DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after May 31, 2024, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants claimed invention filed on 05/31/2024 in the matter of Application N° 18/715,168. Said documents are entered on the record. The Examiner further acknowledges the following:
Thus, claims 1-16 represent all claims currently under consideration.
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, 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 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.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al. (WO2016178586A2), in view of Suzuki et al. (Manufacturing micropatterned collagen scaffolds with chemical-crosslinking for development of biomimetic tissue-engineered oral mucosa (2020), and Lohrasbi et al. (Collagen/cellulose nanofiber hydrogel scaffold: physical, mechanical and cell biocompatibility properties, 2020), and Zhang et al., “preparation and characterization of composite scaffold of alginate and cellulose nanofiber from ramie,” Textile Research journal, Vol. 89, pp. 3260-3268 (2019), DOI 10.1177/0040517518809041. November 4, 2018, and Development of collagen-EDC scaffolds for skin tissue engineering: physicochemical and biological characterization María Luisa Del Prado Audelo et al., and Quantitative Evaluation of the In vivo Biocompatibility and Performance of Freeze-cast Tissue Scaffolds Prajan Divakar et al., 2021, and Collagen/Cellulose Nanofiber Blend Scaffolds Prepared at Various pH Conditions, Chun-Yen Liu 2018.
Patel et al. disclose a method of preparing a collagen composition comprising obtaining a collagen gel and forming a collagen scaffold suitable for biomedical and implantable applications (See claim 1, paragraph 0015, and paragraph 0006).
Regarding the limitation of providing a solution having a collagen concentration of 0.1 to 30 wt.%, Patel et al. disclose obtaining a collagen gel having a collagen concentration of 100 to 190 mg/mL and further disclose collagen concentrations within a broader range of approximately 50 to 250 mg/mL (See paragraph 0015, and 00149). The disclosed 100-190 mg/mL range corresponds approximately to 10-19 wt.% collagen, assuming an aqueous composition having a density of approximately 1 g/mL, and therefore falls within the presently claimed range of 0.1-30wt.%. Accordingly, Patel et al. teach a collagen concentration overlapping the presently claimed range.
Regarding the limitation requiring a cellulose nanofiber concentration of 0 to 30 wt.%, Patel et al. do not disclose requiring cellulose nanofibers in the collagen composition. However, because the presently claimed range expressly encompasses 0 wt.% cellulose nanofibers, a collagen composition containing no cellulose nanofibers satisfies the claimed limitation.
Patel et al. further discloses crosslinking the collagen scaffold using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (See paragraph 0038). EDC is a non-polymeric carbodiimide crosslinking agent used for crosslinking collagen scaffolds. Patel et al. teach that EDC crosslinking increases the mechanical properties of the collagen scaffold, including its stiffness and ultimate tensile strength (See paragraph 00221).
Patel et al., however, do not expressly disclose adding the EDC crosslinking agent at the presently claimed concentration of 1 to 30 wt.%.
Suzuki et al. teach chemically crosslinking collagen hydrogel scaffolds using EDC at a concentration of 1.0%. Specifically, Suzuki et al. disclose preparing a 1.1 wt.% collagen solution and chemically crosslinking the resulting collagen gels using EDC dissolved in ethanol at 1.0% w/v, wherein the collagen gels are immersed in the EDC-containing solution at room temperature for 24 hours. Suzuki et al. teach that EDC crosslinking enhances the mechanical properties and stability of collagen hydrogel scaffolds, including increasing Young’s modulus, reducing contraction, maintaining scaffold microstructure, and providing sufficient durability to permit suturing (See page 12, Fabrication and measurement of physical property of collagen scaffolds, and macroscopic test of handling property).
