DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1-15 are pending and under current examination in this application.
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 1-15 are rejected under 35 U.S.C. § 103 as being unpatentable over Learn et al. (Woven collagen biotextiles enable mechanically functional rotator cuff tendon regeneration during repair of segmental tendon defects in vivo. J Biomed Mater Res B Appl Biomater. 2019 Aug;107(6):1864-1876; electronically published 2018 Nov 28, hereinafter referred to as “Learn”) in view of Wang et al. (Regeneration of skeletal system with genipin crosslinked biomaterials. J Tissue Eng.;11:2041731420974861; published 2020 Nov 29, hereinafter referred to as “Wang”).
Learn teaches mesenchymal stem cell (MSC)-seeded electrochemically aligned collagen (ELAC) threads woven into biotextile scaffolds as grafts to repair rotator cuff tendon defects at the tendon-bone junction [osteotendinous] in New Zealand White rabbits (Abstract), wherein individual threads [monofilaments] were combined [twisted] to form 3-ply yarns before crosslinking in genipin solution. Yarns were woven [braided on top of each other successively] around an array of seven pins [concentric] to a height of 5mm [requiring three or more layers to achieve] to form a scaffold unit [phase]. Two scaffold units [phases] were then stacked in parallel [adjacent and contiguous] and consolidated using a weft fiber passed through the pin-holes [directly attached] to produce a biotextile scaffold (page 4, Scaffold fabrication section, first paragraph). Figure 1 shows the interconnected macroporosities throughout the first and second phases [the two scaffold units], triaxial nature of the yarn (page 15, Figure 1A and 1B; showing X, Y and Z axis), oblique threads (page 15, Figure 1C) and wherein the majority of the ELAC threads are positioned along the load-bearing axis (page 15, Figures 1C and 1D). No other cells were described to be seeded at any concentration (page 5, Cell seeding of scaffolds section; rabbit MSCs sorted by flow in the pages 4-5, Flow sorting of rabbit MSCs were seeded), thus MSCs are more predominate than any other human or animal cells (i.e., being the only cells).
While the MSC used by Learn were allogenic, at the time of the invention, it was well-known in the field of regenerative medicine and orthopedic surgery that MSCs can be derived from two sources, allogeneic or autologous. The use of autologous MSCs was a well-established, conventional and preferred choice to avoid immune-associated complications or rejection. Therefore, given the option of two known, predictable cell sources for the same purpose, and where the choice of autologous MSCs is recognized as the highly preferable choice to avoid immune complications, it would have been obvious to a person of ordinary skill in the art to use autologous MSCs with the ELAC threads to obtain the predictable and beneficial result of improved biocompatibility and reduced immunogenicity in the scaffold. This represents an “obvious to try” situation where there are a finite number of identified, predictable solutions and one skilled in the art has a reason to pursue the known options (see KSR Int’l Co. v. Teleflex Inc., 500 U.S. 398 (2007)).
Learn teaches a generic 3-ply yarn and does not teach the specific claimed nuanced architecture choice of using 4-ply yarns for triaxial threads and 2-ply yarns for oblique threads. However, one of skill in the art would be motivated to make this modification as a matter of routine optimization to improve the mechanical properties of the scaffold taught by Learn by further tailoring the yarn properties to the specific mechanical function of each thread type within the braid. The triaxial threads run parallel to the load-bearing axis, are primarily responsible for carrying the tensile load, and require high strength and stiffness, thus it would be a matter of obvious routine experimental optimization to increase the 3-ply yarn to 4-ply for these threads to increase cross-sectional area to provide greater resistance to tensile failure under tension. Using a stronger yarn for the primary load-bearing threads is a logical choice. The oblique threads weave diagonally around the axial threads to constrain the axial threads, transfer load between axial threads and prevent them from splaying apart under tension, providing shear and torsional stability. A 2-ply yarn is more flexible and pliable than a 3-ply yarn, making it easier to weave tighter braid angles around the axial threads without creating excessive bulk or stress concentrations at the crossover points, which can improve overall structural integrity and fatigue resistance and the flexibility can allow for more control over the size and distribution of the pores between the axial threads. The combination of thicker axial threads and thinner braid threads allows for optimization of the microporosity of the scaffold as well by creating a pore size that is large enough for cell infiltration and tissue ingrowth (interconnected macroporosity) while maintaining a high density of collagen for mechanical strength. A uniform 3-ply yarn might force a compromise, resulting in either pores that are too small or a structure that is not as strong.
