*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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on September 16, 2025 has been entered.
Priority
This application is a divisional of 16/092,953 filed on 10/11/2018, which is a 371 of PCT/IB2017/05 1796 filed on 03/29/2017, which claims foreign priority in IB application PCT/IB2016/052096 filed on 04/13/2016.
Claim Status
Claims 26-41 and 43 are pending. Claim 26 was amended. Claims 1-25, 42, 44, and 45
were canceled. Claim 43 remains withdrawn. Claims 26-41 are examined.
Withdrawn Claim Rejections — 35 USC § 112
Rejections of claims 26-42 are withdrawn because claim 26 was amended to include concentration units and “and” between “polymeric material” and “water and/or aqueous solution”, claim 42 was canceled, and claims 27-41 no longer depend from an indefinite claim.
Withdrawn Claim Rejections — 35 USC § 103
Rejections of claims 26-28, 31-34, 37, and 40 as being unpatentable over Brosnahan (US 6,149,688 Date of Patent November 21, 2000) are withdrawn because the claims require a collagen based scaffold, which is not obvious over Brosnahan because Brosnahan does not teach collagen. Arguments directed to these rejections are moot because rejections are withdrawn.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 26-28 and 31-41 are rejected under 35 U.S.C. 103 as being unpatentable over Harley (WO 2013/002953 A1 Published January 3, 2013).
The claims encompass a polymeric scaffold.
Collagen-glycosaminoglycan membrane shell scaffold core composites for connective tissue engineering that avoids aspects of the typical tradeoff between mechanical properties (i.e. modulus, failure strength) and bioactivity (i.e., permeability and porosity) for porous tissue engineering scaffolds. The relative density of the collagen glycosaminoglycan scaffold core can be about 0.5 to about 0.95 while the membrane shell can be about 0.001 to 25 about 0.2. The core-shell composite can be tubular and the composite can have a diameter of about 1 mm to about 20 mm. The collagen glycosaminoglycan membrane shell can be perforated with about 25 to about 1000 micrometers openings or alternatively can be embossed with any range of pattern features from about 25 to about 1000 micrometers in size. The porous collagen glycosaminoglycan scaffold core can be populated with cells such as adult or embryonic stem cells, tenocytes, osteoblasts, nerve cells, cardiac cells, myocytes, fibroblasts or combinations thereof (Abstract).
Examples teach methods of making a collagen-glycosaminoglycan (CG) membrane, aligned GC scaffolds, and a composite. A CG suspension was prepared from type I microfibrillar collagen (0 .5% w/v) isolated from bovine dermis and chondroitin sulfate (0.05% w/v) derived from shark cartilage in 0.05 M acetic acid [19]. The suspension was homogenized at 4 °C to prevent collagen 5 gelatinization during mixing and was subsequently degassed before use. CG membranes were fabricated from the CG suspension via a modified evaporative process. All CG membranes were found to possess consistent relative densities between 0.75 and 0.80 (20-25% porous) (page 18). Aligned CG scaffolds were fabricated. Briefly, the CG suspension was added to wells of a multicomponent polytetrafluoroethylene (PTFE)-copper mold, and placed on a freeze-dryer shelf at a pre-cooled temperature (-10°C or -60°C) in order to promote directional solidification. After freezing, ice crystals were sublimated under vacuum (200 mTorr) at 0°C to produce CG scaffolds (6 or 8 mm diameter, 15 or 30 mm length) displaying aligned pores.
Scaffold-membrane constructs were fabricated by first cutting CG membrane pieces to size and placing circumferentially within the PTFE-copper mold. The CG suspension was then pipetted inside the rolled membrane and allowed to hydrate the membrane for ~ 15 min at 4°C before the mold was placed into the freeze-dryer held at a final freezing temperature of -10°C; freezing and sublimation steps for these scaffold-membrane constructs were performed exactly as with the anisotropic scaffolds alone. Membrane hydration and subsequent freeze-drying was
hypothesized to promote the integration of the scaffold structure with the membrane. An evaporative process to fabricate CG membranes with tailorable thicknesses over an order of magnitude (23-240 μm) was described, but consistent relative densities of -0.75-0. 80 that are significantly higher than those of the CG scaffold (0.006). CG membranes were mechanically isotropic in-plane, and as with CG scaffolds increasing the degree of physical (DHT) or chemical (carbodiimide) cross-linking significantly increased membrane tensile moduli (page 19).
