DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, 18276593, 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 with traverse of Group I, claims 3, 4, and 21 in the reply filed on 3/4/2026 is acknowledged. .
The requirement for unity of invention is still deemed proper and is therefore maintained. This requirement for unity of invention will be revisited at the time of the next Office Action.
Applicant argues that examination of the unelected Groups does not represent a search or examination burden. Applicant argues that combination of the prior references of Setayeshmehr in view of Yang, does not explain why examination of the unelected groups would explain why there is a serious search burden in terms of product and process-of-use. Applicant argues that MPEP Section 803, requires demonstration of serious burden.
Applicant’s arguments because unpersuasive because MPEP Section 803 does not address Unity of Invention for National Stage application under 35 U.S.C. Section 371. As the technical feature linking the claims does not represent a contribution over the prior art, (see below new rejection over 35 USC 103 over Centeno, US 20090208464, Mao, US 20110300203, and Ding, 20200297761), the technical feature is not considered a special technical feature. Therefore the finding of lack of unity of invention is maintained.
It is note that the unelected claims are withdrawn and not canceled. Unity of Invention, unlike restriction under US practice, is not made final, but the status of the technical feature linking the claims is reviewed throughout examination.
Priority
The filing receipt, mailed 3/7/2025, states that this application, 18276593, was filed 8/9/2023, and claims domestic priority benefit as a 371 of PCT/US2022/016171, filed 02/11/2022, which claims benefit of 63/148,614, filed 02/12/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/25/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
The claims are drawn to methods of repairing a musculoskeletal tissue defect or injury in a mammalian subject, the method comprising contacting the defect or a site of the injury with a bioactive scaffold comprising a bioactive fibrin glue into which a population of skeletal tissue derived mesenchymal progenitor cells (STMSCs) is encapsulated, wherein the bioactive fibrin glue comprises fibrinogen, thrombin, and stromal cell derived factor 1 (SDF-1); wherein the SDF-1 is configured to perform as an anabolic and/or a healing ingredient; and wherein the STMSCs comprise cartilage-derived mesenchymal progenitor cells (CPCs), and variations thereof.
1. Claim(s) 3, 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Centeno, US 20090208464, Mao, US 20110300203, and Ding, 20200297761.
Centeno, US 20090208464, throughout the publication and abstract, teaches a method of repairing a musculoskeletal tissue defect, particularly degenerate intervertebral discs or joints, comprising applying bone marrow mesenchymal stem cells to the site, into scaffold composite comprising fibrinogen.
Centeno, e.g., at para 17 states:
[0017] A system and method is provided for the percutaneous, autologous transplantation of mesenchymal stem cells (MSC's) and progenitor helper cells (PHC) from bone marrow to degenerated intervertebral discs or joints. The systems and methods of the invention are designed to be used by operating room staff in a clinical setting to isolate a MSC population and PHC population during the same surgical procedure as transplantation. The systems and methods can be used as a procedure where target cells are harvested, then isolated, then reimplanted into a target site, all from and into the same patient. The systems and methods further include the use of a novel hyaluronic acid and fibrinogen composite delivered percutaneously through a needle to provide an optimal cell scaffold for the isolated and reimplanted target cells.
Centeno, at para 17, (emphasis added).
Centeno, states that synthetic fibrin glue comprising fibrinogen and thrombin was known in the as a scaffold for mesenchymal stem cells, and chondrocytes, in bony repair.
[0011] The use of autologous fibrin as a tissue engineering scaffold holds great promise. Synthetic fibrin glue has also been used as a scaffold material for mesenchymal stem cells in bony repair. Silverman has determined that fibrin glue can be used as a three dimensional scaffold for chrondocytes in an animal model. Sah has investigated specific formulations of fibrinogen and thrombin on chrodrocytes and matrix formation Bens also investigated specific formulations for bone repair finding that 18 mg/ml of fibrinogen and a thrombin activity of 100 IU/ml was optimal for producing fibrin scaffolds that would allow appropriate MSC spreading and proliferation. Park has tested a fibrin glue and hyaluronic acid (HA) composite with chrondrocytes in an animal model and found earlier cartilage formation, higher GAG, water, and collagen content with hyaluronic acid added. Park used fibrinogen (9-18 mg/mL) and HA of molecular size 3000 kDa (10 mg/mL). The chondrocytes were then homogeneously mixed with aprotinin and 60 U/mL thrombin (1000 U/mg protein) and a fibrin stabilizing Factor XIII, as well as 50 mM CaCl2. No investigation was carried out with stem cells or with differing concentrations of HA, fibrin, and thrombin or different molecular weight HA's. At this time it is unknown if such a scaffold would work in a joint space or intervertebral disc with mesenchymal stem cells or if there is an optimum amount of thrombin, fibrinogen, and hyaluronic acid that would promote specific tissue repair. At this point, no research exists using this composite with mesenchymal stem cells.