Learn teaches woven scaffolds with, “…demonstrated robust mechanical properties similar to that of native tendon, ample porosity for cellular infiltration and integration, along with biological cues to induce appropriate cellular responses (cell attachment and tissue integration, resorption, and remodeling)” (page 9, Discussion section, paragraph 2). Learn does not however teach the combination of a mineralized bone-phase with osteoinductive hydroxyapatite crystals or dicalcium phosphate dihydrate crystals distributed on the surface along with MSCs with his non-mineralized tendon-phase.
Wang teaches, “… genipin crosslinking can help to maintain the stability of the soft materials to ensure sustained stimulation of MSCs and the release of beneficial growth factors. The inorganic elements in bioceramics (such as hydroxyapatite and β-tricalcium phosphate (β-TCP)) are similar to those in native bones, and they help to induce osteogenic differentiation. Genipin crosslinking, as an alternative to sintering, serves as an adhesive to bond bioceramic powder together. The physical properties and biocompatibility of materials consisting of bioceramics in genipin-crosslinked hydrogels have been assessed. Vozzi et al. constructed composite scaffolds involving collagen/gelatin/genipin/hydroxyapatite particles (HAps). HAps are highly stiff, and adding genipin led to a homogeneous mixture of stiff particles in soft materials. The addition of genipin increased the elastic modulus of the hydrogel, preventing HAp sedimentation…Other research focused on creating porous chitosan/nano β-TCP scaffolds… Another strategy for treating bone defects is to coat scaffolds with gels, such as genipin-crosslinked hydrogel (which can tightly adhere to the scaffold surface), leading to an increased stiffness and viscosity of coating gels to enhance biocompatibility… Additionally, MSCs in stiff genipin-treated hydrogel have been shown to exhibit tendencies toward mineralizing and differentiating, which was attributed to the mechanical signals from the stiff hydrogel stimulating MSCs toward osteogenic differentiation.” (pages 10-11, Bone regeneration section, paragraphs 1-3). The combination of his reviewed teachings renders it obvious to try a mineralized bone scaffold comprising ELAC bonded with hydroxyapatite by genipin crosslinking, further coated with MSCs.
Learn provides motivation to combine a mineralized bone-phase with MSCs with the non-mineralized tendon-phase given his results wherein scaffold-alone repairs displayed a mixed mode failure at the interface between the soft tissue and bone and at the midsubstance and the cell-seeded scaffold repairs failed consistently within the midsubstance (page 8, Biomechanical testing section, paragraph 2; page 18, Figure 4). In addition, regeneration of bone–tendon interfaces are a well-known clinical challenge. Thus, Learn in combination with the teachings of Wang provides obviousness to adopt a biphasic scaffold for osteotendinous repair wherein braided ELAC threads form distinct mineralized phase for bone integration and a non-mineralized phase for tendon integration that are braided together as in the two separate scaffold units of Learn to create a strong, porous, three-dimensional scaffold, thereby arriving at the claimed invention with a reasonable expectation of success.
