para.).
Chen (2015) discloses the potential of functional polycaprolactone polymerized from Ɛ-caprolactone for application in biomedical areas (see Abstract), wherein, owing to its bio-compatibility, biodegradability, and tailorable properties, PCL has been extensively studied in biomedical fields, particularly in drug delivery systems and tissue engineering (see p. 3, 2nd col., 1st para.), wherein the lack of functional groups in PCL has limited its potential in the design of new functional polymers with good biocompatibility and biofunctionality, due to its hydrophobic nature and poor wettability, lack of cell attachment, and uncontrolled biological interactions occurring with PCL-based materials, wherein conjugation of peptide ligands with Arg-Gly-Asp (RGD) sequence to functionalized PCL can improve cell adhesion, which, in turn, triggers cell growth and proliferation with the result that the introduction of functional groups into commonly used PCL provides PCL with many possibilities to tune its physicochemical properties such as hydrophilicity and degradation rate, which makes PCL more suitable for biomedical applications (see p. 3, 2nd col., 2nd para.), wherein various functional PCL’s can be prepared via click chemistry using alkyne-derivatized molecules (see p. 4, 1st col., 2nd para.), and wherein azide-alkyne “click” chemistry has proven to be a powerful tool to achieve the coupling of synthetic polymers with nucleic acid, peptides, proteins, and many other molecules, which can help researchers design precisely controlled macromolecular architectures, such as those comprising alkyne-functionalized for bioconjugation via azide-alkyne click chemistry (see p. 5, 2nd col., 2nd para.).
Boren (2007) discloses azide-alkyne cycloaddition reactions catalyzed by Ru(II) comp-lexes such as Cp*RuCl(COD), wherein primary and secondary azides react with a broad range of terminal alkynes containing a range of functionalities selectively producing 1,5-disubstituted 1,2,3-triazoles (see Abstract), and wherein, in an exemplified embodiment, the reactants are heated in an oil bath at 60° C for 12 hours (see p. 8924, 1st col., 3rd para.).
Becker ‘766 discloses polymers and polymer structures made therefrom (and related methods) that have been end and/or monomer functionalized to add functional groups for post-polymerization modification with bioactive materials or other functional species, preferably through one facile "click" reactions, wherein end-group functionalization is accomplished via a functionalized initiating alcohol used during polymerization (see Abstract), wherein polyesters, such as poly(propylene fumarate), have been synthesized and researched for bone tissue engineering (see ¶[0005]), wherein advances in additive manufacturing, such as fused deposition modelling (FDM), which is a layer-by-layer method of extrusion molding solid filaments, have the potential to greatly change tissue engineering for a variety of reasons, not the least of which is that these techniques have the potential to make it possible to quickly design and print scaffolds to meet a patient’s specific requirements (see ¶[0006]), wherein the polymer should be non-toxic, implantable without rejection, and completely resorbable upon degradation, such as poly(Ɛ-caprolactone) (Ɛ-PCL) and poly(propylene fumarate) (PPF), which polymers, as polyesters, are able to degrade either enzymatically or through hydrolysis in vivo (see ¶[0007]), wherein the polymer structures comprise a well-defined, non-toxic, and biodegradable polyester that has tunable mechanical properties and is functionalized with one or more functional groups that can undergo “click” type reactions that give it the ability to undergo surface modification and attach helpful bioactive molecules (see ¶[0018]), wherein functionalized polymers are formed using a 2-step process wherein an end functionalized polymer is obtained by first forming an intermediate by a ring-opening polymerization using an initiating alcohol having a functional end group, and a magnesium catalyst, which intermediate is then isomerized to form the end- functionalized polymer (id.), wherein the functional group added to the polymer comprises alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, tertiary halogen groups, or combinations thereof (see ¶[0021]), wherein, based on tissue engineering requirements, the polymer structures should ideally have molecular interactions with cells to help cells attach, proliferate and differentiate, which interactions are made possible by the functionalization of the polymer in order to attach bioactive molecules (i.e., bioactive drugs, peptides, proteins, sugar) is critical if the functionalized polymer is to be used for bone tissue engineering applications (see ¶[0076]), wherein the functional groups on the polymers that comprise the disclosed polymer structures
are preferably functional groups capable of entering into “click” reactions to facilitate post- polymerization addition of desirable materials, such as bioactive compounds, to the polymers, which reactions are typically simple to perform, high-yielding, stereospecific, wide in scope, create only by-products that can be removed without chromatography, and can be conducted
in easily removable or benign solvents (see ¶[0082]), wherein the end-functionalized polymers will have a number average molecular weight (Mn), as measured by size exclusion chromatography (SEC), of from about 0.7 kDa to about 100,000 kDa (see ¶[0087]), wherein, in order to confirm that the end-functionalized polymers can be derivatized with bioactive peptides, a cell study was performed using mouse MC3T3-E1 cells to assess whether a model peptide (GRGDS, an analog of RGD that has been used widely to enhance cell adhesion) is bioactive after surface functionalization (see ¶[0143]), wherein the azide-functionalized peptide was synthesized via solid phase peptide synthesis for this purpose, and attached to propargyl alcohol end-functionalized polymer discs using copper-mediated azide-alkyne cycloaddition (CuAAC) (see ¶[0143]), and wherein polymer discs derivatized with the GRGDS peptide showed similar cell survival ratios to the end-functionalized polymer (no peptide) and normalization of the survival ratios against a glass slide control showed greater than 90% cell viability for all films, demonstrating that the cytotoxicity of end-functionalized polymer is low and directly comparable to non-peptide-modified polymer (id.).
