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 .
This action is in response to the papers filed December 24, 2025.
Claims 1 and 3-20 are pending in the application. Claim 2 is canceled, claims 1, 7, 8, 10 and 18 are amended and no new claims are added as set forth in the claim set filed 12/24/2025. Claims 1, 10 and 18 are independent claims.
Therefore, claims 1 and 3-20 are examined on the merits.
Priority
No foreign priority or benefit of a prior filed application is claimed.
Thus, the earliest possible priority for the instant application is the effective filing date, May 19, 2023.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
The rejection of claims 7-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Applicant’s arguments and amendments filed 12/24/2025 have been considered and are persuasive. The amendments have corrected the issue of antecedent basis.
Claim Rejections - 35 USC § 103
The rejection of claim 1-3, 7-13, and 15-20 under 35 U.S.C. 103 as being unpatentable over Choi (Int. J. Mol. Sci. 2020, 21, 7391) as in view of Beegle (Stem Cells. 2015 Jun;33(6):1818-28) is withdrawn.
The rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over Choi (Int. J. Mol. Sci. 2020, 21, 7391) as in view of Beegle (Stem Cells. 2015 Jun;33(6):1818-28) as applied to claim 1 above, and in further view of Caicco (J Biomed Mater Res Part A 2013:101A:1472–1477) is withdrawn.
The rejection of claims 5 and 14 under 35 U.S.C. 103 as being unpatentable over Choi (Int. J. Mol. Sci. 2020, 21, 7391) as in view of Beegle (Stem Cells. 2015 Jun;33(6):1818-28) as applied to claims 1 and 10 above, and in further view of Ballios (Stem Cell Rep. 2015, 4, 1031–1045) is withdrawn.
The rejection of claim 6 under 35 U.S.C. 103 as being unpatentable over Choi (Int. J. Mol. Sci. 2020, 21, 7391) as in view of Beegle (Stem Cells. 2015 Jun;33(6):1818-28) as applied to claims 1 and 10 above, and in further view of Genovese (J Tissue Eng Regen Med. 2021 Sep 27;15(12):1131–1143).
Applicant’s arguments and amendments filed 12/24/2025 concerning the 103 rejections previously set forth have been considered and are persuasive in regards to the new limitations recited in the independent claims. However, a new grounds of rejection has been necessitated by the amendments and new 103 rejections addressing all limitations are made below.
New grounds of objections/ Rejections in response to Applicants’ arguments or amendments
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.
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.
Claim 1, 3, 7-11, 13, and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Choi (Int. J. Mol. Sci. 2020, 21, 7391) in view of Youn (Molecules 2022, 27, 5512) and Hu (J Thorac Cardiovasc Surg 2008;135:799 808)
Regarding claim 1, 7-9 and 11, Choi teaches a biomaterial comprising human umbilical cord stem cells from Wharton’s Jelly in a HAMC (hyaluronic acid and methyl cellulose) hydrogel (i.e. thermoresponsive carrier), a liquid at cold temperatures, fully dissolving and kept at 4°C (Abstract, p. 13, 2nd column). Choi teaches body temperature of rats were maintained at 37°C and when injected the HAMC will increase in viscosity (i.e. gel) (p. 3, 1st paragraph).
However, Choi does not teach that the thermoresponsive hydrogel additionally comprises 0.5-5% gellan gum or that hypoxic conditions are utilized in the method.
Youn teaches adding gellan gum to hyaluronic acid hydrogels to form GG/HA hydrogels (Abstract). The gellan gum was in solution at a concentration of 1% w/v and added to a 1% HA solution at a ratio of 10:0 = GG:HA, 9:1 = GG:HA, and 8:2 = GG:HA, which are named GG10, GG9/HA1, and GG8/HA2,respectively (p. 10, last paragraph). The composite of GG and HA is on the rise to be a promising material and is being used in various tissue engineering fields (p. 2, 3rd paragraph). Moreover, GG can be physically crosslinked with the presence of cations (Na+, K+, Ca2+, and Mg2+), which provide a stable structure in the physiological environment; an injectable property; and a viscoelastic character, which is reported to be effective for cell viability and proliferation (p. 2, 3rd paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to additionally have gellan gum at a concentration of 0.5-5% w/v as taught by Youn in the thermoresponsive hyaluronic and methylcellulose hydrogel of Choi with a reasonable expectation of success. An artisan would have been motivated to add gellan gum to the hydrogel as Youn teaches the composite of gellan gum and hyaluronic acid is on the rise to be a promising material and is being used in various tissue engineering fields (p. 2, 3rd paragraph). and the concentrations claimed are known in the art.
However, the combination of Choi and Youn do not teach that the MSC are preconditioned under hypoxic conditions comprising low oxygen levels and 2-8% CO2.
