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 .
DETAILED ACTION
Pursuant to the amendment dated 12/29/2025, claims 1 and 8 are amended and claims 2-5 and 9 are canceled. Claims 1, 6-8 and 10 are pending in the instant application and are examined on the merits herein.
Priority
The instant application is a National Stage Application of PCT/IB2020/062186, filed on 12/18/2020 which claims foreign priority to ITALY 102019000025126, filed on 12/20/2019.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
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.
Claims 1, 6, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Bhumratana et al. (WO 2019/173435 A1, published 12/09/2019, see PTO-892 dated 10/16/2025), Pre et al. (Stem Cell Rev and Rep, published 09/24/2016, see PTO-892 dated 10/16/2025), and Gelardi et al. (Journal of Biological Regulators & Homeostatic Agents, published 12/22/2015, see PTO-892 dated 04/30/2025).
Bhumratana is drawn to compositions comprising a condensed mesenchymal cell body and a hydrogel, and methods of treating connective tissue defects, cartilage injury, and cartilage degradation (abstract). The composition may comprise a condensed mesenchymal cell body (CMB) and a hydrogel (claim 1) and the hydrogel may be hyaluronic acid (claim 14). The hydrogel may be a scaffold and may be hyaluronic acid (HA) or a modified HA (paragraph 0088). The composition may comprise growth factors that can provide for differentiation of CMBs into chondrocytes in the joint. Growth factors present in the composition, along with hydrogel and CMBs, can advantageously provide for physiologic developmental processes of mesenchymal condensation which, after implantation, potentially forms cartilage and integrates with adjacent tissue (paragraph 00102). The CMB may comprise mesenchymal stem cells such as bone marrow-derived stem cells and may be able to differentiate into diverse cell types such as osteoblasts and chondrocytes (paragraph 0075). Bhumratana defines "growth factor" as a substance capable of stimulating cellular growth, proliferation, repair and cellular differentiation (paragraph 0061). Bhumratana teaches that the compositions can be administered together with a pharmaceutically acceptable carrier, excipient, and/or an adjuvant (paragraph 00108). Bhumratana teaches a method of treating a cartilage defect in a patient comprising administering the composition into the cartilage or into the area surround the cartilage (paragraph 0024). A “patient” refers to an animal including a mammal (e.g., a human) (paragraph 0067). The instant specification defines the treatment of skeletal diseases to include the regeneration of bone and cartilage tissues (instant specification page 1), therefore treatment of a cartilage defect as taught by Bhumratana meets the limitation of a method of treating skeletal conditions.
Bhumratana does not teach the use of a T-Lys compound formed by HA, lysine and thymine.
Pre is drawn to HA scaffolds and MSCs in regenerative medicine (title). Pre teaches that crosslinking strategies are commonly used to control the HA degradation rate and mechanical properties, because in physiological environments, it is subjected to various degradation processes due to enzymatic hydrolysis by naturally occurring hyaluronidases (page 665). Pre also teaches that the use of crosslinked HA scaffolds was generally preferred because they have better mechanical properties than linear scaffolds (page 667).
Gelardi is drawn to the study of intranasal T-LysYal® as an adjunctive therapy for patients after functional endoscopic sinus surgery (title). Gelardi teaches that T-LysYal® is a hyaluronic acid (HA) formulation that is a supramolecular system containing lysine hyaluronate, thymine and sodium chloride. The instant specification (page 6, lines 18-20) defines T-LysYal® as a compound that is a derivative of hyaluronic acid, lysine and thymine by the formation of ionic-type bonds. Patients were treated with intranasal T-LysYal® and the treatment was found to significantly reduce the number of patients with symptoms, endoscopic features and inflammatory cells (abstract). Gelardi teaches that T-LysYal® increases fibroblast proliferation and collagen synthesis promoting tissue repair. Gelardi teaches that T-LysYal® is more resistant to lytic enzyme hyaluronidase than HA, a fact which accounts for a superior stability of the product that may exert a repairing activity for a longer period (column 1, page 278).
