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 .
Election/Restrictions
Applicant’s election without traverse of Group II (Claims 3-10; drawn to a method for preparing a hydrogel containing a polymer nanofiber into which a sulfate group is introduced) in the reply filed on December 20, 2024, is acknowledged.
Claims 1-2 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups I and III-IV), there being no allowable generic or linking claim.
DETAILED ACTION
The claims filed on June 18, 2025, have been acknowledged. Claims 3-10 were amended. Claims 1-12 are pending. In light of the Applicant’s elected invention, claims 1-2 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 3-10 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from KR10-2020-0098581 filed on August 6, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received September 22, 2021. While a certified copy of the foreign patent application KR10-2020-0098581 is provided with the instant application, a certified English translation of said foreign patent applications have not been provided.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 3-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments to claim 3 to recite “the polymer compound nanofibers” instead of “resultant” and “the polymer compound solution” instead of “the solution”, and to claim 9 to recite “the sulfate group” instead of “a sulfate group”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 3-4 and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Mirzaei et al. (Nanomed J 1: 137-146. 2014) and Francesko et al. (Adv Biochem Engin/Biotechnol 125: 1-27. 2011), as evidenced by Thompson et al. (Polymer 48: 6913-6922. 2007) and Parhi (Adv Pharm Bull 7: 515-530. 2017).
Regarding claim 3, Mizraei teaches a method of preparing crosslinked chitosan (CS) nanofibers. Chitosan and polyethylene oxide (PEO) solutions were prepared and mixed together at a weight ratio of CS/PEO of 90/10;
The crosslinking agent genipin was added to the CS/PEO solution at a CS/genipin weight ratio of 100/6, 100/3, 100/1, or100/.5;
This solution was immediately electrospun to produce nanofibers;
The nanofibers were exposed to water vapor in a desiccator to crosslink the chitosan nanofibers by genipin (page 139, column 1, paragraph 2 and page 139, column 2, paragraph 2-page 140, column 1 ,paragraph 1).
Mizraei teaches that their electrospun nanofibers would be used for biomedical applications such as wound dressing and scaffold for tissue engineering without the concern of toxicity (abstract)
Mizraei does not teach wherein the nanofibers have a sulfate group introduced into the polymer nanofibers nor wherein they hydrated the nanofibers to generate a hydrogel.
Francesko teaches that chitosan modifications improve their biofunctionality (biocompatibility, biodegradability, antibacterial activity and wound-healing promoting) while preserving the original physicochemical and biochemical properties of the polymers and widening their application potential. Francesko teaches that N-Sulfation of chitosan is a known modification comprising combinations of sulfating agents and reaction media for sulfation of chitosan. The most commonly used is chlorosulfonic acid in homogeneous or heterogeneous conditions in DMF, DMF–dichloroacetic acid, tetrahydrofuran, and formic acid at different temperature range or under microwave irradiation. Francesko teaches that sulfated chitosans are analogues to the natural blood anticoagulant heparin a highly sulfated glucosaminoglycan used in medicine for treatment of various cardiovascular diseases (page 7, paragraph 2-page 9, paragraph 1).