Centeno, at para 11, (emphasis added, citations omitted).
Centeno, states that synthetic fibrin glue comprising fibrinogen and thrombin was known in the as a scaffold for mesenchymal stem cells, and chondrocytes, in bony repair.
[0012] Goldberg describes a process for the use of mesenchymal stem cells mixed with preferably a collagen matrix (but fibrin glue is also discussed) and delivered to a joint via an arthroscopic approach). No discussion of a hyaluronic acid and fibrinogen composite is revealed. Whitmore has described the use of fibrin glue and hyaluronic acid for wound healing, but does not entertain a fibrinogen and hyaluronic acid cell scaffold for the percutaneous delivery of stem cells. Radice has discussed the use of hyaluronic acid as a carrier for bioactive cells and a chondrocyte tissue repair scaffold, but not in combination with fibrinogen. disclose the use of biodegradable hyaluronic acid with a surgical implant. Mansmann discloses an anchoring device that is designed to hold a porous and flexible matrix, made of a material such as collagen or hyaluronic acid, which will hold chondrocyte cells. Again, this is a surgical implant augmented by hyaluronic acid and cells, but is not meant to be administered percutaneously. Naughton reveals the use of a hyaluronic acid and other material scaffold embedded with chondrocyte progenitors, but fibrinogen is not used as a composite with hyaluronic acid, but instead as an adhesive to hold the scaffold in place. Zheng has disclosed a broad patent application which does discuss the use of a biodegradable tissue scaffold with multiple autologous cells types. The use of MSC's among other cells is contemplated. This support matrix preferably includes collagen and or other materials including cells, hyaluronic acid, and possibly an unspecified fibrin Type. It does contemplate that cells and matrix could be delivered though an injection. It does discuss that cartilage repair in a joint is one goal of the invention. It does not reveal the use of this scaffold or these cells to repair an intervertebral disc. It does not disclose that fibrinogen will be mixed with hyaluronic acid to produce a composite outside of the body and then macerated before being mixed with cells and injected through a needle. Benette discloses the use of a biocompatible scaffold for multiple cell types including stem cells that may include fibrin and hyaluronic acid (separately but not in combination) for the potential regeneration of tendon and ligament injuries. In Binette fibrinogen and hyaluronic acid are mentioned among long list of possible combinations, not mentioned in specific combination as a sole composite, and this combination's use in Intervertebral disc regeneration is not discussed. Hill also reveals fibrinogen and hyaluronic acid among another long list of possible combinations for possible stem cell scaffold use. The use of this possible composite in the intervertebral disc not discussed. In none of these patents or applications is the use of a particular combination of fibrinogen, and hyaluronic acid discussed to produce a composite mesenchymal stem cell scaffold which is hardened outside the body and then macerated and injected percutaneously into the Intervertebral disc or a joint for cartilage repair.
Centeno, at para 12, (emphasis added).
Centeno does not teach SDF-1 as a component of fibrin glue and does not teach kartogenin.
Mao, US 20110300203, presents data and argument teaching the inclusion of SDF-1 with bone marrow derived mesenchymal stem cells in supporting tissue regeneration.
[0011] FIG. 3 is micrographs showing DAPI staining for adipose derived stem cells (ASCs) (Panels A-D), bone marrow derived mesenchymal stem cells (MSCs) (Panels E-H), and synovial stem cells (SYNs) (Panels I-L). Panels A, E and I: No cytokines; Panels B, F and J: SDF-1; Panels C, G & K: TGF-.beta.3; Panels D, H and L: SDF-1/TGF-.beta.3. Scale=50 .mu.m.