Scaffolds, membranes, and scaffold-membrane composites were sterilized and dehydrothermally (DHT) cross-linked at 105 cc for 24 h under vacuum (<25 torr) in a vacuum oven prior to use. Scaffolds and composites were then immersed in 100% ethanol overnight, washed with phosphate-buffered saline (PBS) several times over 24 h, and then crosslinked using carbodiimide chemistry for 1 h in a solution of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDAC) and N-hydroxysulfosuccinimide (NHS) at a molar ratio of 5:2:1 EDAC:NHS:COOH. To test 5 the effect of cross-linking density on membrane mechanics, some membranes were hydrated directly in PBS without further cross-linking (Non-cross-linked, NC) or were cross-linked using EDAC chemistry at a molar ratio of either 1 :1 :5 or 5:2:1
EDAC:NHS:COOH. Scaffolds, membranes, and composites were subsequently stored in PBS until use (paragraph bridging pages 19-20).
Regarding claim 26, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have formed a collagen based polymer scaffold having a non-uniform density comprising a polymeric material and water wherein the scaffold has a density at a surface region of the polymer scaffold that is denser as compared to a density at a core region of the scaffold, with a reasonable expectation of success because Harley teaches a composite formed from collagen and glycosaminoglycan wherein the composite comprises a membrane and a scaffold core for connective tissue engineering wherein the membrane has a higher density compared to the core.
The limitation “so that the polymer scaffold is configured to provide for improved cell ingrowth” is met because Harley’s composite has a surface density that is denser compared to a density at a core region of the composite and it would have been reasonable to expect the composite to be configured as claimed because it meets all structural limitations of the claimed scaffold.
The limitation “wherein the core region and the surface region are both based on the same polymer chemical composition” is met because it is apparent from Harley’s method of making the composite that the membrane and the scaffold core are made from the polymer chemical composition. Top of page 18 teaches a method of making a CG suspension that is used to make the membrane and the scaffold core.
The phrase “given that the different densities are a results of different collagen drying techniques” describes the claimed product as a product by process. It is apparent from Harley’s method of making that the difference in densities between the membrane and the core is a result of drying technique. CG membranes were fabricated from the CG suspension via a modified evaporative process, where the degassed CG suspension was pipetted into a Petri dish and allowed to air dry in a chemical fume hood at room temperature for 2-3 days. CG scaffolds were fabricated, wherein the CG suspension was added to wells of a multicomponent polytetrafluoroethylene (PTFE)-copper mold, and placed on a freeze-dryer shelf at a pre-cooled temperature in order to promote directional solidification. After freezing, ice crystals were sublimated under vacuum at 0°C to produce CG scaffolds (6 or 8 mm diameter, 15 or 30 mm length) displaying aligned pores (-10°C: 243 ± 29 mm; -60°C: 55 ± 18 mm).
Regarding the polymer mass fraction and the water and/or aqueous solution mass fraction, Harley teaches that the composites can be stored hydrated in PBS or distilled water, or dried prior to use (top of page 12); Harley teaches kits that include one or more composites sterilely packaged wherein the composites can be in an appropriate medium such as PBS; Optionally, the composite can be dried or partially dried and present in a storage container suitable for preserving the core-shell composite until use (page 17 lines 1-6). In view of these teachings it is apparent that Harley intended for the composites to contain water in an amount from 0 wt. % (dried) and greater than 0 wt. % (partially dried or stored in distilled water). The composite is formed from collagen and chondroitin sulfate, which are polymeric materials. The claimed concentration range of polymeric material in the composite is obvious because it overlaps with the concentration range of from 100 wt. % to less than 100 wt. %. The claimed concentration range of water is obvious because it overlaps with the range of 0 wt. % and greater. In an embodiment when the composite is dry, the polymeric material content is 100 wt.% of the composite and water content is 0 wt. %. In an embodiment when the composite is partially hydrated or stored in water, the polymeric material content is less than 100 wt. % and the water content is greater than 0 wt. %. The instant specification was reviewed and there is no evidence that the claimed concentration ranges are critical.