It would have been obvious to one of ordinary skill in the art, prior to the instant effective filing date at the effective filing date to employ EDC at the concentration taught by Suzuki et al. in the collagen scaffold of Patel et al. because Patel et al. expressly identify EDC as a suitable carbodiimide crosslinking agent for collagen, while Suzuki et al. demonstrate a suitable EDC concentration for effectively crosslinking collagen hydrogel scaffolds. One of ordinary skill in the art would have been motivated to employ the disclosed EDC concentration to improve the mechanical strength, structural stability, and durability of the collagen hydrogel, with a reasonable expectation of success because both Patel et al. and Suzuki et al. employ EDC for chemically crosslinking collagen-based hydrogel/scaffold materials.
Regarding the limitation of adding riboflavin at a concentration of 0.1 to 10 wt.%, Patel et al. disclose treating dehydrated collagen scaffolds with 0.1% riboflavin in phosphate-buffered saline. The disclosed concentration of 0.1% corresponds to the lower endpoint of the presently claimed riboflavin range (See paragraph 00214).
Regarding the limitation of exposing the intermediate hydrogel material to ultraviolet A light, Patel et al. disclose that, following treatment of the collagen scaffold with 0.1% riboflavin, the scaffold is irradiated using a 370 nm UVA light source positioned approximately 10 nm above the scaffold. Patel et al. disclose irradiating the scaffold for 30 minutes, turning the scaffold over, and repeating the UVA irradiation for an additional 30 minutes (See paragraph 00214).
Patel et al. further teaches that riboflavin functions as a photosensitizer that crosslinks collagen matrices when used in conjunction with ultraviolet light. Patel et al. demonstrate that both EDC crosslinking and riboflavin/UVA crosslinking increase the mechanical properties of collagen scaffolds relative to uncross linked collagen material (See paragraph 00223).
Although Patel et al. evaluate EDC crosslinking and riboflavin/UVA crosslinking as separate crosslinking treatments, it would have been obvious to one of ordinary skill in the art to further treat an EDC-crosslinked collagen hydrogel with riboflavin followed by UVA irradiation in order to provide additional crosslinking and thereby further enhance the mechanical strength and structural stability of the resulting collagen hydrogel. One of ordinary skill in the art would have had a reasonable expectation of success because Patel et al. expressly teach that both EDC and riboflavin/UVA are suitable methods for crosslinking the same collagen scaffold material, and Suzuki et al. further demonstrate that EDC treatment provides mechanically stable and durable collagen hydrogel scaffolds.
It would have been obvious to provide a collagen solution within the claimed concentration range, chemically crosslink the collagen using EDC at the concentration taught by Suzuki et al. to form an intermediate crosslinked hydrogel, and subsequently treat the intermediate hydrogel with riboflavin followed by UVA irradiation as taught by Patel et al., thereby obtaining a mechanically strengthened collagen hydrogel material suitable for implantation.
Patel et al. in view of Suzuki et al. disclose the method of claim 1 as discussed above, but do not expressly disclose wherein the concentration of cellulose nanofibers in the solution is 0.1-30 wt.%.
Regarding claim 2, Lohrasbi et al. teaches incorporating cellulose nanofibers into a collagen hydrogel, wherein up to 8% CNF by total dry weight is added to a collagen acidic solution prior to gel formation. The disclosed amount of up to 8% CNF overlaps the presently claimed range of 0.1-30 wt.% (See Abstract, and page 929).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the invention to incorporate cellulose nanofibers at the disclosed concentration into the collagen hydrogel of Patel et al., because Lohrasbi et al. teaches that incorporation of CNF into collagen hydrogels improves the physical and mechanical properties of the resulting hydrogel, including water retention, hydrolytic stability, compression strength, and fracture strain. One of ordinary skill in the art would have had a reasonable expectation of success because Lohrasbi et al. expressly demonstrates that cellulose nanofibers can be incorporated into collagen solutions to form stable collagen/CNF hydrogel materials.