Francesko teaches that chitosan has also been combined into a PEC [polyelectrolyte complex] membrane for treatment of highly exuding wounds and prevention of bacterial infections. In skin repair the most efficient chitosan PEC hydrogels are those with glycosaminoglycans (GAG)—long unbranched polysaccharides with repeating disaccharide units. Anionic in nature, GAGs are found in the skin matrix and are well known to bind and modulate the activity of a number of cytokines and growth factors. Membranes of chitosan combined with heparin stimulated the dermal wound healing by slowly releasing heparin into the wound area in human skin, thereby protecting locally produced growth factors. Chitosan-heparin hydrogels were also more efficient in treatment of full thickness skin defects in rats compared to chitosan alone (page 13, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the chitosan nanofibers of Mizraei by introducing sulfate groups and forming hydrogel, as identified by Francesko, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Francesko teaches that chitosan modifications improve their biofunctionality while preserving the original physicochemical and biochemical properties of the polymers. Furthermore, Francesko teaches that sulfated chitosans are analogues to the natural blood anticoagulant heparin and hydrogels of chitosan combined with heparin stimulated the dermal wound healing by slowly releasing heparin into the wound area in human skin, thereby protecting locally produced growth factors. Chitosan-heparin hydrogels were also more efficient in treatment of full thickness skin defects in rats compared to chitosan alone. As Mizraei and Francesko are focused on nanofiber constructs for wound healing, it would have been obvious to introduce a sulfate group onto the chitosan nanofibers as this generates an analogue to heparin and then generate a hydrogel as chitosan-heparin hydrogels have been shown to improve wound healing more than chitosan alone. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation “wherein, in the forming the crosslink between the polymer compound nanofibers, the polymer compound nanofibers are connected to each other by the crosslink to form a network structure”, Mizraei shows that crosslinking of the chitosan/PEO nanofibers with genipin leads to a network structure (Figure 3).
Regarding the limitation “empty space of the network structure is filled with water as gelling proceeds in the hydrating the polymer compound nanofibers”, as stated supra, Francesko provides motivation for forming a chitosan hydrogel as the hydrogels are more efficient than chitosan alone (page 13, paragraph 2) and Parhi evidences that when a dry hydrogel comes in contact with water, absorption of water into its matrix starts. At first water molecules entering the matrix will directly attach to the hydrophilic groups, forming hydrophilic bound water or primary bound water. The polymeric network swells because of complete hydration of the polar groups that resulted in the exposer of hydrophobic groups. These exposed groups also interact with water molecules, leading to hydrophobically-bound water, or ‘secondary bound water’. The combination of primary and secondary bound water is often called the bound water. This water is considered as integral part of hydrogel structure and can only be separated out from the hydrogel under extreme conditions. After the saturation of hydrophilic and hydrophobic groups, the additional water that is absorbed due to the osmotic driving force of the network chains is called free water or bulk water (page 516, column 1, paragraph 4).
Therefore, it would naturally flow that the gelling process of the chitosan/PEO crosslinked nanofibers would lead to water filling the empty space and hydrating the polymer compound nanofibers to form a hydrogel.
Regarding claim 4, Thompson evidences that the effects of 13 material and operating parameters on electrospun fiber diameters. The results show that the five parameters (volumetric charge density, distance from nozzle to collector, initial jet/orifice radius, relaxation time, and viscosity) have the most significant effect on the jet radius (i.e. fiber diameter). The other parameters (initial polymer concentration, solution density, electric potential, perturbation frequency, and solvent vapor pressure) have moderate effects on the jet radius. Parameters relative humidity, surface tension, and vapor diffusivity have minor effects on the jet radius. As such, there are at least 13 parameters that may be adjusted to control the diameter of the fiber.
Regarding claim 7, as stated supra, Mizraei teaches that the crosslinking agent is genipin (page 139, column 2, paragraph 7-9).
Regarding claim 8, as stated supra, Mizraei teaches that the CS/genipin weight ratio is 100/6 (i.e. 0.06) (Table 2).
Regarding claims 9-10, as stated supra, Francesko teaches that chlorosulfonic acid is the most commonly used sulfating agent for the sulfonation of chitosan (page 8, paragraph 4).
Response to Arguments
Applicant's arguments filed June 18, 2025, are acknowledged.
Applicant argues that newly amended claim 3 contains the patentable feature of “… in the forming the crosslink between … as gelling proceeds in hydrating the polymer compound nanofibers” that is not taught by Mizraei, Francesko, and Thompson as they are silent regarding the newly amended patentable limitation (page 6, paragraph 3-page 10, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As stated in the rejection above, Mizraei shows that crosslinking of the chitosan/PEO nanofibers with genipin leads to a network structure (Figure 3), Francesko provides motivation for forming a chitosan hydrogel as the hydrogels are more efficient than chitosan alone (page 13, paragraph 2), and Parhi evidences that when a dry hydrogel comes in contact with water, absorption of water into its matrix starts. Therefore, the newly amended claim limitation is not considered to be a patentable feature as the features are taught in the prior art.