Regarding claim 27, it would have been obvious to have formed the core having pore sizes in the range of 55(+,-)18 and 243(+,-)29 microns, with a reasonable expectation of success because Harley teaches said pore size ranges as suitable for the core (page 22 lines 3-6). The claimed range is obvious because it encompasses prior art ranges.
Regarding claim 28, it would have been obvious to have formed the composite having a membrane embossed with a pattern of features from about 25 to about 1000 microns, with a reasonable expectation of success because Harley teaches that the membrane can be embossed with any range of pattern features from about 25 to about 1000 micrometers in size. It would have been reasonable to expect the pore sizes in the membrane to be in the range of less than 37 microns because the core is described as having pores in the range of 55(+,-)18 which gives 37 as the lower end of the range. The membrane has a higher density than the core, therefore the pore size in the membrane would have to be less than the pore size in the core. The claimed pore size range is obvious because it overlaps with the range of less than 37 microns.
Regarding claim 31, prior art tubular graft is made from collagen and has the same characteristics as claimed polymeric scaffold. The prior art tubular graft is suturable absent evidence to the contrary.
Regarding claim 32, it would have been obvious to have formed the composite having a length of 30 mm, with a reasonable expectation of success because Harley teaches that composites are 30 mm long (page 20 lines 29-31). The claimed length of at least 1 cm is obvious because it encompasses 30 mm.
Regarding claim 33, it would have been obvious to have formed the composite to include a bioactive agent, with a reasonable expectation of success because Harley teaches integrating one or more therapeutic agents into the scaffold core or membrane (page 13 lines 3-5).
Regarding claims 34 and 35, it would have been obvious to have formed the composite without cells, with a reasonable expectation of success because Hartley teaches that the composite is optionally seeded with appropriate cells (page 16 lines 6-9). Therefore, it would have been obvious to have formed embodiments of the scaffold without cells and seeded with cells.
Regarding claim 36, it would have been obvious to have immersed the composite in a PBS medium because Harley teaches kits comprising the composite immersed in a PBS medium (page 3 lines 31-33 and page 17 lines 1-4).
Regarding claim 37, Harley teaches a composite dehydrothermally crosslinked (page 19 lines 30-33). This teaching meets the claimed limitation because the composite prior to and after dehydrothermal crosslinking does not comprise a crosslinking agent.
Claims 38 and 39 describe scaffold properties under certain conditions. Harley does not teach a reswell range when placed in an aqueous solution as claimed. Harley’s composite meets all of the structural limitations of the presently claimed scaffold. It would have been reasonable to expect Harley’s composite to have the same properties as presently claimed polymeric scaffold, when placed under identical conditions, because the two are structurally indistinguishable. The Office does not have the means to test prior art products in order to determine if the prior art products have the same properties as claimed products.
Regarding claim 40, Harley’s composite comprises a membrane around a core, which meets the limitation of a polymeric material layer.
Regarding claim 41, Harley’s composite is described as tubular.
Claims 29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Harley as applied to claims 26-28 and 31-41 above, and further in view of Wegst (US 2012/0149111 A1 Published June 14, 2012).
The claims further define the scaffold by a Young’s modulus at the surface and at the core. The teachings of Harley are relied upon as summarized above. While Harley teaches that the composite is suitable for central and peripheral nerve repair (page 3 lines 23-30), Harley does not teach a Young’s modulus of composites suitable for nerve repair.
The teachings of Wegst are related to scaffolds having highly aligned porosity intended for guiding neurons, and methods of use in spinal cord and peripheral nerve injury repair (Abstract). The scaffold is formed from a polymer (paragraph 0038), selected from collagen (paragraph 0108). The scaffolds have a Young’s modulus of about 1-15 kPa. The resulting modulus of various portions of the scaffold can be controlled by manipulation of the local freezing front velocity and cooling rate experienced by the sample during freeze casting (paragraph 0122).