Regarding claim 3, Patel et al. in view of Suzuki et al. and Lohrasbi et al. disclose the method of claim 1 as discussed above. Lohrasbi et al. further disclose preparing collagen/cellulose nanofiber (CNF) nanocomposite hydrogels containing 3%, 6%, and 8% CNF by weight of total polymer (See page 930). In particular, the hydrogel containing 3 wt.% CNF by total polymer weight comprises approximately 97 wt.% collagen and 3 wt.% CNF, thereby providing a collagen-to-cellulose nanofiber ratio of approximately 97:3. The disclosed ratio of 97:3 falls within the presently claimed collagen -to-cellulose nanofiber ratio of 95:5 to 99.9:0.1. Lohrasbi et al. teach the presently claimed collagen-to-cellulose nanofiber ratio.
It would have been obvious to one of ordinary skill in the art at the effective filing date to incorporate cellulose nanofibers into the collagen hydrogel of Patel et al. at a collagen-to-CNF ratio of approximately 97:3, as taught by Lohrasbi et al., because Lohrasbi et al. teach that incorporation of CNF into collagen hydrogels improves the physical and mechanical properties of the resulting hydrogel, including water retention, hydrolytic stability, compression strength, and fracture strain. On of ordinary skill in the art would have had a reasonable expectation of success because Lohrasbi et al. expressly demonstrate preparation of collagen/CNF hydrogels having the disclosed ratio.
Regarding claim 4, Patel et al. further disclose that crosslinking of the collagen composition may be achieved using one or more crosslinking agents selected from, inter alia, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (See paragraph 0161). Patel et al. further teach that EDC has been used extensively for crosslinking collagen scaffolds (See paragraph 0223). Patel et al. expressly teach a non-polymeric short range carbodiimide crosslinking agent selected from the presently claimed group, namely EDC.
Regarding claim 5, Patel et al. further discloses collagen compositions comprising Type I collagen. Type I collagen is one of the collagen species expressly recited in claim 5. Patel et al. teach the additional limitations wherein the collagen is selected from the group consisting of Type I collagen (See pages 928 and 929).
Regarding claim 6, Patel et al. in view of Suzuki et al. and Lohrasbi et al. disclose the method of claim1 and the use of cellulose nanofibers in a collagen hydrogel as discussed above, but do not expressly disclose wherein the cellulose nanofibers are derived from biomass, plants, and/or bacteria.
Zhang et al. disclose cellulose nanofibers (CNFs) obtained from raw ramie fibers and incorporated into a composite hydrogel scaffold. Ramie is a plant-derived biomass material (See Abstract). Zhang et al. teach cellulose nanofibers derived from a plant as presently claimed.
It would have been obvious to one of ordinary skill in the art at the effective filing date of the invention to employ the plant-derived cellulose nanofibers of Zhang et al. as the cellulose nanofibers in the collagen/CNF hydrogel taught by Lohrasbi et al. because Zhang et al. teach that plant-derived ramie CNFs are suitable reinforcing materials for hydrogel scaffolds and that incorporation of such CNFs improves the mechanical properties of the resulting scaffold. One ordinary skill in art would have had a reasonable expectation of success because both Zhang et al. and Lohrasbi et al. employ cellulose nanofibers as reinforcing components in hydrogel scaffold materials.
Regarding claim 7, Griffith et al. disclose the method of claim 1 as discussed above, including carbodiimide crosslinking of a collagen hydrogel followed by treatment with 0.1% riboflavin and UVA irradiation. Griffith et al., however, do not expressly disclose wherein the molar ratio of the non-polymeric short range carbodiimide crosslinking agent to riboflavin is 10:1 to 500:1.
Del Prado Audelo et al. disclose Type I collagen scaffolds chemically crosslinked using EDC at concentrations of 35mM, 45mM, and 55mM. Del Prado Audelo et al. further teaches that increasing EDC concentration improves the structural and thermal stability and resistance to enzymatic degradation of the collagen scaffold.
Griffith et al.’s 0.1% w/v riboflavin solution corresponds to approximately 2.66 mM riboflavin. Accordingly, employing the EDC concentrations taught by Del Prado Audelo et al. in combination with the 0.1% riboflavin concentration taught by Griffith et al. provides EDC -to-riboflavin molar ratios of approximately 13.2:1, 16.9:1, and 20.7:1 for 35 mM, 45 mM, and 55 mM EDC (See page 77), respectively. Each of these calculated ratios falls within the presently claimed range of 10:1 to 500:1.