Furthermore, Applicant disagrees it would have been obvious to modify the chitosan nanofibers of Mizraei by introducing sulfate groups and forming a hydrogel. Applicant argues that Mizraei has no motivation to include the claimed sulfate group as Mizraei is focused on enhancing water-stability of the chitosan/PEO nanofibers using genipin. Mizraei is only focused on keeping the water stability of the chitosan/PEO nanofibers to ensure they retain their fibrous structure after immerging in PBS for 24 hours.
In contrast, in the present application, the introduction of a sulfate group is a fundamental step for creating a hydrogel that precisely mimics the extracellular matrix (ECM) in vivo. By introducing sulfate groups directly into structural proteins such as collagen or gelatin, which are major components of the ECM rather than just polysaccharides used in Mirzaei and Francesko, the claimed method aims to replicate not only "the physical three-dimensional structure" but also "the degree of water swelling" of the natural ECM. Applicant cites to Figure 4 and example 2 to show that adding the sulfate group to the nanofibers increased the degree of water swelling. Therefore, the effect of the claimed sulfate group is fundamentally opposite to Mirzaei's purpose of preserving fibrous structure against excessive swelling that causes structural loss. Introducing sulfate would likely lead to increased water uptake and a parting of the network, potentially undermining Mirzaei's core goal of maintaining fibrous integrity (page 6, paragraph 3-page 10, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, it is noted that the features of cross-linking structural proteins such as collagen or gelatin, which are major components of the ECM rather than just polysaccharides to replicate not only "the physical three-dimensional structure" but also "the degree of water swelling" of the natural ECM features are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997) (The court held that the PTO is not required, in the course of prosecution, to interpret claims in applications in the same manner as a court would interpret claims in an infringement suit. Rather, the “PTO applies to verbiage of the proposed claims the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in applicant’s specification.”). See MPEP 2111.
Mizraei directly contemplates that nanofibrous chitosan matrices can be used for medical applications as they mimic the natural ECM, in which cells can attach, proliferate, and differentiate. As part of this application, Mizraei identifies that chitosan-based electrospun nanofibers are not stable in biological medium and they easily swell and lose their fibrous structure in contact with water. Therefore, chitosan-based nanofibers need to be crosslinked to maintain their structural integrity. As such, Mizraei examines the use of genipin as a less toxic crosslinking agent. As part of their study, they also perform cell attachment experiments with fibroblast cells. Furthermore, Mizraei identifies chitosan cross-linked by genipin to be known to form hydrogels (page 138, column 1, paragraph 1-page 139, column 1, paragraph 3). As such, the main purpose of Mizraei is to determine the suitability of cross-linking chitosan/PEO nanofibers with genipin for potential use in medical applications.
Furthermore, Mizraei teaches that crosslinking chitosan/PEO nanofibers with genipin through exposure to water vapor allowed the nanofibers to retain their fibrous structure after immerging in water (page 142, column 2, paragraph 1-page 143, column 1, paragraph 1). Mizraei does not suggest that additional modifications to the chitosan would lead to a disruption of the nanofibrous structure. On the contrary, in order to complete the art of record and rebut Applicant’s arguments, Chen et al. (Sci China Chem 56. 1701-1709. 2013) evidences that they generated hydrogels comprising enzymatically cross-linked sulfated chitosan (whole document). Therefore, it would have been well understood in the art that modifying chitosan with a sulfate group could occur when generating a sulfated chitosan hydrogel with a reasonable expectation of success.
Additionally, regarding Applicant’s statement that the sulfate group is fundamentally opposed to Mizraei’s purpose of preserving fibrous structure, Arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements regarding the general interchangeability of one component for another or the addition or deletion of one component is never straightforward or predictable in an unpredictable art, are not evidence without a supporting declaration. Furthermore, as shown by Chen, the art provides evidence that sulfating a chitosan as part of a hydrogel would not cause structural integrity of the nanofibers to be lost.
