DETAILED ACTION
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 .
Formal Matters
Applicant’s response in the reply filed on 06 May 2026 is acknowledged and has been fully considered. Claims 1-23 are pending. Claims 1-10 and 12-23 are under consideration in the instant office action. Claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 24 July 2025, 20 November 2025, 11 February 2026, and 08 April 2026 are noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. Signed copies are attached herein.
Election/Restrictions
Applicant's election without traverse of alginate salts of alkaline earth metals (e.g., calcium, strontium, barium) as the alginate type; hyaluronate as the hyaluronate type; and calcium crosslinkers as the crosslinker type in the reply filed on 06 May 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
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.
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.
Note: The claims are examined with respect to the elected species wherein alginate salts of alkaline earth metals (e.g., calcium, strontium, barium) as the alginate type; hyaluronate as the hyaluronate type; and calcium crosslinkers as the crosslinker type.
Claims 1-3, 6-10, 12-14, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Jamnezhad et al. (Nanomed Res J 5(4):1-10, 2020) in view of Afzali et al. (Polymers, 14, 1550, Pages 1-29, 2022) and Li et al. (Crystal Growth & Design, Vol. 9, No. 8, 2009 3470-3476).
Applicants’ claims
Applicants claim a hydrogel system comprising a lyophilized hydrogel comprising alginate and hyaluronate; and a crosslinker; wherein the hydrogel has a lamellar morphology comprising parallel layers of the hydrogel. Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Jamnezhad et al. teach freeze-dried (lyophilized) composites explicitly based on alginate and hyaluronic acid for bone fillers/scaffolds. These are processed into porous tissues via freeze-drying (see abstract, introduction, and results sections on preparation of alginate-HA freeze dried composites) (freeze-drying process, morphology characterization).
Jamnezhad et al. teach in the materials and methods section in this research project, the novel alginate hyaluronic acid filler fabricated using chemical process and freeze-drying technique after discussion with orthopedic surgeons. In this work, starting materials are as following; hyaluronic acid (HLA, 98% purity, Merck company, Germany), alginate (Alginate, 98% purity, Sigma-Aldrich, US), Titanium oxide nanoparticles (TiO2 , 50 nm 70 nm, 98% purity, Merck company, Germany), acetic acid (CH₃COOH, 99.9% purity, Razi, and Iran) and deionized water. First, 80 ml of deionized water was mixed with 5 g of alginate in a hotplate with 50°C at 500 rpm in order to homogenize the polymeric solution. Then, another 3.75 g of alginate was added and the stirrer set to 60°C at 700 rpm. Next, 2 vol % of acetic acid was diluted with 5 mL of deionized water and added to the primary solution. Furthermore, 10 g of alginate and 8.75 g of hyaluronic acid (HLA) was added to the solution, the stirrer was set to 1000 rpm for 2 hours to become more homogeneous. The magnetic stirrer was set to 70°C at 800 rpm, 3 mL of glutaraldehyde crosslinking agent with chemical formula C5H8O2 was added to the solution and divided into three different falcon tube containing 30 mL of solution. Titanium dioxide nanoparticles were added to each Petri dishes and the specified amounts as follows: first sample (S1) containing 0.000 g, second sample (S2) 0.500 g and the third sample (S3) 1.000 g were prepared. Solutions were left on the stirrer at 65°C at 450 rpm for 6 hours to become homogeneous. Then, solutions were poured into the respective Petri dishes and kept at -65°C for 24 hours. The fourth sample (S4) was made multilayered by pouring 10 mL of first solution and second solution into the petri dish, placing it in a freezer for a minute and overlaying it with 10 mL of S1 thereafter. Next, the mixtures were placed on a freeze-drying machine for 24 hours, consisting of an 18-hours main drying process and 6 hours of final drying. After the freeze-drying process was done, the porous filler scaffolds were prepared and cut into pieces for further mechanical and biological evaluations (pages 2-3). The porosity percentages can be estimated by inspecting the SEM images. As it is seen in the SEM images, the porosities have a diameter between 100 µm and 200 µm, which shows the spaces between material layers (the examiner notes the space is similar to a void recited in claim 3). Fig. 4 (a b) shows the SEM image of sample 3 with addition of TiO2 and HLA in which the TiO2 nanoparticles have agglomerated arrangement with 20-40 micron size (page 5).
HLA-TiO2 prepared using freeze drying technique is a scaffold which can produce a super porous injectable filler with a specific form. As this project aims to mimic natural bone tissue, the chosen materials can also be used as a cryogen.