Learn also further provide rationale for only seeding MSCs on the first mineralized bone-phase in his discussion by stating, “Biomechanical testing data suggest that addition of MSCs to woven collagen scaffolds may enhance repair stiffness and strength. Furthermore, MSC supplementation likely enhanced the integration between the bone and the scaffold as reflected by consistent failure occurring at the midsubstance region. This is potentially the result of cell-mediated integration between soft (tendon) and hard (bone) tissues.” (page 9, Discussion section, paragraph 3). In addition, “ELAC fibers within the group containing the scaffold alone (no MSCs) appear to be sufficient to induce tenogenic differentiation of the cells that infiltrate and encapsulate the scaffold, as no significant differences in presence of tenomodulin were noted between scaffold-alone and cell-seeded groups.” (page 10, Discussion section, paragraph 7). Thus, since the MSCs enhanced stiffness and strength, however did not offer any advantage in inducing tendon cells, it would be logical to only include seeding MSCs in the first mineralized bone-phase to reinforce stiffness and strength of bone as compared to tendon and remove their inclusion from the tendon phase as they do not appear to confer an advantage.
In summary, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to add the mineralized bone-phase with osteoinductive hydroxyapatite crystals as taught by Wang to the invention of Learn to arrive at the claimed invention with a reasonable expectation of success in making the change.
Learn provides the foundational scaffold architecture and motivation for a biphasic design. Learn teaches a mechanically functional, triaxial braided collagen scaffold wherein threads are twisted to form ply yarns, with specific yarns serving as axial and oblique threads constructed from more than three concentric layers of yarn, braided successively on top of each other to achieve a defined, interconnected macroporosity suitable for cell infiltration and regeneration of load-bearing tissues with a defined load-bearing axis, wherein the majority of the collagen threads are positioned along this axis to withstand tensile forces. Furthermore, Learn identifies the critical clinical problem of repairing tendon-to-bone insertions, an inherently biphasic tissue environment. While Learn's specific embodiment is a unitary tendon graft, it explicitly motivates the need for strategies to address the entire osteotendinous junction, thereby providing a clear reason for one of ordinary skill to consider a biphasic scaffold.
Wang provides the motivation and teaching to use genipin crosslinking and mineralization for bone regeneration. Wang explicitly teaches the use of genipin as a superior, biocompatible crosslinking agent for collagen-based biomaterials, that enhances the mechanical properties and biostability of collagen scaffolds, which are desirable properties for the load-bearing scaffold of Learn. Wang also teaches the mineralization of collagen scaffolds with calcium phosphate minerals, specifically osteoinductive hydroxyapatite, to promote bone formation, and that such mineralized, genipin-crosslinked collagen scaffolds are suitable for bone regeneration.
A skilled artisan, seeking to solve the well-known problem of regenerating the bone-tendon interface, would be motivated to create a biphasic scaffold. They would logically employ Learn's braided architecture for both phases to ensure mechanical integrity. For the bone-phase, it would be obvious to apply the well-established teachings of Wang to crosslink the collagen threads with genipin and mineralize them with hydroxyapatite, distributing the mineral on the surface and within the macroporosity as a standard outcome of mineralization processes. The non-mineralized tendon-phase would remain crosslinked, with genipin as a uniform crosslinking method for the entire construct, as taught by Learn and Wang to be beneficial for collagen's mechanical stability.
Assembly of the biphasic structure would have been a matter of substituting one of the tendon regeneration scaffold units taught by Learn to be contiguously and adjacently attached to another for a mineralized scaffold unit seeded with MSCs for bone regeneration attached by interlocking wefts, to form a single, integrated implant for surgical use. The seeding MSCs onto the mineralized bone-phase to promote osteogenesis is an obvious application of this conventional technique to the scaffold created by the combination of Learn and Wang. Therefore, the claimed biphasic scaffold is the predictable result of applying Wang's known methods for creating osteogenic collagen materials (i.e., genipin crosslinking and mineralization) to the mechanically superior braided collagen architecture of Learn, which is itself motivated to address the biphasic nature of the osteotendinous junction. A person of ordinary skill would have had a reasonable expectation of success in doing so to create an improved scaffold for rotator cuff and other osteotendinous repairs.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L. SCOTLAND whose telephone number is (571) 272-2979. The examiner can normally be reached M-F 9:00 am to 5:00 pm EST.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615