[0016] The inventor has discovered that tissue scaffolds that release the cytokines stromal cell-derived factor-1 (SDF-1) and transforming growth factor-.beta.3 (TGF-.beta.3) recruits surrounding bone marrow derived mesenchymal stem cells (MSCs), adipose derived stem cells (ASCs), and synovial cells (SYNs), which can then differentiate into tissue cells, for example chondrocytes. See Example below. Thus, scaffolds that comprise SDF-1 and a TGF-.beta. are useful for tissue regeneration, particularly cartilage regeneration.
[0035] The scaffold is generally fabricated into a shape that follows the geometry of the structure where tissue growth is desired. For example, where cartilage growth on a femoral condyle of a knee joint is desired, the scaffold would be flat and thin. By contrast, where cartilage growth to repair a defect of the nose or ear is desired, the scaffold would take a nose or ear shape.
[0040] For in vivo applications, these methods are particularly useful for cartilage repair/replacement. For example, the methods can be used to replace or augment existing cartilage, to introduce new or altered cartilage, to modify artificial prosthesis, or to add to biological tissues or structures.
Mao, US 20110300203 para 11, 16, 35, 40, (emphasis added).
Ding, 20200297761 teaches the use of kartogenin to stimulate mesenchymal stem cells.
[0006] Nevertheless, total joint replacement of knee, hip, and glenohumeral joints is still the most effective treatment, which can rescue joint function to near normal. However, since the damage of cartilage in osteoarthritis is usually serious, osteochondral transplantation, autotransplantation of perichondrium and periosteum, and chondrocyte transplantation may not be applicable. Recently, the studies show that newly discovered kartogenin (KGN) may stimulate mesenchymal stem cells (MSCs) in cartilage tissue to differentiate into chondrocytes, and local administration of KGN in the early stage of osteoarthritis may improve the damaged joints.
Ding, 20200297761 at para [0006], (emphasis added.
It would have been prima facie obvious before the filing date of the instant application for one of ordinary skill in the art to have combined SDF-1 and kartogenin as a component of fibrin glue, as taught by Centeno.
One of ordinary skill in the art would have motivated to have combined SDF-1 and kartogenin as a component of fibrin glue comprising encapsulated bone derived mesenchymal stem cells because SDF-1 and kartogenin were known in the prior art to support the growth and recruitment of bone derived mesenchymal stem cells.
2. Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Centeno, US 20090208464, Mao, US 20110300203, and Ding, 20200297761, as applied to claims 3, 4 , above, and further in view of Grainger, US 20010006640, Gurewich, US 20190241647 and Ying, US 20190315886.
The teachings of over Centeno, US 20090208464, Mao, US 20110300203, and Ding, 20200297761 are relied upon, as a above.
Centeno, US 20090208464, Mao, US 20110300203, or Ding, 20200297761, do not teach SEQ ID NO: 1, 2, and 3.
Grainger, US 20010006640, teaches at para [0072], reference SEQ ID NO: 56, that is identical to instant SEQ ID NO: 1, and which is described to be the chemokine SDF1beta.
Gurewich, US 20190241647, teaches at para [0058]-[0059], reference SEQ ID NO: 35, that is identical to instant SEQ ID NO: 2, and which is described to be fibrinogen.
Ying, US 20190315886, teaches at para [0136], [0153], reference SEQ ID NO: 1 and reference SEQ ID NO: 2, that has 100% identity to instant SEQ ID NO: 3, and which is described to be thrombin.
It would have been prima facie obvious before the filing date of the instant application for one of ordinary skill in the art to have combined the amino acid sequences of SEQ ID NO: 1, 2, and 3 in the fibrin glue composition as taught and suggested by Mao, US 20110300203, and Ding, 20200297761, as applied to claims 3, 4 , above, and further in view of Grainger, US 20010006640, Gurewich, US 20190241647 and Ying, US 20190315886.
One of ordinary skill in the art would have motivated to have combined the amino acid sequences of SEQ ID NO: 1, SDF-1 were known in the prior art to support the differentiation of bone derived mesenchymal stem cells into chondrocytes. One of ordinary skill in the art would have motivated to have combined the amino acid sequences of SEQ ID NO: 2 and 3, fibrinogen and thrombin would support the fibrin glue scaffolding.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark L Shibuya whose telephone number is (571)272-0806. The examiner can normally be reached M-F, 9AM-4:30PM.
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MARK L. SHIBUYA
Primary Patent Examiner
Art Unit 1631
/MARK L SHIBUYA/Primary Patent Examiner, Art Unit 1631