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HLA-TiO2 prepared using freeze drying technique is a scaffold which can produce a super porous injectable filler with a specific form. As this project aims to mimic natural bone tissue, the chosen materials can also be used as a cryogen (see conclusion). Jamnezhad et al.’s freeze dried alginate -HA tissues exhibit porous/layered architectures typical of directional ice-templating in such polysaccharides. This matches parallel layers. Jamnezhad et al. teach in bone tissue engineering, scaffolds may form an extracellular matrix (ECM) that can harbor cells, ensure proper biological signaling and facilitate the formation of new tissue scaffolds with suitable and desired topological space. The space in the scaffolds contain cells and able to exchange biological molecules, which may lead to the formation of new hard tissue (see page 2).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Jamnezhad et al. do not specifically teach calcium cation based compounds as a crosslinker. Jamnezhad et al. is also silent with regard to the limitation reciting “wherein the hydrogel has a lamellar morphology”. These deficiencies are cured by the teachings of Afzali et al. and Li et al.
Afzali et al. teach sodium alginate (SA) and hyaluronic acid (HA) lyophilized scaffolds, with varying ratios producing distinct morphologies. Freeze-drying (lyophilization) of alginate-HA composites produces sheet-like/lamellar structures due to ice crystal templating. Afzali et al. describe sheet-like structures, ribbon-like sheets, parallel layered porous morphologies in SA-HA scaffolds (e.g., ribbon-like sheets with a mean pore diameter….showing sheet-like structures; with top/bottom differences from directional freezing effects). Higher SA content yields sheet-like /lamellar forms (see abstract, figure 3 and results (pages 334-340)); SEM showing sheet-like/ribbon-like parallel layered structures in SA:HA composites post lyophilization; wall thickness and pore descriptions confirming lamellar features. Calcium chloride is used in the hydrogel preparation which is a known ionic crosslinker of alginate (see materials and page 5). Afzali et al. teach the solvent displacement method was used to investigate the porosity of the lyophilized scaffolds as previously reported. To determine the geometrical dimensions (thickness and diameter) and to calculate the total pore volume of formulations; a digital Vernier caliper was used. Samples (n = 3) were weighed (W0) and immersed in 10 mL of absolute ethanol for 3 h to allow complete saturation, with the void space in the scaffolds displaced by ethanol. Eventually, the samples were carefully removed from the solvent, quickly blotted with tissue paper approximately for 15 s on each side, and immediately weighed (Wt) to avoid the loss of ethanol. Equation (2) was used to calculate the porosity of the dressings.
Porosity (%) = [(Wt − W0)/(ρethV) × 100)]
ρeth : density of ethanol = 0.789 g/cm3
Li et al. teach hydrogels of calcium alginate are the cross-linked networks containing a large fraction of water, which were used as the precursors of calcium carbonate (CaCO3) mineralization for the first time. The well-defined geometry, the permeability, and the ion-exchange property of these pregels favored the facile fabrication of calcite superstructures through the slow inpouring of ammonia and carbon dioxide gases. When calcium alginate hydrogels sponged up a relatively high amount of liquid, the resulting products with the outside calcite sequences transcribed the spongelike pregel beads with the outside nucleation sites of carboxyl groups. The inner characteristic of these CaCO3 superstructures showed the endocentric growth trends of calcite, indicating the permeability of hydrogel beads and the diffusing directions of permeated gases. In the presence of low liquid content, the pregels favored the formation of calcite superstructures with relatively smooth surfaces, demonstrating the inside lamellar array of calcite nanoparticles. This strategic approach indicated to a great extent the biologically controlled mineralization mechanism, dealing with (1) the preadsorption of calcium ions by the functional groups of biomolecules, (2) the confined crystallization within the three dimensional networks, and (3) the proper arrangement of nanosized calcites by association with the organic architectures. Surprisingly, even the apparently “single-crystalline” CaCO3 was proven to comprise tiny calcite rhombohedrons. Furthermore, these building blocks coaligned each other with respect to the polymers’ conjugated backbones. Therefore, these suggest a novel pathway of multivalent metal pregelation phases for the biomimetic fabrication of functional materials (see abstract). Li et al. explicitly references lyophilized samples (see supporting information Fig S6). The process involves freeze-drying the hydrogel to study its structure. The lyophilized pregels exhibited the cracked sheet-like structure….which the examiner notes that due to the lamellar arrangement of crosslinked alginate molecules. Li et al. further discusses inside lamellar array of calcite nanoparticles within the hydrogel matrix, confirming parallel layered/sheet like organization arising from the crosslinked alginate structure. SEM images of lyophilized hydrogels confirm the morphology. The hydrogels of calcium alginate were prepared as follows. First, the aqueous solutions of sodium alginate (1.0 wt %) and calcium chloride (1.0 mol/L) were prepared. Second, a certain volume of CaCl2 solution (0.5-2.0 mL) was transferred into a 10 mL glass vial containing 5 mL of sodium alginate solution. The admixture was then left undisturbed