It would have been obvious to one of ordinary skill in the art, prior to the instant effective filing date to employ an EDC concentration within the range taught by Del Prado Audelo et al. in the carbodiimide-crosslinked collagen hydrogel of Griffith et al., because Del Prado Audelo et al. teach that such EDC concentrations effectively stabilize collagen scaffolds and improve their structural, thermal, and enzymatic stability. One of ordinary skill in the art would have had a reasonable expectation of success because both references use carbodiimide crosslinking to improve the properties of collagen-based biomaterials.
Regarding claim 8, Griffith et al. disclose the method of claim 1 as discussed above and further disclose preparing transparent collagen hydrogels by mixing collagen with a carbodiimide crosslinker at a pH of 4-7, particularly at a pH of 5-5.5 Griffith et al. further exemplify adjusting the collagen mixture to a pH of approximately 5 or 5.5 during preparation of the carbodiimide crosslinked collagen hydrogel (See paragraph 0091). The expressly disclosed pH values of approximately 5-5.5 fall within the presently claimed pH range of 3-6. Accordingly, Griffith et al. teach the additional limitation of claim 8.
Regarding claim 9, Griffith et al. disclose the method of claim 1 as discussed above and further disclose, following carbodiimide crosslinking and curing of the collagen hydrogel, extensively washing the formed hydrogel with phosphate-buffered saline (PBS) to remove residual crosslinking agents (See paragraph 0116, 0180, and 0190). Griffith et al. thereafter treat the washed, pre-carbodiimide-crosslinked collagen hydrogel with 0.1% riboflavin and expose the hydrogel to UVA irradiation. Accordingly, Griffith et al. expressly teach rinsing the formed intermediate hydrogel material prior to exposing the intermediate hydrogel material to ultraviolet A light, as presently claimed.
Regarding claim 10, Griffith et al. disclose an implantable collagen hydrogel material comprising crosslinked collagen. Griffith et al. disclose collagen hydrogels comprising recombinant human collagen, including recombinant human Type III collagen, at concentrations within the presently claimed range, including collagen concentrations of approximately 10-20 wt.% (See paragraph 0137) and an exemplary collagen concentration of approximately 18 wt.% (See paragraph 0166). The disclosed collagen concentrations fall within and therefore overlap the presently claimed collagen concentration of 0.1-30 wt.%. Griffith et al. further disclose chemically crosslinking the collagen molecules using a carbodiimide crosslinking agent and further disclose crosslinking collagen hydrogels using riboflavin/UVA treatment. Accordingly, Griffith et al. teach an implantable hydrogel material comprising crosslinked collagen at a concentration falling with the presently claimed range of 0.1-30 wt.%.
Regarding claim 11, Griffith et al. discloses the implantable crosslinked collagen hydrogel material of claim 10 as discussed above, but do not expressly disclose cellulose nanofibers in a concentration of 0.1-30wt.%., wherein the cellulose nanofibers are crosslinked and wherein crosslinks are present between the cellulose nanofibers and collagen molecules.
Lohrasbi et al. disclose collagen/cellulose nanofibers hydrogel scaffolds comprising cellulose nanofibers at concentrations falling within the presently claimed range and teach that incorporation of cellulose nanofibers improves the physical and mechanical properties of collagen hydrogels.
Divakar et al. further disclose composite scaffolds comprising collagen and nanocellulose, wherein the collagen/nanocellulose composite scaffold is chemically crosslinked by treatment with 33mM EDC and 6 mM NHS (See page 3, Scaffold Crosslinking). Divakar et al. therefore demonstrate the suitability of carbodiimide mediated crosslinking for collagen/nanocellulose composite scaffold materials.