As such, Applicants arguments are unpersuasive.
Claims 3-5, 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Siimon et al. (Materials Science and Engineering C 42: 538–545. 2014), Casper et al. (Biomacromolecules 8: 1116-1123. 2007), and Lee et al. (App Mater Interfaces 6: 9338-9348. 2014), as evidenced by Thompson et al. (Polymer 48: 6913-6922. 2007) and Parhi (Adv Pharm Bull 7: 515-530. 2017).
Regarding claim 3, Siimon teaches a method of generating gelatin nanofibers with glucose crosslinking, comprising:
Preparing a 10M aqueous acetic acid solution (a polymer compound solution preparing step);
Gelatin was mixed with glucose (a crosslinking agent) at different ratios (5-30%);
The mixtures were dissolved in 10 M aqueous acetic acid solution at about 40 °C by vigorous stirring to obtain solutions containing 25% gelatin
These solutions underwent electrospinning to form nanofibers
The nanofibers were cross-linked by placing them in an oven for 3 hours (abstract, page 539, column 1, paragraphs 4-5, and Figure 1).
Siimon teaches that cell viability remained high for 5% glucose concentration in both type A and type B gelatin (Figure 5) suggesting these nanofibers are suitable for tissue engineering (abstract).
Siimon does not teach a sulfate group introducing step.
However, Casper teaches a method of producing electrospun gelatin nanofibers wherein a bioactive recombinant fragment of perlecan is attached to the gelatin nanofibers. Fibers were coated, after processing, with perlecan domain I (PlnDI) to improve binding of basic fibroblast growth factor (FGF-2), which binds to native heparan sulfate chains on PlnDI. PlnDI-coated electrospun collagen fibers were more effective at binding FGF-2. Because FGF-2 modulates cell growth, differentiation, migration and survival, the ability to effectively bind FGF-2 to an electrospun matrix is a key improvement in creating a successful tissue engineering scaffold (abstract, page 1117, column 1, paragraph 3-page 1119, column 1, paragraph 1 and Figure 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the gelatin nanofibers of Siimon by attaching perlecan binding domain I (which contains sulfate groups) to the nanofibers, as identified by Casper, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Casper has successfully reduced to practice that perlecan binding domain I can be attached to cross-linked gelatin nanofibers. Furthermore, Casper teaches that one would want to attach perlecan to the nanofibers because perlecan binds to FGF2 which modulates cell growth, differentiation, migration and survival. As such, the ability to effectively bind FGF-2 to an electrospun nanofibers is a key improvement in creating a successful tissue engineering platform. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Siimon and Casper do not teach a hydrogel obtaining step.
However, Lee teaches they developed multi-functional biomimetic tissue engineered nanofibrous scaffolds comprising polycaprolactone (PCL)/gelatin nanofibers and poly(ethylene glycol) (PEG) hydrogel. When hMSCs were seeded onto hydrogel-incorporated nanofibrous scaffolds, they selectively adhered and grew only in the fiber region due to the non-adhesiveness of the PEG hydrogel, enabling spatial positioning of hMSCs on a micrometer scale. For osteogenic differentiation of hMSCs, basic fibroblast growth factor (bFGF; also known as FGF2) and bone morphogenetic protein-2 (BMP-2) were loaded on the fibers and within the hydrogel matrix, respectively, to enable sequential delivery of low doses of bFGF during the early stages and sustained release of BMP-2 for long periods. hMSCs cultured on the scaffolds capable of sequential delivery of bFGF and BMP-2 showed stronger osteogenic commitment in culture than those on scaffolds without any growth factors or scaffolds with single administration of either bFGF or BMP-2 under the same conditions. The results demonstrate that hydrogel incorporated fibrous scaffolds can provide not only biomimetic structures with micropatterned nanostructures but also a suitable biochemical environment with controlled release of multiple growth factors, which may eventually facilitate the control of stem cell fates for various regenerative therapies.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the gelatin nanofibers of Siimon and Casper by incorporating them into a PEG hydrogel, as identified by Lee, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Lee has successfully reduced to practice that gelatin based nanofibers can be incorporated into hydrogels. Furthermore, Lee teaches incorporating the nanofibers into a hydrogel allows for osteogenic differentiation of hMSCs by loading bFGF on the fibers and BMP-2 within the hydrogel matrix. The results demonstrate that hydrogel incorporated fibrous scaffolds can provide not only biomimetic structures with micropatterned nanostructures but also a suitable biochemical environment with controlled release of multiple growth factors, which can facilitate the control of stem cell fates for various regenerative therapies. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation “wherein, in the forming the crosslink between the polymer compound nanofibers, the polymer compound nanofibers are connected to each other by the crosslink to form a network structure”, Siimon shows that crosslinking of the gelatin nanofibers with glucose leads to a network structure (Figure 1).