for 9h to avoid the interfusion of air bubbles into the forming spongelike gel and to ensure the complete exchange of Ca2+ and Na+ ions. Third, after the removal of excess liquid, the lumpish gel was rinsed three times using deionized water and occasionally shaking. Finally, the gel was weighed to evaluate the weight percentage of gel to the gross weight of sodium alginate and calcium chloride solutions (referred to as the percentage of sponged liquid), which was then sealed in the glass bottle waiting for the next conduct (page 3471). Li et al. teach that during the time-dependent experiments of CaCO3 mineralization, the reactions were stopped and the systems were lyophilized to track the formation process of calcite superstructures (Figure 5 and Figure S6 in the Supporting Information). The lyophilized pregels exhibited the cracked sheet-like structure (Figure 5a and Figure S6-a in the Supporting Information), which was due to the lamellar arrangement of cross-linked alginate molecules with the high swelling degree. Figure 5b, as well as Figure S6-b in the Supporting Information, further indicated that these sheets comprised the gel spheres of calcium alginate (page 3473).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Jamnezhad et al. by using calcium based compound as a crosslinker and create a hydrogel with a lamellar morphology because Afzali et al. teach sodium alginate (SA) and hyaluronic acid (HA) lyophilized scaffolds, with varying ratios producing distinct morphologies. Freeze-drying (lyophilization) of alginate-HA composites produces sheet-like/lamellar structures due to ice crystal templating. Afzali et al. describe sheet-like structures, ribbon-like sheets, parallel layered porous morphologies in SA-HA scaffolds (e.g., ribbon-like sheets with a mean pore diameter….showing sheet-like structures; with top/bottom differences from directional freezing effects). Higher SA content yields sheet-like /lamellar forms (see abstract, figure 3 and results (pages 334-340)); SEM showing sheet-like/ribbon-like parallel layered structures in SA:HA composites post lyophilization; wall thickness and pore descriptions confirming lamellar features. Calcium chloride is used in the hydrogel preparation which is a known ionic crosslinker of alginate (see materials and page 5). Additionally, Li et al. teach hydrogels of calcium alginate are the cross-linked networks containing a large fraction of water, which were used as the precursors of calcium carbonate (CaCO3) mineralization for the first time. The well-defined geometry, the permeability, and the ion-exchange property of these pregels favored the facile fabrication of calcite superstructures through the slow inpouring of ammonia and carbon dioxide gases. When calcium alginate hydrogels sponged up a relatively high amount of liquid, the resulting products with the outside calcite sequences transcribed the spongelike pregel beads with the outside nucleation sites of carboxyl groups. The inner characteristic of these CaCO3 superstructures showed the endocentric growth trends of calcite, indicating the permeability of hydrogel beads and the diffusing directions of permeated gases. In the presence of low liquid content, the pregels favored the formation of calcite superstructures with relatively smooth surfaces, demonstrating the inside lamellar array of calcite nanoparticles. This strategic approach indicated to a great extent the biologically controlled mineralization mechanism, dealing with (1) the preadsorption of calcium ions by the functional groups of biomolecules, (2) the confined crystallization within the three dimensional networks, and (3) the proper arrangement of nanosized calcites by association with the organic architectures. Surprisingly, even the apparently “single-crystalline” CaCO3 was proven to comprise tiny calcite rhombohedrons. Furthermore, these building blocks coaligned each other with respect to the polymers’ conjugated backbones. Therefore, these suggest a novel pathway of multivalent metal pregelation phases for the biomimetic fabrication of functional materials (see abstract). Li et al. explicitly references lyophilized samples (see supporting information Fig S6). The process involves freeze-drying the hydrogel to study its structure. The lyophilized pregels exhibited the cracked sheet-like structure….which the examiner notes that due to the lamellar arrangement of crosslinked alginate molecules. Li et al. further discusses inside lamellar array of calcite nanoparticles within the hydrogel matrix, confirming parallel layered/sheet like organization arising from the crosslinked alginate structure. SEM images of lyophilized hydrogels confirm the morphology. The hydrogels of calcium alginate were prepared as follows. First, the aqueous solutions of sodium alginate (1.0 wt %) and calcium chloride (1.0 mol/L) were prepared. Second, a certain volume of CaCl2 solution (0.5-2.0 mL) was transferred into a 10 mL glass vial containing 5 mL of sodium alginate solution. The admixture was then left undisturbed for 9h to avoid the interfusion of air bubbles into the forming spongelike gel and to ensure the complete exchange of Ca2+ and Na+ ions. Third, after the removal of excess liquid, the lumpish gel was rinsed three times using deionized water and occasionally shaking. Finally, the gel was weighed to evaluate the weight percentage of gel to the gross weight of sodium alginate and calcium chloride solutions (referred to as the percentage of sponged liquid), which was then sealed in the glass bottle waiting for the next conduct (page 3471). Li et al. teach that during the time-dependent experiments of CaCO3 mineralization, the reactions were stopped and the systems