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 composite implantable devices using solid free-form fabrication methods, particularly three-dimensional printing processes, to manufacture the devices for use in tissue regeneration and for seeding and implanting cells, which methods can be used with a variety of polymeric, inorganic and composite materials to create structures with defined compositions, strengths, and densities, wherein, in order to encourage cellular attachment and growth, the overall porosity, as well as the individual pore diameter, or size, being important in determining the ability of cells to migrate into, colonize, and differentiate while in the device, wherein pore sizes above 150 µm and a porosity of 50 to 90% are necessary for cell invasion of the carrier by bone forming cells, wherein the resulting device is a fully resorbable synthetic scaffold, containing a bone-appropriate region, in a cell-scaffold-based tissue engineering approach to repair articular defects, wherein the device contains geometry, pores, and fluid communication channels that are conducive to cell migration, attachment, growth, and differentiation, wherein, while the layers become hardened, or at least partially hardened, as each of the layers is laid down, once the desired final part configuration is achieved and the layering process is complete, the form and its contents are heated (or cured) at a suitably selected temperature to further promote binding of the particles, wherein manipulation of the printing parameters and component characteristics allow the design and fabrication of macroarchitecture, microarchitecture, and internal and surface characteristics, wherein the printer “ink” comprises polycaprolactone (PCL) with 45 – 75 µm particle sizes, wherein the materials used in the manufacture of the devices are biocompatible, bioresorbable over periods of weeks or longer, and generally encourage cell attachment, wherein the device matrix comprises biologically active materials, including osteoconductive materials such as hydroxyapatite (HA), wherein resorbable polymers of the polyester family, such as (poly(Ɛ-caprolactone) (PCL), are used, largely because their degradation rates can be tailored to match the rate of new tissue formation, and wherein either exogenously added cells or exogenously added factors, including genes, may be added to the implant before or after its placement in the body, as taught by Sherwood ‘936, wherein the implants are modified by the attachment of bone-specific biomolecules, such as a glycine-histidine-lysine (GHK) peptide, via simple click modification in order to promote the desired bone-like matrix synthesis, wherein the implants are functionalized with N-terminal azides of GHK peptides, with the sequence GGGGHKSP, prepared by solid phase peptide synthesis, the functionalization accomplished with click chemistry involving a simple mixing process of peptide and polymer in water at ambient temperature for 6 hours using a cytocompatible Cp*RuCl(cod) catalyst (see p. 686, 1st col., 2nd para.), wherein, for GHK-functionalized hydrogels, a low concentration peptide formulation failed to produce significant improvements in mineralization until day 35, while a high concentration peptide formulation promoted significant early mineralization starting at day 3, as well as continued enhancement of mineralization up to day 35, as taught by Guo (2019), wherein poly(Ɛ-caprolactone) is functionalized with a terminal alkyne group in order to make PCL more suitable for biomedical applications, wherein the functionalized PCL’s are prepared via click chemistry to achieve the coupling of peptides and proteins to the polymer, as taught by Chen (2015), wherein click chemistry is used to modify alkyne-modified PCL via cycloaddition reactions catalyzed by Ru(II) complexes such as Cp*RuCl(COD), and wherein the reaction is conducted in an oil bath at 60° C for 12 hours, as taught by Boren (2007), wherein an azide-functionalized peptide was synthesized via solid phase peptide synthesis and attached to propargyl alcohol end-functionalized polymer discs using copper-mediated azide-alkyne cycloaddition, and