The teachings of Harley and Wegst are related to scaffolds formed from collagen and intended for central and peripheral nerve repair, and it would have been obvious to have combined their teachings because they are in the same field of endeavor. It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed inventio to have formed Harley’s composite having a Young’s modulus in the range of 1-15 kPa, with a reasonable expectation of success because Wegst teaches that a Young’s modulus in the range of 1-15 kPa is suitable for making collagen scaffolds intended for central and peripheral nerve repair. The selection of a known physical characteristic based on its suitability for its intended purpose supports obviousness. The skilled artisan would have recognized that Harley’s composite has a range of Young’s moduli because the composite has a membrane and a core having different porosities and densities as described above. The claimed ranges of Young’s moduli are obvious because they overlap with the range of 1-15 kPa.
Claims 26-28 and 31-41 are rejected under 35 U.S.C. 103 as being unpatentable over Li (US 5,376,376 Date of Patent December 27, 1994) and Vyakarnam (US 2001/0033857 Al Published October 25, 2001).
The claims encompass a polymeric scaffold.
The teachings of Li are related to a tubular resorbable vascular wound dressing made from collagen (Abstract). The teachings pertain to interventional therapeutic approaches and surgical approaches to blood vessel repair and regeneration. More specifically, the bioresorbable, biocompatible, non-thrombogenic, porous tubular vascular wound dressings comprised of collagen based material, which vascular wound dressings are used to repair damaged or diseased blood vessel segments so as to provide a segment of tubular vascular wound dressing to mechanically support the damaged or diseased vessel, to facilitate the regeneration of the host vessel, and to provide a means to deliver therapeutic agents at the selected sites (column 1 lines 9-21). A method of making the dressing is described in column 5 lines 45-65. Walls of the dressing are porous having pores in the range from about 0.1 microns to about 150 microns that are tortuously arranged to facilitate anchorage of the walls with the host tissue via cellular infiltration. The porous nature of the dressing also allows nutrient diffusion through the walls (column 7 lines 44-50). In one embodiment, the dressing is intended to be used as a medicinal delivery vehicle, and various optional medicaments may be added to the collagen, including TGF beta among others (column 10 lines 27-38). The dressing has a length of 0.5 to 15 cm (column 13 lines 17-26). The dressing is formed according to Example 2 in columns 15 and 16, where among other steps a freeze dried tubular collagen sponge matrix is equilibrated at room temperature overnight. A stream of water mist is sprayed onto the collagen matrix. The water mist treated collagen matrix is allowed to stand and the is subjected to a compression procedure. The compressed collagen matrix is then subjected to a second compression procedure. The compressed tubular collagen matrix is crosslinked in a formaldehyde crosslinking chamber at 95% relative humidity and excess formaldehyde vapor. The crosslinked collagen matrix is evacuated to remove residual formaldehyde and the dressings are packaged for sterilization.
Column 18 lines 35-47 describes determining swelling of the wound dressing prepared in example 2, where the dry weight of the dressing is first determined followed by immersing the dressing in a buffered solution for 1 hour. The wet weight is then determined and swelling is calculated by taking the difference between the wet and the dry weight and dividing by the dry weight. The Swelling of the wound dressing is from about 0.5 g/g to about 15 g/g.
Li does not teach whether the pores are uniformly or non-uniformly distributed throughout the collagen matrix.