were lyophilized to track the formation process of calcite superstructures (Figure 5 and Figure S6 in the Supporting Information). The lyophilized pregels exhibited the cracked sheet-like structure (Figure 5a and Figure S6-a in the Supporting Information), which was due to the lamellar arrangement of cross-linked alginate molecules with the high swelling degree. Figure 5b, as well as Figure S6-b in the Supporting Information, further indicated that these sheets comprised the gel spheres of calcium alginate (page 3473). Additionally, Li et al. teach hydrogels of calcium alginate are the cross-linked networks containing a large fraction of water, which were used as the precursors of calcium carbonate (CaCO3) mineralization for the first time. The well-defined geometry, the permeability, and the ion-exchange property of these pregels favored the facile fabrication of calcite superstructures through the slow inpouring of ammonia and carbon dioxide gases. When calcium alginate hydrogels sponged up a relatively high amount of liquid, the resulting products with the outside calcite sequences transcribed the spongelike pregel beads with the outside nucleation sites of carboxyl groups. The inner characteristic of these CaCO3 superstructures showed the endocentric growth trends of calcite, indicating the permeability of hydrogel beads and the diffusing directions of permeated gases. In the presence of low liquid content, the pregels favored the formation of calcite superstructures with relatively smooth surfaces, demonstrating the inside lamellar array of calcite nanoparticles. This strategic approach indicated to a great extent the biologically controlled mineralization mechanism, dealing with (1) the preadsorption of calcium ions by the functional groups of biomolecules, (2) the confined crystallization within the three dimensional networks, and (3) the proper arrangement of nanosized calcites by association with the organic architectures. Surprisingly, even the apparently “single-crystalline” CaCO3 was proven to comprise tiny calcite rhombohedrons. Furthermore, these building blocks coaligned each other with respect to the polymers’ conjugated backbones. Therefore, these suggest a novel pathway of multivalent metal pregelation phases for the biomimetic fabrication of functional materials (see abstract). Li et al. explicitly references lyophilized samples (see supporting information Fig S6). The process involves freeze-drying the hydrogel to study its structure. The lyophilized pregels exhibited the cracked sheet-like structure….which the examiner notes that due to the lamellar arrangement of crosslinked alginate molecules. Li et al. further discusses inside lamellar array of calcite nanoparticles within the hydrogel matrix, confirming parallel layered/sheet like organization arising from the crosslinked alginate structure. SEM images of lyophilized hydrogels confirm the morphology. The hydrogels of calcium alginate were prepared as follows. First, the aqueous solutions of sodium alginate (1.0 wt %) and calcium chloride (1.0 mol/L) were prepared. Second, a certain volume of CaCl2 solution (0.5-2.0 mL) was transferred into a 10 mL glass vial containing 5 mL of sodium alginate solution. The admixture was then left undisturbed for 9h to avoid the interfusion of air bubbles into the forming spongelike gel and to ensure the complete exchange of Ca2+ and Na+ ions. Third, after the removal of excess liquid, the lumpish gel was rinsed three times using deionized water and occasionally shaking. Finally, the gel was weighed to evaluate the weight percentage of gel to the gross weight of sodium alginate and calcium chloride solutions (referred to as the percentage of sponged liquid), which was then sealed in the glass bottle waiting for the next conduct (page 3471). Li et al. teach that during the time-dependent experiments of CaCO3 mineralization, the reactions were stopped and the systems were lyophilized to track the formation process of calcite superstructures (Figure 5 and Figure S6 in the Supporting Information). The lyophilized pregels exhibited the cracked sheet-like structure (Figure 5a and Figure S6-a in the Supporting Information), which was due to the lamellar arrangement of cross-linked alginate molecules with the high swelling degree. Figure 5b, as well as Figure S6-b in the Supporting Information, further indicated that these sheets comprised the gel spheres of calcium alginate (page 3473). One of ordinary skill in the art would combine alginate (Ca2+-crosslinked) with hyaluronate in lyophilized scaffolds for enhanced biocompatibility, hydration, and osteoconductivity in bone fillers. Directional freezing/lyophilization predictably yields lamellar/parallel layered morphology via ice templating as demonstrated by Jamnezhad et al., Afzali et al., and Li et al. One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Jamnezhad et al., Afzali et al., and Li et al. because all of the references teach alginate and/or hyaluronate based scaffolds made by freeze drying to produce parallel multilayer structures. With regard to the selection of a given design of the number and types of layers, channels, voids, shapes, sizes it is prima facie obvious to change such parameters (see MPEP 2144.04).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 4-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jamnezhad et al. (Nanomed Res J 5(4):1-10, 2020) in view of Afzali et al. (Polymers, 14, 1550, Pages 1-29, 2022) and Li et al. (Crystal Growth & Design, Vol. 9, No. 8, 2009 3470-3476) as applied to claims 1-3, 6-10, 12-14, and 21-23 above, and further in view of Serafin et al. (International Journal of Biological Macromolecules, 233, 2023, 123438).