the end-functionalized PCL is prepared using a 2-step process by first forming an intermediate by a ring-opening polymerization using an initiating alcohol having a functional end group, such as an alkyne, and a magnesium catalyst, which intermediate is then isomerized to form the end-functionalized polymer, wherein the alkyne functional group on the polymer is capable of entering into “click” reactions to facilitate post-polymerization addition of bioactive compounds to the polymers, wherein the end-functionalized polymer have a number average molecular weight (Mn), as measured by size exclusion chromatography (SEC), of from about 0.7 kDa to about 100,000 kDa, as taught by Becker ‘766. One of skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the express teachings of Guo (2019) to the effect that the lack of functional groups in PCL has limited its potential in the design of new functional polymers with good biocompatibility and biofunctionality, due to its hydrophobic nature and poor wettability, lack of cell attachment, and uncontrolled biological interactions occurring with PCL-based materials, and that alkyne modification of the PCL allows for use of click chemistry to attach biologically effective molecules to PCL-based implants for bone repair, by the teachings of Chen (2015) to the effect that implants comprising alkyne-functionalized PCL allows for the design of precisely controlled macromolecular architectures, such as those comprising bioconjugation via azide-alkyne click chemistry, by the teachings of Becker ‘766 to the effect that click chemistry reactions are typically simple to perform, high-yielding, stereospecific, wide in scope, create only by-products that can be removed without chromatography, and can be conducted in easily removable or benign solvents, and that a cell study using mouse MC3T3-E1 cells demonstrated that polymer discs derivatized with the peptide showed similar cell survival ratios to the end-functionalized polymer (no peptide) and normalization of the survival ratios against a glass slide control showed greater than 90% cell viability for all films, demonstrating that the cytotoxicity of end-functionalized polymer is low and directly comparable to non-peptide-modified polymer.
With respect to those claims reciting limitations comprising ranges of quantitative properties, such as pore-related measurements, process conditions, and component properties (see claims 3, 5, 10, and 11), it is the Examiner’s position that the cited references disclose quantitative ranges that significantly overlap with the claimed ranges and, as such, would render the claimed invention obvious. See MPEP § 2144.05. “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 light of the forgoing discussion, the Examiner concludes that the subject matter defined by claims 1 – 7 and 9 - 11 would have been obvious within the meaning of 35 USC § 103.
Claim 8 is rejected pursuant to 35 U.S.C. § 103, as being obvious over Sherwood ‘936, in view of Guo (2019), Chen (2015), Boren (2008), and Becker ‘766, as applied in the above rejection of claims 1 – 7 and 9 – 11, and further in view of US 10,752,772 to Kogot, J., et al., issued 25 August 2020 (“Kogot ‘772”).
The Invention As Claimed
The invention with respect to claim 1 is described above. In addition, Applicants claim a method of making a biocompatible article comprising the steps of preparing a 3D-printable mixture, and depositing successive layers of the mixture in a predetermined pattern to form a porous biocompatible article, wherein the depositing comprises extruding the peptide-containing composite at a temperature of from 70 to 100° C.
The Teachings of the Cited Art
The disclosures of Sherwood ‘936, Guo (2019), Chen (2015), Boren (2008), and Becker ‘766, are relied upon as applied in the above rejection of claims 1 – 7 and 8 – 11. The references do not disclose a method of making a biocompatible article, wherein the article is prepared by 3D printing techniques where a printable mixture comprising a peptide-containing composite is deposited on a substrate by extrusion at a temperature of from 70 to 100° C. The teachings of Kogot ‘772 remedy this deficiency.
