154Notice 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 15, 2026, has been entered.
Election/Restrictions
Applicant’s election without traverse of Group II (Claims 12-18; drawn to a method of use in alleviating or treating a tendon disease) in the reply filed on December 30, 2024, is acknowledged.
Claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group I), there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
DETAILED ACTION
The amended claims filed on January 15, 2026, have been acknowledged. Claims 11 and 14 were cancelled. Claim 12 was amended. In light of the Applicant’s elected invention, claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12-13 and 15-18 are pending and examined on the merits.
Priority
The applicant claims foreign priority from KR10-2020-0162290 filed on November 27, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received January 15, 2026. Claims 12-13 and 15-18 find support in foreign application KR10-2020-0162290 filed on November 27, 2020.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claim 14 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s cancellation of claim 14.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over Rubio-Azpeitia et al. (The Orthopaedic Journal of Sports Medicine 5: 1-11. 2017), Kwon et al. (The American Journal of Sports Medicine 46:1901–1908. 2018), and Naaldijk et al. (BMC Biotechnology 16: 1-11. 2016) as evidenced by Wang et al. (Journal of Dermatological Science 88. 159–166. 2017). is withdrawn in light of Applicant’s amendments to claim 12 to recite that the pharmaceutical composition comprises hyaluronic acid and the cancellation of claim 14.
New 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 12-3 and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Rubio-Azpeitia et al. (The Orthopaedic Journal of Sports Medicine 5: 1-11. 2017), United States Patent Application No: 20140309738 (Harley), and Naaldijk et al. (BMC Biotechnology 16: 1-11. 2016) as evidenced by Wang et al. (Journal of Dermatological Science 88. 159–166. 2017). This is a new rejection made in response to Applicant’s amendments to claim 12. Applicant’s traversal has been fully considered but is moot in response to the new rejection of record.
Regarding claim 12, claim 12 only recites the fibroblasts as being a part of the pharmaceutical composition and claims the fibroblasts are cultured in a cell culture medium without identifying that tenocytes are in the culture dish. Therefore, claim 12 is not interpreted to require tenocytes be cultured with the fibroblast nor as part of the pharmaceutical composition.
Rubio-Azpeitia teaches that they examined whether biological modifications induced by PRP on the tendon could help optimize the regenerative capacity of transplanted cells (tendon cells, BM-MSCs, and skin fibroblasts) (page 2, column 2, paragraph 1). Rubio-Azpeitia teaches that their cultured skin fibroblasts expressed higher levels of Collagen I than tenocytes (Figure 3). Skin fibroblasts and tenocytes were cultured at 37°C in 5% CO2 in DMEM F12 with 10% FBS for expansion (page 2, column 2, paragraph 2). Rubio-Azpeitia teaches that the tenocyte-CM [conditioned media] combined with PRP stimulated tenogenesis in skin fibroblasts and reduced the secretion of inflammatory proteins to improve tendon healing (abstract).
Rubio-Azpeitia does not teach that the skin fibroblasts were administered to a subject with hyaluronic acid.
However, Rubio-Azpeitia directly contemplates the translation of their experimental results to clinical practice. Rubio-Azpeitia teaches that their work addressed 2 main issues related to the current clinical problem. First, using 3-dimensional (3D) hydrogel cultures that closely imitate the in vivo environment when cells are delivered in combination with PRP, they explored the most appropriate cell source to fulfill the requirements of the injured tendon to specifically enhance extracellular matrix formation and to modulate inflammation. Second, they focused on modifying the target tissue prior to cell transplantation to improve its efficacy (page 2, column 1, paragraph 5).
Rubio-Azpeitia specifically states that implantation of skin fibroblasts or combined with PRP subsequent to preconditioning the target tendon with PRP injections would have more opportunities to regenerate the tendon (page 8, column 2, paragraph 1).
Furthermore, Harley teaches a coreshell composite comprising a porous collagen glycosaminoglycan scaffold core and a collagen glycosaminoglycan membrane shell having a higher density than the core, wherein the membrane shell is cross-linked to the core. The porous collagen glycosaminoglycan scaffold core can be populated with cells. The cells present in the scaffold core can be fibroblasts. Harley teaches a method of treating a tissue or defect in a subject in need thereof. The method comprises administering one or more of the core-shell composites of the invention to the subject, thereby treating the tissue defect. The tissue defect can be a defect rotator cuff tissue or tendon tissue, such as tendinopathies or tendon injuries due to overuse, tendon rupture, paratenonitis, tendinosis, paratenonitis with tendinosis, and tendinitis. The core-shell composite can be seeded with one or more types of cells prior to administering the core-shell composite to the subject. The invention provides a new class of core-shell CG biomaterial composites that integrate a high density (high tensile strength) isotropic CG membrane with a low density (highly porous) anisotropic CG scaffold. CG membranes are integrated with aligned CG scaffolds in a manner to maintain adequate permeability to support cell proliferation and bioactivity. Such a composite biomaterial improves regenerative capacity by significantly improving construct mechanical integrity while still presenting a highly porous scaffold microstructure containing aligned contact guidance cues providing significant value for musculoskeletal tissue engineering applications. Membrane shells of the invention can be comprised of hyaluronic acid. The cells can be derived from the subject to be treated (autologous source) or from allogeneic sources (paragraphs 0005-0018 and 0032-0040).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the skin fibroblast and culture method of Rubio-Azpeitia with the method of administering fibroblasts and hyaluronic acid core shell composites to subjects with tendon defects for tendon repair of Harley to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Rubio-Azpeitia and Harley are focused on repairing tendon damage and both show improved activity of their fibroblasts for repair/improved structural repair after administration, respectively. Rubio-Azpeitia teaches that the tenocyte-CM [conditioned media] combined with PRP stimulated tenogenesis in skin fibroblasts and reduced the secretion of inflammatory proteins to improve tendon healing and Harley teaches that their composites maintain adequate permeability to support cell proliferation and bioactivity. Such a composite biomaterial improves regenerative capacity by significantly improving construct mechanical integrity while still presenting a highly porous scaffold microstructure containing aligned contact guidance cues providing significant value for musculoskeletal tissue engineering applications. As such, it would have been obvious to take the next step of injecting the skin fibroblasts populated within the composite comprising hyaluronic acid of Harley into a damaged tendon for improved tendon regeneration. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Rubio-Azpeitia and Harley do not teach wherein the pharmaceutical composition also includes a cryoprotectant.