Applicants’ claims
Applicants claim a hydrogel system comprising a lyophilized hydrogel comprising alginate and hyaluronate; and a crosslinker; wherein the hydrogel has a lamellar morphology comprising parallel layers of the hydrogel. Claim 4 recites the hydrogel system of claim 3, wherein: the void has a depth between 400 and 1900 microns; the depth starts from an outer surface of the hydrogel and extends into the hydrogel. Claim 5 recites the hydrogel system of claim 4, wherein the depth extends into the hydrogel and orthogonal to the outer surface of the hydrogel.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Jamnezhad et al., Afzali et al., and Li et al. are described in detail above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Jamnezhad et al., Afzali et al., and Li et al. do not specifically teach the depth of the voids which the examiner interpreted as the pore sizes as recited in claim 4, stiffness, toughness and hardness of the hydrogel. These deficiencies are cured by the teachings of Serafin et al.
Serafin et al. teach the currently presented study aims to comprehensively characterize commonly used hydrogel systems comprised of alginate, alginate blends with HA/gelatin and gelatin blended with HA to provide a robust evaluation of their physico-chemical behaviors, such as porosity, mechanical properties, swell ability, rheological behavior and cellular biocompatibility. Such material assessment of representative concentrations of natural biomaterial hydrogel blends will allow for informed hydrogel choice for specific targeted TE treatments (see introduction). Porosity and pore size of scaffolds for TE strategies is one of the most important factors to consider when determining the efficacy of the scaffold. When implanted in-situ, the surrounding cellular environment requires the ability to exchange oxygen, nutrients, and waste removal for its survival. When these functions are not facilitated by a block, nonporous scaffold, the cellular ability to regenerate the damaged tissue/organ of interest is severely diminished. Tailoring the pore size to specific cell needs is also important, as for example pore size that is too small does not support cellular migration, while too large of a pore size decreases cellular attachment. These desired parameters can change when considering different cell types, but generally pore size ranging between 100 and 500 μm is regarded as optimal, with most of the described hydrogel scaffolds possessing pore sizes within this range. It should be noted that the process of freezing has a significant effect on the formation of pores prior to lyophilisation. The hydrogel samples presented here were initially frozen at 20 degree Celsius for a period of 2 h, followed by freezing in -80 ºC until lyophilisation. The slow freezing process allows for the formation of ice crystals from the water component of the hydrogels within, leaving behind pores within the architecture when freeze-dried. Alternatively, when hydrogels samples are frozen quickly when submerged in liquid nitrogen at 196 ◦ C, the formation of ice crystals is rapid, resulting in small, collapsed, striated porosity (shown in Supplementary Information Fig. S5) (see results and discussion). Serafin et al. shows Young’s Modulus varying with alginate/HA ratios. Freeze dried versions achieve values optimized for nerve/bone/cartilage (e.g., 0.1-10 MPa).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Jamnezhad et al., Afzali et al., and Li et al. by preparing voids or pores with sizes as recited because Serafin et al. teach the currently presented study aims to comprehensively characterize commonly used hydrogel systems comprised of alginate, alginate blends with HA/gelatin and gelatin blended with HA to provide a robust evaluation of their physico-chemical behaviors, such as porosity, mechanical properties, swell ability, rheological behavior and cellular biocompatibility. Such material assessment of representative concentrations of natural biomaterial hydrogel blends will allow for informed hydrogel choice for specific targeted TE treatments (see introduction). One of ordinary skill in the art would have been motivated to do so because Serafin et al. teach that porosity and pore size of scaffolds for TE strategies is one of the most important factors to consider when determining the efficacy of the scaffold. When implanted in-situ, the surrounding cellular environment requires the ability to exchange oxygen, nutrients, and waste removal for its survival. When these functions are not facilitated by a block, nonporous scaffold, the cellular ability to regenerate the damaged tissue/organ of interest is severely diminished. Tailoring the pore size to specific cell needs is also important, as for example pore size that is too small does not support cellular migration, while too large of a pore size decreases cellular attachment. These desired parameters can change when considering different cell types, but generally pore size ranging between 100 and 500 μm is regarded as optimal, with