Kogot ‘772 discloses a method for producing a 3-D printable material comprised of a marine biodegradable base polymer, such as polycaprolactone (PCL), and a gelling agent, such as agar, in a ratio preselected to achieve a desired rate of degradation of a structure printed from the material, wherein the composition may also include biological materials to further promote or control the biodegradation of the structure, and other additives such as nutrients for microorganisms, wherein the 3-D printing of the material occurs at relatively lower temperatures to avoid damage to the biological materials (see Abstract), wherein the composition is extruded to produce 3-D printable filaments that are then used in a 3-D printer to form marine biodegradable structures with selected rates of degradation for specific uses (see Col. 2, ll. 10 – 13), wherein biological materials (e.g., microorganisms, enzymes, etc.) may be added to the composition in order to increase the rate of degradation, requiring that the extrusion occur at relatively low temperatures to avoid harming the microorganisms or other biologicals (see Col. 2, ll. 14 – 21), wherein the rate of erosion of a device manufactured with the composition depends upon the percentage of agar in the composition, higher percentages of agar result in faster erosion (see Col. 3, ll. 24 – 26), wherein examples of biological materials that can be incorporated into the structure include proteins and enzymes (see Col. 3, ll. 30 – 31), wherein the
low temperature of the mixing, extrusion and 3-D printing processes allows the biological materials to be included that could not be created using previously known 3-D printing processes
that use temperatures that would kill the biological materials (see Col. 3, ll. 36 – 43), wherein the preferred base polymer would be polycaprolactone (PCL), a polyester that degrades due to hydrolysis of ester bonds with a melting temperature of 60° C., which temperature is close to the melting temperature of agar and is safe for biological materials (see Col. 3, ll. 55 – 61), and wherein the low temperature (in a range from 60° C to 120° C) of the mixing, extrusion, and 3-D printing process allows the biological materials to be included (see Col. 5, ll. 39 – 42).
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 bone repair grafts by 3D printing processes according to the teachings of Sherwood ‘936, Guo (2019), Chen (2015), Boren (2008), and Becker ‘766, wherein the grafts include biological materials, such as peptides, requiring that the extrusion occur at relatively low temperatures, in the range of 60 to 120° C to avoid harming the biological materials. One of skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the express teachings of Kogot ‘772 to the effect that extrusion at relatively low temperatures is necessary to preserve the viability of biological materials included in the graft (see Col. 5, ll. 39 – 42).
With respect to the temperature range recited in the claim, the Examiner acknowledges that the cited reference discloses a temperature range that is not congruent with the limitation. However, it is the Examiner’s position that the cited reference discloses a temperature range that significantly overlaps with the claimed range and, as such, would render the claimed invention obvious. See MPEP § 2144.05.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by claim 8 would have been obvious within the meaning of 35 USC § 103.
Claims 1 and 12 – 21 are rejected pursuant to 35 U.S.C. § 103, as being obvious over Wei ‘343, in view of Kang, H.-W., NATURE BIOTECHNOLOGY 34(3): 312 – 319 (2016) (“Kang (2016)”), and US 2020/0281724 A1 to Weber, F., claiming priority to 20 September 2017 (“Weber ‘724”).
The Invention As Claimed
The invention with respect to claim 1 is described above. In addition, Applicants claim a method making a biocompatible article comprising the steps of preparing a 3D-printable mixture, and depositing successive layers of the mixture in a predetermined pattern to form a porous biocompatible article, wherein the 3D printable mixture comprises hydroxyapatite (HA) at 50 to 80% wgt, and tetrahydrofurfuryI methacrylate as a binder, wherein the porosity is from 20 – 55%, wherein the article has pores with an average size of 600 to 1000 µm, wherein the ceramic material is a powder, with average particle sizes of from 50 nm to 50 µm, wherein the step of depositing comprises extruding the mixture at a temperature of from 10 to 40 °C and a pressure of from 0.3 to 5 bar to form a layer, applying ultraviolet radiation to the layer, and repeating the extruding and applying steps until a desired number of layers is achieved, wherein the method further comprises sintering the article at a temperature of from 1000 to 1400° C for 3 to 12 hours to form a sintered article, and wherein the method further comprises rotating the article by about 90 degrees after a predetermined number of depositing steps.