It would have been prima facie obvious to combine Bhumratana, Pre, and Gelardi before the effective filing date of the claimed invention by using T-LysYal® as the hyaluronic acid compound as taught by Gelardi in the scaffold with the MSC cells taught by Bhumratana to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the HA in Bhumratana’s scaffold with the T-LysYal® because Gelardi teaches that T-LysYal® increases fibroblast proliferation and collagen synthesis promoting tissue repair and is more stable than HA and Pre teaches that crosslinking is used in HA hydrogels to control degradation. One of ordinary skill in the art would have a reasonable expectation of success because Bhumratana teaches that a modified HA may be used, Pre teaches that crosslinking HA hydrogels helps to control degradation, and Gelardi teaches that T-LysYal®, a hyaluronic acid composition, is more stable than HA.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Bhumratana et al. (WO 2019/173435 A1, published 12/09/2019, see PTO-892 dated 10/16/2025), Pre et al. (Stem Cell Rev and Rep, published 09/24/2016, see PTO-892 dated 10/16/2025), and Gelardi et al. (Journal of Biological Regulators & Homeostatic Agents, published 12/22/2015, see PTO-892 dated 04/30/2025) and further in view of Benedetto (Stem Cell Research, published 09/30/2015, see PTO-892 dated 04/30/2025).
The combined teachings of Bhumratana, Pre, and Gelardi reject claims 1 and 6 as discussed above.
Bhumratana further teaches that BMSCs may be derived from various bone marrow tissue sites (paragraph 0076).
The combined teachings of Bhumratana, Pre and Gelardi do not teach MSCs that are stem cells of the dental germ.
Benedetto is drawn to study of the osteogenic differentiation of mesenchymal stem cells from dental bud (title). Benedetto teaches that dental tissues have been identified as a source of postnatal MSCs. Dental bud is easy to access and can yield a high number of cells with ≥95% expression of mesenchymal stemness makers and osteogenic capacity. Benedetto teaches that the cells are a promising source for bone regeneration (abstract). Benedetto also teaches that tooth extraction to obtain dental bud MSCs (DBMSCs) is less invasive compared to extraction of bone marrow (column 2, page 623). Benedetto teaches that DBSCs not only differentiated into osteoblast-like cells depositing mineral matrix, but also expressed a pattern of adhesion receptors as cadherins very similar to bone marrow MSCs, switching to the typical osteoblast phenotype as they were maintained in osteogenic conditions (column 2, page 624)
It would have been prima facie obvious to combine the combined teachings of Bhumratana, Pre and Gelardi with the teachings of Benedetto before the effective filing date of the claimed invention to use DBMSCs as taught by Benedetto in the method of treating skeletal conditions as taught by Bhumratana, Pre and Gelardi to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the MSC to be DBMSCs because Benedetto teachings that DBMSCs are less invasive to harvest and that they are a promising source for bone regeneration. One of ordinary skill in the art would have a reasonable expectation of success because Benedetto shows that BDMSCs are able to differentiate into osteoblast-like cells and the combined teachings of Bhumratana, Pre and Gelardi teach that MSCs can be used to treat skeletal conditions comprising a T-LysYal® composition and MSC stem cells.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered in so much as they apply to the amended claims but they are not persuasive.
Applicant argues that Bhumratana does not teach a T-lys compound formed by hyaluronic acid, lysine and thymine and that Gelardi and Pre do not correct for Bhumratana’s deficiencies. Applicant argues that Gelardi is directed to the use of T-LysYal for treatment of patients after functional endoscopic sinus surgery (FESS) and does not describe “hard tissue”. The argument is unpersuasive. Bhumratana teaches treating a skeletal disease with a modified HA scaffold. Gelardi was not relied upon to teach the treatment of “hard tissue”, but rather to teach the administration of T-LysYal and to provide a motivation of using T-LysYal over HA to improve resistance to lytic enzyme hyaluronidase. Pre was used to provide further motivation to investigate HA scaffolds as crosslinked HA scaffolds can have improved HA degradation rates. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Benedetto is completely silent with regard to HA and T-LysYal and therefore cannot correct the deficiencies of the combination of the teachings of Bhumratana, Gelardi and Pre. The argument is unpersuasive. Benedetto was not relied upon to teach the HA or T-LysYal. Benedetto was used to teach that dental bud is easy to access as a source of MSCs. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693