most of the described hydrogel scaffolds possessing pore sizes within this range. It should be noted that the process of freezing has a significant effect on the formation of pores prior to lyophilisation. The hydrogel samples presented here were initially frozen at 20 degree Celsius for a period of 2 h, followed by freezing in -80 ºC until lyophilisation. The slow freezing process allows for the formation of ice crystals from the water component of the hydrogels within, leaving behind pores within the architecture when freeze-dried. Alternatively, when hydrogels samples are frozen quickly when submerged in liquid nitrogen at 196 ◦ C, the formation of ice crystals is rapid, resulting in small, collapsed, striated porosity (shown in Supplementary Information Fig. S5) (see results and discussion). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Jamnezhad et al., Afzali et al., Li et al., and Serafin et al. because all of the references teach alginate and/or hyaluronate based scaffolds made by freeze drying. With regard to the selection of a given design of the number and types of layers, channels, voids, shapes, sizes it is prima facie obvious to change or optimize such parameters (see MPEP 2144.04).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 15-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jamnezhad et al. (Nanomed Res J 5(4):1-10, 2020) in view of Afzali et al. (Polymers, 14, 1550, Pages 1-29, 2022) and Li et al. (Crystal Growth & Design, Vol. 9, No. 8, 2009 3470-3476) as applied to claims 1-3, 6-10, 12-14, and 21-23 above, and further in view of Coury et al. (US Patent No. 7,008,635).
Applicants’ claims
Applicants claim a hydrogel system comprising a lyophilized hydrogel comprising alginate and hyaluronate; and a crosslinker; wherein the hydrogel has a lamellar morphology comprising parallel layers of the hydrogel. Dependent claims 15-20 recite different properties of the hydrogel.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Jamnezhad et al., Afzali et al., and Li et al. are described in detail above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Jamnezhad et al., Afzali et al., and Li et al. do not specifically teach the different properties of the hydrogel recited in claims 15-20. These deficiencies are cured by the teachings of Coury et al.
Coury et al. teach hydrogels intended for orthopedic applications, including repair and regeneration of cartilage, bone, joint surfaces and related tissues, must possess greater strength and toughness than hydrogels used in soft tissue repair. A hydrogel formulation is provided which has high strength, toughness, a suitable mechanical modulus and low equilibrium hydration. It may also have controlled porosity or degradation time. It can be made to polymerize in situ with high ("good" to "excellent") adherence to target tissue or surfaces. A preferred formulation for forming such gels comprises 40 to 80% by weight of a low-molecular weight polar monomer and 30 to 10% of a hydrophilic macromeric crosslinker (abstract). Polymeric materials have been developed which can be effective in treatment of orthopedic tissues, such as cartilage, bone and accessory structures, and implants. In one embodiment, the material includes a mixture of two components which copolymerize to form a hydrogel that contains hydrophilic and hydrophobic regions. The first component is covalently-crosslinkable, hydrophilic, polymeric, of high biocompatibility, and optionally spontaneously hydrolyzing ("biodegradable"). It is preferably sufficiently hydrophilic to be water-soluble at a temperature between about 0 and 70.degree. C. The second component is more hydrophobic (although it is preferably water-soluble under the same conditions), is covalently polymerizable, provides structural strength and limits the water absorption capacity of the formed gel. Upon reaction in situ in the presence of polymerization initiators bound to or adhered to the tissue ("priming systems"), the resulting polymerized hydrogel adheres tightly to the tissues, and has suitable mechanical properties, including toughness, strength and resiliency to facilitate repair or regeneration of the tissue. It also remains as a hydrogel, retaining the advantages of biocompatibility and lubricity. The hydrogel is optionally biodegradable (see summary of invention). MODULUS: A material's modulus is the ratio of stress (applied force per unit area) over strain (ratio of compressed or stretched length to original length). It is expressed in units of force per unit area, such as Pascals or PSI, and is typically measured quantitatively on a device such as an Instron.RTM. mechanical tester. The gels described herein have a modulus that is quite high for a hydrogel. The most preferred values of the tensile or compressive modulus, at small strains and after swelling, are over 1 megaPascal (MPa). Gels with a post-swelling modulus of 500 kiloPascals (kPa) or greater are preferred. Gels with a modulus of 100 kPa, preferably 200 kPa or more, are of use in the invention. Gels