The teachings of Vyakarnam are related to a three-dimensional interconnected open cell porous foams that have a gradient in composition and/or microstructure through one or more directions. These foams can be made from a blend of absorbable and biocompatible polymers that are formed into foams having a compositional gradient transitioning from predominately one
polymeric material to predominately a second polymeric material. These gradient foams are particularly well suited to tissue engineering applications and can be designed to mimic tissue transition or interface zones (Abstract). A biocompatible gradient foam is provided that has a substantially continuous transition in at least one characteristic selected from the group consisting of composition, stiffness, flexibility, bioabsorption rate, pore architecture and/or microstructure. This gradient foam can be made from a blend of absorbable polymers that form compositional gradient transitions from one polymeric material to a second polymeric material. In situations where a single chemical composition is sufficient for the application, a biocompatible foam is provided that may have microstructural variations in the structure across one or more dimensions that may mimic the anatomical features of the tissue (paragraph 0009). It is also provided a method for the repair or regeneration of tissue contacting a first tissue with a gradient foam at a location on the foam that has appropriate properties to facilitate the growth of said tissue. The concept of a continuous transition in physical properties, chemical composition and/or microstructural features in the porous scaffold (foam) can facilitate the growth or regeneration of tissue. These foam structures are particularly useful for the generation of tissue junctions between two or more different types of tissues. For a multi-cellular system in the simplest case, one cell type could be present on one side of the scaffold and a second cell type on the other side of the scaffold. Vascular grafts are an example of such regeneration: with an endothelial layer on the inside of the graft and a smooth muscle cell layer on the outside (paragraph 0012). The features of such foams can be controlled to suit desired application by selecting the appropriate conditions for lyophilization to obtain one or more of the following properties: (1) interconnecting pores of sizes ranging from about 10 to about 200 um (or greater) that provide pathways for cellular ingrowth and nutrient diffusion; (2) a variety of porosities
ranging from about 20% to about 98% and preferably ranging from about 80% to about 95%; (3) gradient in the pore size across one direction for preferential cell culturing; (4) channels that run through the foam for improved cell invasion, vascularization and nutrient diffusion; (5) micro- patterning of pores on the surface for cellular organization; (6) tailor ability of pore shape and/or orientation; (7) anisotropic mechanical properties; (8) composite foams with a polymer composition gradient to elicit or take advantage of different cell response to different materials; (9) blends of different polymer compositions to create structures that have portions that will break down at different rates; (10) foams co-lyophilized or coated with pharmaceutically active compounds including but not limited to biological factors such as RGD's, growth factors (PDGF, TGF-~, VEGF, BMP, FGF etc.) and the like; (11) ability to make 3 dimensional shapes and devices with preferred microstructures; and (12) lyophilization with other parts or medical devices to provide a composite structure (paragraph 0028). The creation of tubular structures with gradients is disclosed. In vascular grafts, having a tube with pores in the outer diameter which transitions to smaller pores on the inner surface or vis versa may be useful in the culturing of endothelial cells and smooth muscle cells for the tissue culturing of vessels (paragraph 0047). Multilayered tubular structures allow the regeneration of tissue that mimics the mechanical and/or biological characteristics of blood vessels will have utility as a vascular graft. Concentric layers, made from different compositions under different processing conditions could have tailored mechanical properties, bioabsorption properties, and tissue ingrowth rates. The inner most, or luminal layer would be optimized for endothelialization through control of the porosity of the surface and the possible addition of a surface treatment. The outermost, or adventitial layer of the vascular graft would be tailored to induce tissue ingrowth, again by optimizing the porosity (percent porosity, pore size, pore shape and pore size distribution) and by incorporating
bioactive factors, pharmaceutical agents, or cells. There may or may not be a barrier layer with low porosity between these two porous layers to increase strength and decrease leakage (paragraph 0048). The foams are made from biocompatible, bioabsorbable polymers that include biomolecules (paragraph 0050).
The teachings of Li and Vyakarnam are related to porous tubular vascular grafts formed from polymer biomolecules and it would have been obvious to have combined their teachings because they are in the same field of endeavor.