Regarding the limitation “empty space of the network structure is filled with water as gelling proceeds in the hydrating the polymer compound nanofibers”, as stated supra, Lee provides motivation for forming a hydrogel, and Parhi evidences that when a dry hydrogel comes in contact with water, absorption of water into its matrix starts. At first water molecules entering the matrix will directly attach to the hydrophilic groups, forming hydrophilic bound water or primary bound water. The polymeric network swells because of complete hydration of the polar groups that resulted in the exposer of hydrophobic groups. These exposed groups also interact with water molecules, leading to hydrophobically-bound water, or ‘secondary bound water’. The combination of primary and secondary bound water is often called the bound water. This water is considered as integral part of hydrogel structure and can only be separated out from the hydrogel under extreme conditions. After the saturation of hydrophilic and hydrophobic groups, the additional water that is absorbed due to the osmotic driving force of the network chains is called free water or bulk water (page 516, column 1, paragraph 4).
Therefore, it would naturally flow that the gelling process of the gelatin crosslinked nanofibers would lead to water filling the empty space and hydrating the polymer compound nanofibers to form a hydrogel.
Regarding claim 4, Thompson evidences that the effects of 13 material and operating parameters on electrospun fiber diameters. The results show that the five parameters (volumetric charge density, distance from nozzle to collector, initial jet/orifice radius, relaxation time, and viscosity) have the most significant effect on the jet radius (i.e. fiber diameter). The other parameters (initial polymer concentration, solution density, electric potential, perturbation frequency, and solvent vapor pressure) have moderate effects on the jet radius. Parameters relative humidity, surface tension, and vapor diffusivity have minor effects on the jet radius. As such, there are at least 13 parameters that may be adjusted to control the diameter of the fiber.
Regarding claim 5, as stated supra, Siimon teaches that the crosslinking agent is glucose (abstract).
Regarding claim 8, as stated supra, Siimon teaches that the gelatin represents 25% of the solution and glucose is 5% of the solution (page 539, column 1, paragraph 4 and Figure 5). This equates to a ratio of 0.2.
Regarding claim 9, as stated supra, Casper teaches that perlecan binding domain I is the sulfating agent.
Claims 3-4, 6, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Flaig et al. (ACS Biomater. Sci. Eng. 6: 2388−2400. 2020. Published March 2020) and Eslami et al. (Journal of Biomaterials Applications 29: 399–410. 2014) and Parhi (Adv Pharm Bull 7: 515-530. 2017).
Regarding claim 3, Flaig teaches a method of generating cross-linked PLA:PGS nanofibers functionalized with a sulfate group, comprising:
PLA (polylactic acid) pellets were dissolved in DCM (a polymer compound solution);
pPGS (poly glycerol-co-sebacic acid; a crosslinking agent) was dissolved in DMF. Both solutions were stirred with a magnetic stirrer overnight and mixed together at least 1 h before electrospinning;
The mixed solution underwent electrospinning to generate nanofibers;
The nanofibers were then heated for 48 h to achieve the crosslinking process of the pPGS into the elastomeric PGS;
Cross-linked nanofibers were functionalized with Matrigel. Matrigel is a protein mixture of laminin, collagen IV, entactin, collagen, and heparin sulfate proteoglycan and some growth factors (abstract, page 2389, column 1, paragraph 2-2390, column 2, paragraph 4, and page 2398, column 1, paragraph 4)
Flaig teaches that they implanted the Matrigel functionalized nanofibers on the surface of the heart of mice and were found to be biocompatible (page 2394, column 2, paragraph 5-page 2395, column 2, paragraph 2).