with a modulus above about 50 kPa can be used in low-stress situations. TOUGHNESS: The values of elongation and modulus can be combined to give a quantitative measurement of toughness, which is the area under the stress-strain curve to the failure point. However, there are several potential complicating factors, such as rate of elongation and shape of the test piece. For the purposes described herein, the area under the curve should only be used as a means of comparison of related samples. "Toughness" is used herein only in a comparative sense unless otherwise specified. A qualitative measure of toughness, for gels of a particular thickness, is obtained by compressing a piece of gel between the jaws of a locking surgical hemostat. A standard compressive load can be achieved by specifying how many "clicks"--detents giving progressively higher compressive force--on the locking mechanism are used. Gels that do not fracture in this test are tougher than those that do fracture.
Although poly(ethylene glycol) (PEG) is preferred for forming the macromeric backbone because of its biocompatibility and stability, other macromolecules are also useful. These include, as illustrated below, PEG--PPO (copolymers of polyethylene glycol and polypropylene oxide), hydrophilic segmented urethanes, and multivalently-derivatizable surfactants, in each case derivatized to carry reactive groups. A wide variety of other hydrophilic natural and synthetic polymers are suitable for use in backbones for forming macromers to make the hydrogels. These include hydrophilic synthetic polymers, such as polyvinylpyrrolidone, polyvinyl alcohol (including partially deacetylated polyvinylacetate), poly[meth]acrylic acid and poly[meth]acrylamides (where "[meth]" indicates optional methyl substitution of the acrylate group), and mixed water-soluble copolymers such as copolymers of maleic acid and ethylene. Natural, synthetic and semi-synthetic saccharides and polysaccharides include hydroxyalkyl celluloses, dextran, Ficoll.TM., bacterial fermentation products such as xanthan or gellan, and food-grade materials such as alginates, carrageenans, pectins, agars, glucomannans, galactomannans, hyaluronic acid, heparin, chondroitin sulfate, and other glycosaminoglycans, and starch. Proteins and nucleic acids can be used. Multivalently-substitutable lipids, such as "dimer fatty acid", monoacylglycerol, phosphatidyl inositol, cardiolipin, and derivatives thereof, can also be used as components of a backbone for forming a macromer. Moreover, these materials have the appropriate mechanical strength and other mechanical properties, such as resilience and stiffness, to withstand the forces applied in these anatomical situations. In addition, the same physical properties make the hydrogels suitable for coating of implants applied to the joints and similar structures. Among the therapeutic benefits provided by these hydrogels is the provision of lubricity to a treated surface. The hydrogel coating can simulate the natural lubricity of an orthopedic surface, such as cartilage, thereby allowing favorable joint articulation while preventing damage as the underlying tissue heals.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Jamnezhad et al., Afzali et al., and Li et al. by preparing hydrogels with properties as recited in claims 15-20 because Coury et al. teach hydrogels intended for orthopedic applications, including repair and regeneration of cartilage, bone, joint surfaces and related tissues, must possess greater strength and toughness than hydrogels used in soft tissue repair. A hydrogel formulation is provided which has high strength, toughness, a suitable mechanical modulus and low equilibrium hydration. It may also have controlled porosity or degradation time. It can be made to polymerize in situ with high ("good" to "excellent") adherence to target tissue or surfaces. A preferred formulation for forming such gels comprises 40 to 80% by weight of a low-molecular weight polar monomer and 30 to 10% of a hydrophilic macromeric crosslinker (abstract). Polymeric materials have been developed which can be effective in treatment of orthopedic tissues, such as cartilage, bone and accessory structures, and implants. In one embodiment, the material includes a mixture of two components which copolymerize to form a hydrogel that contains hydrophilic and hydrophobic regions. The first component is covalently-crosslinkable, hydrophilic, polymeric, of high biocompatibility, and optionally spontaneously hydrolyzing ("biodegradable"). It is preferably sufficiently hydrophilic to be water-soluble at a temperature between about 0 and 70.degree. C. The second component is more hydrophobic (although it is preferably water-soluble under the same conditions), is covalently polymerizable, provides structural strength and limits the water absorption capacity of the formed gel. Upon reaction in situ in the presence of polymerization initiators bound to or adhered to the tissue ("priming systems"), the resulting polymerized hydrogel adheres tightly