The Teachings of the Cited Art
Wei ‘343 discloses computer implemented methods for producing a porous implant that include obtaining a 3-D image of an intended tissue repair site, generating a 3-D model of the porous implant based on the 3-D image of the intended repair site (see Abstract), wherein the implant is a layered 3-D printed porous implant, the implant comprising a first layer of implant material mixed with porogen, a second layer of implant material mixed with porogen, the second layer disposed on the first layer, a third layer of implant material mixed with porogen, the third layer disposed on the second layer, each layer repeating until the 3-D printer has completed the porous implant (see ¶[0012]), wherein the 3-D printing device includes a rotatable printing surface to facilitate continuous extrusion of a predetermined porous hollow implant (see ¶[0016]; see also ¶[0020], FIG. 5), wherein the implants are used to treat bone defects in a patient in need thereof by implantation at the tissue repair site (see ¶[0013]), wherein the intended tissue repair site is a bone repair site, an osteochondral defect site, an articular cartilage defect site or a combination thereof, the tissue including soft tissue, muscle, ligaments, tendons, cartilage, and hard tissue as found in bones (see ¶[0176]), wherein polymer material can be sintered through use of a temperature control/heating unit (see ¶[0166], FIG. 1), wherein a laser is focused on the deposited material in order to sinter and cure the material (see ¶[0173]), wherein the process of preparing the implants comprises determining an implant material and an amount of a porogen to add to an implant material to obtain a desired porosity of the porous implant (see ¶[0175]), wherein the implant material comprises a carrier material and a bone material, including a natural material, a biodegradable carrier, and a growth factor (see ¶[0194]), wherein the biodegradable material comprises a biodegradable polymer (see ¶[0195]), and wherein the implant material further comprises inorganic polymers, such as hydroxyapatite, calcium HA, carbonated calcium HA, beta-tricalcium phosphate (beta-TCP), alpha-tricalcium phosphate (alpha-TCP), and other calcium phosphates (see ¶[0215]), the particles present at relative loadings of 10 – 95% wgt (see ¶[0230]), and with particle sizes in the range of 25 to about 4000 µm (see ¶[0133]), wherein the matrix of the porous implant may be seeded with harvested bone cells and/or bone tissue, such as for example, cortical bone, autogenous bone, allogenic bones and/or xenogenic bone (see ¶[0234]), wherein the carrier material constitutes an ink that dries, is cured, or reacts, to form a porous, biodegradable, biocompatible material that is osteoinductive and has a load bearing strength comparable, the ink, in some aspects, being supplied in the form of a precursor powder and a precursor liquid (see ¶[0237]), wherein the material comprises a bioerodible polymer and a synthetic ceramic, the polymer particles being in the form of powders, microspheres, sponges, pastes, gels, and/or granules, preferably powders (see ¶[0244]), wherein the implant material further comprises tetrahydrofurfuryl methacrylate (see ¶[0274]), wherein, in some embodiments, a preselected amount of the ink is heated to the appropriate temperature and jetted through the print head or a plurality of print heads of a suitable inkjet printer to form a layer on a print pad in a print chamber (see ¶[0287]), and wherein the implant comprises macropores with pore diameters greater than about 100 µm, micropores with diameters below about 10 µm, and nanopores with diameters about 1 nm (see ¶[0293]). The reference does not explicitly disclose a method of making a biocompatible article by 3D printing a mixture layer-by-layer wherein the printable mixture comprises where the deposition is accomplished by extrusion at 10 - 40° C and a pressure of 0.3 – 5 bar, or a process where sintering occurs at 1000 - 1400° C for 3 – 12 hours. The teachings of Kang (2016) and Weber ‘724 remedy those deficiencies.
Kang (2016) discloses an integrated tissue–organ printer (ITOP) that can fabricate stable, human-scale tissue constructs of any shape (see Abstract), wherein the correct shape of a tissue construct is obtained from a human body by processing computed tomography (CT) or magnetic resonance imaging (MRI) data in computer-aided design (CAD) software (see p. 312,m 2nd col., last para.), wherein 3D constructs were created by combining fluorescently labeled 3T3 fibroblasts in composite hydrogels with supporting poly(caprolactone) (melting temperature of 60° C), and printed in two patterns (see p. 313, 1st col., 3rd para.; see also, Figs. 2c, 2f), wherein PCL was used internally in order to endow printed constructs with structural strength, and Pluronic F127 was used as an external sacrificial scaffold (see p. 318, 1st col., 2nd para.), and wherein the PCL polymer was loaded into a metal syringe that was heated at 92.5 °C for melting, and printed through a 250-µm cone-shaped metal nozzle at 800 KPa (0.8 bar) of air pressure (see METHODS, 2D and 3D printing process).