Liu et al. further disclose collagen scaffolds comprising TEMPO-oxidized cellulose nanofibers, wherein TEMPO oxidation provides carboxyl-functionalized cellulose nanofibers suitable for interaction with collagen (See Abstract and page 1362). The prior art further establishes that the carboxyl groups of TEMPO-oxidized cellulose nanofibers can be activated using EDC/NHS chemistry and covalently coupled to amine-containing molecules through amide-bond formation.
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date to employ carboxyl functionalized, TEMPO-oxidized cellulose nanofibers as the cellulose nanofibers in the EDC/NHS-crosslinked collagen/nanocellulose scaffold because such CNFs were known to reinforce collagen scaffolds and their surface carboxyl groups were known to undergo EDC/NHS-mediated coupling with amine-containing molecules. Since collagen contains available amino groups, one of ordinary skill in the art would have reasonably expected EDC/NHS activation of the carboxylated cellulose nanofibers to provide covalent amide crosslinks between the cellulose nanofibers and collagen molecules, thereby providing a chemically integrated and mechanically reinforced collagen/CNF scaffold.
Regarding claim 12, Griffith et al. disclose the implantable crosslinked collagen hydrogel material of claim 10 as discussed above and further disclose optically transparent collagen hydrogels suitable for corneal implantation. Griffith et al. report that the collagen hydrogels exhibit light transmission greater than approximately 90% in the visible wavelength region (See claim 20, and paragraph 0074, and 0093). The light transmission disclosed by Griffith et al. therefore exceeds and falls within the presently claimed limitation requiring the hydrogel material to exhibit a light transmission of at least 80%.
Regarding claim 13, Griffith et al. disclose the implantable crosslinked collagen hydrogel material of claim 10 as discussed above and further disclose that the collagen hydrogels are suitable for biomedical and pharmaceutical applications, including use as cell and/or drug delivery carriers and tissue-engineering scaffolds (See paragraph 0082). Griffith et al. Further demonstrate the ability of the collagen hydrogel to support cells by seeding immortalized human corneal epithelial cells and human corneal endothelial cells onto the collagen hydrogel and culturing the cells thereon.
Regarding claim 14, Griffith et al. disclose the implantable crosslinked collagen hydrogel material of claim 10 as discussed above and further disclose that the hydrogel material is suitable for use in ophthalmic devices. Griffith et al. disclose ophthalmic devices comprising the crosslinked collagen hydrogel, including corneal substitutes, corneal implants, corneal onlays, corneal inlays, and full-thickness corneal implants (See paragraph 0082, 0093, 0019,).
Regarding claim 15, Griffith et al. disclose the implantable crosslinked collagen hydrogel material of claim 10 as discussed above and further disclose that the hydrogel material is suitable for use as an ophthalmic device, including a corneal implant (See paragraph 0084, and 0085 and 0093).
Regarding claim 16, Patel et al., in view of Suzuki et al. and Lohrasbi et al., disclose the method of claim 2 as discussed above. Lohrasbi et al. further disclose collagen/cellulose nanofiber composite hydrogels containing cellulose nanofibers at 3%, 6%, and 8% by total dry weight (See Fig.1, page 932). In particular, the collagen/CNF hydrogel containing 3% cellulose nanofibers corresponds to approximately 97% collagen and 3% cellulose nanofibers, thereby providing a collagen-to-cellulose nanofibers ratio of approximately 97:3. The disclosed ratio of 97:3 falls within the presently claimed collagen-to-cellulose nanofiber ratio of 95:5 to 99.9:0.1.
It would have been obvious to one of ordinary skill in the art, prior to the instant effective filing date of the claim invention to employ the collagen-to-CNF ratio taught by Lohrasbi et al. in the collagen hydrogel of Patel et al. because Lohrasbi et al. teach that incorporation of CNF into collagen hydrogels improves the physical and mechanical properties of the resulting hydrogel, including water retention, hydrolytic stability, compression strength, and fracture strain.
Conclusion
No claim is allowed.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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