Regarding claim 26, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have formed a porous tubular vascular graft form collagen and having pores in the range from 0.1 microns to 150 microns, with a reasonable expectation of success because Li teaches a porous vascular graft in the form of a tube wherein the graft is formed from collagen and the pores range from 0.1 microns to 150 microns. Li does not state whether the pore size is uniform or non-uniform throughout the graft. It would have been obvious to have formed Li’s porous tubular graft having a gradient of pore sizes where the gradient extends from the outer surface of the tubular structure to the inner surface of the tubular structure and pore size ranges from lower end of the range to the upper end of the range across the thickness of the wall of the tubular structure, with a reasonable expectation of success because it was known from Vyakarnam that in vascular grafts, having a tube with pores in the outer diameter which transitions to smaller pores on the inner surface or visa versa may be useful in the culturing of endothelial cells and smooth muscle cells for the tissue culturing of vessels. The inner surface of the tube would have contained pores of the largest size (150 microns) and the outer surface of the tube would have contained pores of the smallest size (0.1 microns) and a gradient of pore size would have been present throughout the
thickness of the tube wall. Li’s porous tubular vascular graft modified by Vyakarnam would have had non-uniform density. One of skill in the art would have had a reasonable expectation of success making Li’s tubular graft having a gradient of pore sizes because Vyakarnam teaches an embodiment where a single chemical composition is used to form the porous foam having microstructural variations in the structure across one or more dimensions that may mimic the anatomical features of the tissue (paragraph 0009). Li’s vascular graft is formed from a single chemical composition. According to Li’s Example 2, the tubular graft is formed from collagen where the collagen tube is treated with water mist and crosslinked under 95% relative humidity conditions. The method of making does not require removing the water from the collagen tube, and it would have been reasonable to conclude that the collagen tube comprises water from the water mist treatment and exposure to humidity adsorbed into the collagen tube. Swelling of collagen tube formed by example 2 was measured by immersing the collagen tube in buffered solution. Li teaches that the swelling of the dressing ranged from 0.5 g/g to 15 g/g. In view of the method of making, it is apparent that the collagen tube contained some water after it was made and since the method does not teach removing water prior to packaging, it would have been reasonable to conclude that the collagen tube comprises water in addition to collagen. A swell ratio of 0.5 g/g means that the collagen tube in swollen state contains 50% of water by weight. Therefore, it would have been reasonable to conclude that prior to immersing the collagen tube in buffered solution, the collagen tube contained less than 50 % by weight of water. This interpretation is reasonable because in swollen state the tube contained 50 wt. % water. Thus, the collagen tube would have contained collagen (a polymeric material) in a concentration of greater that 50 wt. % and water in a concentration of less than 50 wt. % based on the total weight of the collagen tube. The claimed concentration range of polymeric material is obvious because it overlaps with greater than 50 wt. %. The claimed concentration range of water or aqueous solution is obvious because it overlaps with less than 50 wt. %. The specification was reviewed and there is no evidence that claimed concentrations of polymeric material and water or aqueous solution are critical. The inner lumen of the tubular graft is the core of the structure and has a density that is lower than the density at the outer surface of the tubular graft.
Li’s tubular graft is a collagen based because it is formed from collagen.
The limitation “so that the polymer scaffold is configured to provide for improved cell ingrowth” is met because Li’s graft has a surface density that is denser compared to a density at a core region of the scaffold and it would have been reasonable to expect the graft to be configured as claimed because it meets all structural limitations of the claimed graft.
The limitation “wherein the core region and the surface region are both based on the same polymer chemical composition” is met because Li teaches forming the tubular graft from collagen which includes the whole graft, meaning that the core and the surface are made from the same chemical composition.
The phrase “given that the different densities are a results of different collagen drying techniques” describes the claimed product as a product by process. Vyakarnam teaches selecting the appropriate conditions for lyophilization to obtain one or more properties including interconnected pores of sizes from 10 microns to 200 microns (or greater) that provide pathways for cellular ingrowth and nutrient diffusion and a variety of porosities ranging from about 20% to about 98 % (paragraph 0028). Thus, it would have been obvious to have formed Li’s collagen based tubular graft having a gradient of pore sizes as described above by selecting appropriate lyophilization conditions. One of ordinary skill would have had a reasonable expectation of success in doing so because Li described freeze drying (lyophilization) as a suitable technique for drying a collagen solution to form the graft.
Regarding claims 27 and 28, Li teaches that pore sizes range from 0.1 to 150 microns in the vascular graft. The inner lumen (the core) would have had the largest pores of the range or 150 microns, while the outer surface would have had the smallest pores in the range or 0.1 microns. The claimed range of pore diameters at the core is obvious because it overlaps with 150 microns and less and the claimed range of pore diameters at the surface is obvious because it overlaps with 0.1 microns or more.