However, Naaldijk teaches that preservation of human skin fibroblasts is essential for the creation of skin tissue banks (abstract). Clinical approaches in regenerative medicine frequently involve the transplantation of cells, tissue constructs, and organs. While many studies have worked to optimize the culturing of live cells prior to transplantation, a major obstacle in this field is the distribution and timing of finite products for clinical use. As allogenic products are becoming more frequently used, it is paramount to optimize the long-term storage of cells and tissues to help minimize clinical costs and make the distribution easier (page 6, column 1, paragraph 2). Naaldijk teaches that cell viability of fibroblasts cryopreserved in suspension was maintained with 5% HES, 5% DMSO solutions. Adherent, cryopreserved fibroblasts were successfully maintained with a 5% HES, 5% DMSO solution (abstract). Naaldijk teaches that a randomized phase III clinical trial found that autologous blood stem cell transplantation could be effectively accomplished using cells cryopreserved in a 5% DMSO, 6% HES solution and none of the patients who received DMSO/HES cryopreserved cells showed any serious toxicities (page 9, column 2, paragraph 3). Therefore, DMSO would be used as part of the cryopreservation and would still be in the pharmaceutical composition for administration.
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 combined method of administering fibroblasts and hyalurin acid based composites to subjects with torn tendons for tendon repair of Rubio-Azpeitia and Harley by using cryopreserved fibroblasts using HES/DMSO 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 Naaldijk teaches that as allogenic products are becoming more frequently used, it is paramount to optimize the long-term storage of cells and tissues to help minimize clinical costs and make the distribution easier. Naaldijk teaches that cell viability and maintenance of cryopreserved fibroblasts with 5% HES, 5% DMSO solutions and that transplantation could be effectively accomplished using cells cryopreserved in a 5% DMSO, 6% HES solution and none of the patients who received DMSO/HES cryopreserved cells showed any serious toxicities. Therefore, it would have been obvious that the method of Rubio-Azpeitia and Harley for tendon repair could be used with cryopreserved fibroblasts as there would be no way of knowing when a tendon rupture or tendon damage is going to occur and cryopreserved cells would allow for the cells to be banked and ready for any patients that experiences tendon damage without needing to collect and prepare fresh cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 13, Rubio-Azpeitia does not teach administering their fibroblasts and therefore, is silent as to using allogenic fibroblasts.
However, as stated supra, Harley teaches that the fibroblasts can be autologous or allogenic (paragraph 0032).
Therefore, it would have been well understood to one of ordinary skill in the art that autologous or allogeneic fibroblasts can be administered to patients for tendon repair as Harley directly contemplates adding autologous or allogeneic cells to their composites for treating tendon defects. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 15, Rubio-Azpeitia teaches that skin fibroblasts that expressed more TGF-β than tenocytes. As can be seen in Figure 3D, the box and whisker plot shows many skin fibroblasts express more TGF-β than the lowest quartile of tenocyte cells.
Regarding claim 16, Wang evidences that fibroblasts secrete SCF which binds to the c-Kit receptor and activates the ERK intracellular signaling cascade (page 162, column 1, paragraph 4).
Regarding claim 17, as stated supra, Rubio-Azpeitia teaches that they were focused on how to treat tendon injury (page 2, column 1, paragraph 5) and Harley teaches treating tissue defects wherein the tissue defect can be a defect rotator cuff tissue or tendon tissue, such as tendinopathies or tendon injuries due to overuse, tendon rupture, paratenonitis, tendinosis, paratenonitis with tendinosis, and tendinitis (paragraphs 0005-0018 and 0032-0040).
Regarding claim 18, Naaldijk, as stated supra, teaches that cell viability of fibroblasts cryopreserved in suspension was maintained with 5% HES, 5% DMSO solutions. Adherent, cryopreserved fibroblasts were successfully maintained with a 5% HES, 5% DMSO solution (abstract). Naaldijk teaches that a randomized phase III clinical trial found that autologous blood stem cell transplantation could be effectively accomplished using cells cryopreserved in a 5% DMSO, 6% HES solution and none of the patients who received DMSO/HES cryopreserved cells showed any serious toxicities (page 9, column 2, paragraph 3). Therefore, DMSO would be used as part of the cryopreservation and would still be in the pharmaceutical composition for administration.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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