Flaig does not teach wherein the nanofibers are incorporated in a hydrogel.
However, Eslami teaches that integrating PGS-PCL microfibers into hydrogels improves the three dimensional distribution of mitral valvular interstitial cells and the microfibers preserved their mechanical properties in the hydrogel. The hydrogel component of the composite scaffold retains cells within the composite structure, while the PGS–PCL component provides mechanical strength and a porous structure to support tissue growth (abstract and page 400, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the PLA:PGS nanofibers of Flaig by incorporating them into a hydrogel, as identified by Eslami, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Eslami has successfully reduced to practice that microfibers can be incorporated into hydrogels for cardiac application (the same stated goal of the nanofibers of Flaig). Furthermore, Eslami teaches that integrating PGS-PCL microfibers into hydrogels improves the three dimensional distribution of mitral valvular interstitial cells and the microfibers preserved their mechanical properties in the hydrogel. The hydrogel component of the composite scaffold retains cells within the composite structure, while the PGS–PCL component provides mechanical strength and a porous structure to support tissue growth. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation “wherein, in the forming the crosslink between the polymer compound nanofibers, the polymer compound nanofibers are connected to each other by the crosslink to form a network structure”, Flaig shows that crosslinking of the PLA nanofibers with pPGS leads to a network structure (Figure 2).
Regarding the limitation “empty space of the network structure is filled with water as gelling proceeds in the hydrating the polymer compound nanofibers”, as stated supra, Eslami provides motivation for forming a hydrogel, and Parhi evidences that when a dry hydrogel comes in contact with water, absorption of water into its matrix starts. At first water molecules entering the matrix will directly attach to the hydrophilic groups, forming hydrophilic bound water or primary bound water. The polymeric network swells because of complete hydration of the polar groups that resulted in the exposer of hydrophobic groups. These exposed groups also interact with water molecules, leading to hydrophobically-bound water, or ‘secondary bound water’. The combination of primary and secondary bound water is often called the bound water. This water is considered as integral part of hydrogel structure and can only be separated out from the hydrogel under extreme conditions. After the saturation of hydrophilic and hydrophobic groups, the additional water that is absorbed due to the osmotic driving force of the network chains is called free water or bulk water (page 516, column 1, paragraph 4).
Therefore, it would naturally flow that the gelling process of the PLA:PGS crosslinked nanofibers would lead to water filling the empty space and hydrating the polymer compound nanofibers to form a hydrogel.
Regarding claim 4, Thompson evidences that the effects of 13 material and operating parameters on electrospun fiber diameters. The results show that the five parameters (volumetric charge density, distance from nozzle to collector, initial jet/orifice radius, relaxation time, and viscosity) have the most significant effect on the jet radius (i.e. fiber diameter). The other parameters (initial polymer concentration, solution density, electric potential, perturbation frequency, and solvent vapor pressure) have moderate effects on the jet radius. Parameters relative humidity, surface tension, and vapor diffusivity have minor effects on the jet radius. As such, there are at least 13 parameters that may be adjusted to control the diameter of the fiber.
Regarding claim 6, as stated supra, Flaig teaches that the crosslinking agent is pPGS (poly glycerol-co-sebacic acid) (page 2389, column 2, paragraph 3-6).
Regarding claim 9, as stated supra, Flaig teaches that cross-linked nanofibers were functionalized with Matrigel. Matrigel is a protein mixture of laminin, collagen IV, entactin, collagen, and heparin sulfate proteoglycan and some growth factors (abstract and page 2398, column 1, paragraph 4). Matrigel is the sulfating agent.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KEENAN A BATES/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631