Regarding claim 31, prior art tubular graft is made from collagen and has the same characteristics as claimed polymeric scaffold. The prior art tubular graft is suturable absent evidence to the contrary.
Regarding claim 32, it would have been obvious to have formed the tubular graft having a length of 0.5-15 cm because Li teaches forming the tubular graft to have a length of 0.5-15 cm. The claimed range of lengths is obvious because it overlaps with 0.5-15 cm.
Regarding claim 33, it would have been obvious to have formed the tubular graft to comprise a bioactive agent because Li teaches using the tubular graft as a drug delivery vehicle and teaches forming the graft with a bioactive agent.
Regarding claim 34, Li does not teach adding cells to the tubular graft, and it would have been reasonable to interpret the lack of a teaching of cells in the graft to mean that the graft does not comprise cells.
Regarding claim 35, it would have been obvious to have used the porous tubular graft to serve as a scaffold for tissue engineering by seeding cells into the graft, with a reasonable expectation of success because it was known from Vyakarnam that a scaffold is useful for tissue
engineering by seeding cells into the scaffold. The skilled artisan would have been motivated to seed the graft with cells because Vyakarnam teaches that the in vitro seeding of cells could provide for a more rapid development and differentiation process for the tissue. It is clear that cellular differentiation and the creation of tissue specific extracellular matrix is critical for the tissue engineering of a functional implant (paragraph 0091).
Regarding claim 36, it would have been obvious to have measured the shrinkage temperature of the tubular graft by immersing the graft into PBS at 25°C for about 10-30 minutes and heating 1°C per minute followed by measuring, with a reasonable expectation of success because Li teaches measuring the shrinkage temperature of the tubular graft by immersing the graft into PBS at 25°C for about 10-30 minutes and heating 1°C per minute followed by measuring (column 12 lines 46-65).
Regarding claim 37, Li teaches a method of forming the porous tubular graft where the final step (h) requires crosslinking the collagen matrix conduit with a crosslinking agent (column 5 lines 45-64). The structure formed in step (g) is a tubular graft that is not crosslinked and the claimed structure is obvious over the prior art structure prior to the crosslinking step.
Claims 38 and 39 describe scaffold properties under certain conditions. Li teaches that the graft has a swelling capacity of 0.5-15 g/g (column 6 lines 65-68), however prior art references do not teach a reswell range when placed in an aqueous solution as claimed. Li’s graft modified with Vyakarnam meets all of the structural limitations of the presently claimed scaffold and it is formed from collagen which is a suitable polymeric material as evidenced by claim 42. It would have been reasonable to expect the prior art graft to have the same properties as presently claimed polymeric scaffold, when placed under identical conditions, because the two
are structurally indistinguishable. The Office does not have the means to test prior art products in order to determine if the prior art products have the same properties as claimed products.
Regarding claim 41, Li’s porous collagen graft is in the form of a tube.
Claims 29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Li and Vyakarnam as applied to claims 26-28 and 31-41 above, and further in view of Miyamoto (US 2006/0194036 Al Published August 31, 2006).
The claims further define the scaffold of claim 26 by Young’s modulus.
The teachings of Li and Vyakarnam are relied upon as summarized above. They do not teach a Young’s modulus of tubular vascular graft.
The teachings of Miyamoto are related to a tube or artificial blood vessel intended for implantation into a body (Abstract). A Young’s modulus required for a tube or artificial blood vessel to be implanted inside a body is 1x104 to 2x106 Pa (paragraph 0005).
The teachings of Miyamoto and Li modified by Vyakarnam are related to tubular grafts and it would have been obvious to have combined them because they are in the same field of endeavor. It would have been prima facie obvious to have formed Li’s porous tubular graft as modified in view of Vyakarnam to have a Young’s modulus in the range of 1x104 to 2x106 Pa, with a reasonable expectation of success because it was known from Miyamoto that a Young’s modulus required for a tube or artificial blood vessel to be implanted inside a body is 1x104 to 2x106 Pa. The selection of a known physical characteristic based on its suitability for its intended purpose supports obviousness. The skilled artisan would have recognized that Li’s modified tubular graft has a range of Young’s moduli because the tubular graft has regions of different porosities as described above. The claimed ranges of Young’s moduli are obvious because they overlap with the range of 1x104 to 2x106 Pa which is equivalent to a range of 10 kPa to 2000 kPa.