to the tissues, and has suitable mechanical properties, including toughness, strength and resiliency to facilitate repair or regeneration of the tissue. It also remains as a hydrogel, retaining the advantages of biocompatibility and lubricity. The hydrogel is optionally biodegradable (see summary of invention). MODULUS: A material's modulus is the ratio of stress (applied force per unit area) over strain (ratio of compressed or stretched length to original length). It is expressed in units of force per unit area, such as Pascals or PSI, and is typically measured quantitatively on a device such as an Instron.RTM. mechanical tester. The gels described herein have a modulus that is quite high for a hydrogel. The most preferred values of the tensile or compressive modulus, at small strains and after swelling, are over 1 megaPascal (MPa). Gels with a post-swelling modulus of 500 kiloPascals (kPa) or greater are preferred. Gels with a modulus of 100 kPa, preferably 200 kPa or more, are of use in the invention. Gels with a modulus above about 50 kPa can be used in low-stress situations. TOUGHNESS: The values of elongation and modulus can be combined to give a quantitative measurement of toughness, which is the area under the stress-strain curve to the failure point. However, there are several potential complicating factors, such as rate of elongation and shape of the test piece. For the purposes described herein, the area under the curve should only be used as a means of comparison of related samples. "Toughness" is used herein only in a comparative sense unless otherwise specified. A qualitative measure of toughness, for gels of a particular thickness, is obtained by compressing a piece of gel between the jaws of a locking surgical hemostat. A standard compressive load can be achieved by specifying how many "clicks"--detents giving progressively higher compressive force--on the locking mechanism are used. Gels that do not fracture in this test are tougher than those that do fracture. Although poly(ethylene glycol) (PEG) is preferred for forming the macromeric backbone because of its biocompatibility and stability, other macromolecules are also useful. These include, as illustrated below, PEG--PPO (copolymers of polyethylene glycol and polypropylene oxide), hydrophilic segmented urethanes, and multivalently-derivatizable surfactants, in each case derivatized to carry reactive groups. A wide variety of other hydrophilic natural and synthetic polymers are suitable for use in backbones for forming macromers to make the hydrogels. These include hydrophilic synthetic polymers, such as polyvinylpyrrolidone, polyvinyl alcohol (including partially deacetylated polyvinylacetate), poly[meth]acrylic acid and poly[meth]acrylamides (where "[meth]" indicates optional methyl substitution of the acrylate group), and mixed water-soluble copolymers such as copolymers of maleic acid and ethylene. Natural, synthetic and semi-synthetic saccharides and polysaccharides include hydroxyalkyl celluloses, dextran, Ficoll.TM., bacterial fermentation products such as xanthan or gellan, and food-grade materials such as alginates, carrageenans, pectins, agars, glucomannans, galactomannans, hyaluronic acid, heparin, chondroitin sulfate, and other glycosaminoglycans, and starch. Proteins and nucleic acids can be used. Multivalently-substitutable lipids, such as "dimer fatty acid", monoacylglycerol, phosphatidyl inositol, cardiolipin, and derivatives thereof, can also be used as components of a backbone for forming a macromer. Moreover, these materials have the appropriate mechanical strength and other mechanical properties, such as resilience and stiffness, to withstand the forces applied in these anatomical situations. In addition, the same physical properties make the hydrogels suitable for coating of implants applied to the joints and similar structures. Among the therapeutic benefits provided by these hydrogels is the provision of lubricity to a treated surface. The hydrogel coating can simulate the natural lubricity of an orthopedic surface, such as cartilage, thereby allowing favorable joint articulation while preventing damage as the underlying tissue heals. One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Jamnezhad et al., Afzali et al., Li et al., and Serafin et al. because all of the references teach alginate and/or hyaluronate based scaffolds made by freeze drying. One of ordinary skill in the art as demonstrated by Coury et al. can optimize these parameters as they are result effective parameters. Furthermore since the combined teachings of the references met the structure all of those properties would necessarily be there and are substantially similar as they are innate properties of the hydrogel. With regard to the selection of a given design of the number and types of layers, channels, voids, shapes, sizes it is prima facie obvious to change or optimize such parameters (see MPEP 2144.04).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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