Weber ‘724 discloses an osteoconductive graft comprising a biocompatible material that is interspersed with a network of non-overlapping pores connected by channels (see Abstract), wherein the pore-channel structure is generated by an additive manufacturing process building a graft body from two-dimensional layers at high geometric resolution, the graft material being composed of fine particles of a biocompatible material, held together for the manufacturing process by a polymerizable resin material (present at 1% to 50% wgt), wherein the resin material is removed from the graft material by heat treatment in a sintering step subsequent to the additive manufacturing process (see ¶[0010]), wherein the graft is treated by heating it at a temperature, and for a time, sufficient to sinter the inorganic component and to remove the resin material (see ¶[0029]), wherein the osteoconductive graft material comprises a bone substitute material selected from bioglass, hydroxyapatite, calcium phosphate, calcium sulfate, CaCO3, or mixtures thereof, provided in particulate form of appropriate size to allow additive manufacturing processes to process the material (see ¶[0030]), wherein the inorganic material for making the graft comprises hydroxyapatite (HA) (see ¶[0036]), wherein the grafts are prepared by depositing, in a 3-dimensional pattern, an inorganic particulate material suspended in a photopolymerizable monomer, wherein the pattern is characterized by a network of non-overlapping spherical pores connected by channels (see ¶[0056]), wherein the 3-dimensional structure is built by subsequently depositing contiguous layers of the particulate material, wherein each layer is between 10 pm and 100 pm (see ¶[0059]), and wherein the structure is sintered, for example, at temperatures of 500 - 1700° C for a period of from 1 – 10 days (see ¶[0060]), in order to eliminate the resin binder and increase the mechanical stability of the scaffolds so that they can be implanted in vivo (see ¶[0079]), and wherein, in a specific embodiment, the sintering step was at 1100° C for 3 hours (see ¶[0087]).
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 porous implants by processes comprising obtaining a 3-D image of an intended tissue repair site, generating a 3-D model of the porous implant based on the 3-D image of the intended repair site, and building the implant with a layered 3-D printing process, the implant comprising a first layer of implant material mixed with porogen, a second layer of implant material mixed with porogen, the second layer disposed on the first layer, a third layer of implant material mixed with porogen, the third layer disposed on the second layer, each layer repeating until the 3-D printer has completed the porous implant, wherein the 3-D printing device includes a rotatable printing surface to facilitate continuous extrusion of a predetermined porous hollow implant, wherein the implants are used to treat osteochondral defects, wherein polymer material can be sintered through use of a temperature control/heating unit, wherein the process of preparing wherein the implant material comprises a carrier material and a bone material, including a natural material, a biodegradable polymer, and a growth factor, wherein the implant material further comprises particles of hydroxyapatite, present at relative loadings of 10 – 95% wgt, and with particle sizes in the range of 25 to about 4000 µm, wherein the matrix of the porous implant may be seeded with harvested bone cells, wherein the carrier material constitutes an ink that dries, is cured, or reacts, to form a porous, biodegradable, biocompatible material that is osteoinductive and has a load bearing strength comparable to bone, wherein the ink, in some aspects, is supplied in the form of a precursor powder and a precursor liquid, wherein the material comprises a bioerodible polymer and a synthetic ceramic, the biodegradable polymer is preferably in the form of powders, wherein the implant material further comprises tetrahydrofurfuryl methacrylate, wherein, in some embodiments, a preselected amount of the ink is heated to the appropriate temperature and jetted through the print head or a plurality of print heads of a suitable inkjet printer to form a layer on a print pad in a print chamber, and wherein the implant comprises macropores with pore diameters greater than about 100 µm, micropores with diameters below about 10 µm, and nanopores with diameters about 1 nm, as taught by Wei ‘343, wherein PCL was used internally in the grafts in order to endow printed constructs with structural strength, and Pluronic F127 was used as an external sacrificial scaffold, and wherein the PCL polymer was loaded into a metal syringe that was heated at 92.5° C for melting, and printed through a 250-µm cone-shaped metal nozzle at 800 KPa (0.8 bar) of air pressure, as taught by Kang (2016), and wherein the material of the graft, being composed of fine particles of a biocompatible material, was held together for the manufacturing process by a polymer resin, which material is removed from the graft by a sintering step subsequent to the additive manufacturing process which also removes the resin material, and wherein the graft structure is sintered, when the graft comprises HA, at 1100° C for 3 hours in order to increase the mechanical stability of the scaffolds so that they can be implanted in vivo, as taught by Weber ‘724. 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 Kang (2016) to the effect that effective extrusion printing of graft material comprising PCL in a 3D process is accomplished by heating to 92.5° C at an air pressure of 0.8 bar.
With respect to those claims reciting limitations comprising ranges of quantitative properties, such as pore-related measurements, process conditions, and component prope