Combining prior art elements according to known methods to obtain predicable results supports obviousness. Present specification was reviewed and there is no evidence of unexpected results, and there is no evidence that claimed numerical ranges are critical.
Response to Arguments
Applicant’s arguments submitted in the remarks dated September 5, 2025, were fully considered but are not persuasive for the following reasons.
Arguments that Vyakarnam’s preferred technique is to use different foam materials for different porosity regions, and does not describe collagen drying techniques are not persuasive because Vyakarnam teaches an embodiment where a single chemical composition is sufficient for the application, in which case a biocompatible foam is provided that may have microstructural variations in the structure across one or more dimensions that may mimic the anatomical features of the tissue (paragraph 0009). Thus, the reference teaches an embodiment where different porosities are present in a structure having a single chemical composition.
Vyakarnam further teaches that the features of such foams can be controlled to suit desired application by selecting the appropriate conditions for lyophilization to obtain one or more of the following properties: (1) interconnecting pores of sizes ranging from about 10 to about 200 um (or greater) that provide pathways for cellular ingrowth and nutrient diffusion; (2) a variety of porosities ranging from about 20% to about 98% and preferably ranging from about 80% to about 95%; (3) gradient in the pore size across one direction for preferential cell culturing; (4) channels that run through the foam for improved cell invasion, vascularization and nutrient diffusion; (5) micro- patterning of pores on the surface for cellular organization; (6) tailor ability of pore shape and/or orientation; (7) anisotropic mechanical properties; (8) composite foams with a polymer composition gradient to elicit or take advantage of different cell response to different materials; (9) blends of different polymer compositions to create structures that have portions that will break down at different rates; (10) foams co-lyophilized or coated with pharmaceutically active compounds (paragraph 0028). Thus, the reference teaches using different lyophilization parameters to create different pore sizes, porosities, and pore gradient in the structure, which meets the claimed product by process limitation that describes how the different pore sizes are achieved.
Applicant’s argument that Vyakarnam does not teach collagen, techniques for drying collagen, and there would be no logical reason to have used Vyakarnam’s techniques or materials in the collagen based wound dressing of Li, are not persuasive because Vyakarnam’s teachings are relied upon for motivation to make Li’s collagen structure having a non-uniform density as required by claims. Vyakarnam teaches lyophilization as a suitable method of making an implant having different regions with different pore sizes and densities. It was known from Li that lyophilization is a suitable technique for drying collagen (See column 5 lines 45-65). Li teaches freeze drying, which is lyophilization. Therefore, there would have been a reasonable expectation of success in making Li’s implant having non-uniform density as taught by Vyakarnam wherein the non-uniform density is achieved by lyophilization.
Applicant’s argument regarding unexpected results is not persuasive because applicant did not provide evidence to support such argument. See MPEP 716.02 for the requirements applicant has to meet in order to overcome obviousness rejections with unexpected results.
Applicant cited paragraphs in the instant specification that describe issues in using collagen gels as scaffolds and that present inventors’ subject matter provides unexpected results with respect to collagen based scaffolds.
The cited paragraphs were considered, however their teachings are not sufficient to overcome the rejections with unexpected results.
Applicant referred to Rule 132 Declaration filed in the parent application for evidence of unexpected results. The declaration filed in the parent application was not considered because the declaration has to be filed in the instant application in order to be considered.
Applicant referred to Figure 5 and stated that polymer mass fraction of at least 60 wt. % is an unusual feature for collagen based scaffold.
Figure 5 was considered however, the data presented does not support a finding of unexpected results. Measuring water content after performing different drying techniques and observing different results for different techniques does not support a finding of unexpected results.
Conclusion
No claims are allowed.
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/ALMA PIPIC/
Primary Examiner, Art Unit 1617