Hu teaches hypoxic preconditioning of MSCs increases the expression of pro-survival and pro-angoigenic factors which resulted in an increase in angiogenesis and enhanced morphological and functional health benefits after implantation in vivo (p. 799, Results). Hu cultures BM-MSCs in 0.5% oxygen and 5% CO2 in order to precondition them in a hypoxic environment (p. 880, 1st column; p. 880, Sublethal hypoxia protocol). The instant specification describes hypoxic conditions as an oxygen concentration 10% or less. This is accompanied by a carbon dioxide concentration which can be about 2-8% carbon dioxide (para. 0035). Therefore, Hu meets the limitations of a hypoxic environment comprising 2-8% carbon dioxide.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to precondition the cells of Choi in hypoxic conditions such as low oxygen with 5% CO2 as taught by Hu before combining them with the HAMC hydrogel with a reasonable expectation of success. An artisan would be motivated to precondition the cells as Hu teaches preconditioning of MSCs in hypoxic conditions enhances morphological and functional health benefits after implantation in vivo (p. 799, Results).
Regarding claim 3, the combined teachings of Choi, Youn and Hu make obvious claim 1. Choi teaches a biomaterial comprising human umbilical cord stem cells from Wharton’s Jelly in a HAMC (hyaluronic acid and methyl cellulose) hydrogel (i.e. co-dissolution) (p. 16, 1st column).
Regarding claim 10, 13 and 15, as seen above the combination of the combined teachings of Choi, Youn and Hu make obvious the utilization of hypoxic WJ-MSC. Choi teaches obtaining an umbilical cord, isolating the viable stem cells, which are cultured and expanded under hypoxic conditions in view of Hu, and combining the stem cells with the HAMC or PBS (i.e. inert carrier) (p. 13, 3rd paragraph)
Regarding claims 16 and 17, as seen above the combination of the combined teachings of Choi, Youn and Hu make obvious claim 10. Moreover, Choi teaches that the inert carrier has a thermo-gelation agent such as methyl cellulose with the hyaluronic acid (p. 13, 2nd paragraph).
Regarding claims 18-20, as seen above, Choi, Youn and Hu make obvious a method of making a biomaterial including hypoxia preconditioned WJ-MSC as claimed in claim 1. Moreover, Choi teaches administering the biomaterial to rats with injury induced disc degeneration (i.e. defect or injury in the spine) (p. 14, Sections 4.5-4.6). The HAMC is injected as a liquid and gels at the target repair site (p. 3, 1st paragraph).
Therefore the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Choi (supra) in view of Youn (supra) and Hu (supra) as applied to claim 1 above, and in further view of Caicco (J Biomed Mater Res Part A 2013:101A:1472–1477; previously cited).
Choi, Youn and Hu make obvious a biomaterial and method of transplantation of said biomaterial comprising methyl cellulose, hyaluronic acid, gellan gum and hypoxia preconditioned WJ-MSC as described above and incorporated herein in its entirety. Moreover, Choi teaches a 1% HAMC concentration which is 0.5% HA/0.5% MC (p. 14, Section 4.4)
However, Choi, Youn, and Hu do not teach concentrations of HAMC wherein the concentrations are 0.2% to 2% (w/v) hyaluronic acid and 2-10% (w/v) methyl cellulose.
Caicco teaches HAMC gels at physiological temperatures in less than 5 mins at different concentrations of both components (Abstract, Figure 2). In particular, HAMC gels can be made at 0.5 HA /0.5 MC (which is utilized in Choi) to 1.0 HA/1.0 MC (p. 1473, 1st column). Therefore, the teachings include overlapping ranges with the presently recited range in claim 4. Moreover, Gel strength could be tuned through simple adjustment of the MC and HA contents in the gel (p. 1475, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize a blend of HA and MC wherein the concentrations are 0.2% to 2% (w/v) hyaluronic acid and 2-10% (w/v) methyl cellulose instead of 0.5 and 0.5 w/v of Choi with a reasonable expectation of success. Caicco teaches gelation within said range and gel strength could be tuned through simple adjustment of the MC and HA contents in the gel (p. 1475, 1st column). This invites routine optimization for the gel strength within the range claimed.
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claim 5 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Choi (supra) in view of Youn (supra) and Hu (supra) as applied to claims 1 and 10 above, and in further view of Ballios (Stem Cell Rep. 2015, 4, 1031–1045; previously cited)
Choi, Youn and Hu make obvious a biomaterial and method of transplantation of said biomaterial comprising methyl cellulose, hyaluronic acid, gellan gum and hypoxia preconditioned WJ-MSC as described above and incorporated herein in its entirety.
However, regarding claims 5 and 14, Choi, Youn and Hu do not explicitly teach single cell suspensions being combined with the HAMC hydrogel solution.
Ballios teaches combining single cell suspensions with 0.5/0.5 HAMC hydrogel solutions (the same concentration as Choi) for transplantation (p. 15, 2nd paragraph; p. 16, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to obtain the WJ-MSC of Choi in a single cell suspension through methods known in the art as taught by Ballios to combine with a HAMC hydrogel solution to produce an injectable biomaterial with a reasonable expectation of success. An artisan would be utilizing known methods in the prior art to yield predictable results (i.e. combining cells with HAMC hydrogels for transplantation) (MPEP 2143; Rationale A).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Choi (supra) in view of Youn (supra) and Hu (supra) as applied to claims 1 and 10 above, and in further view of Genovese (J Tissue Eng Regen Med. 2021 Sep 27;15(12):1131–1143; previously cited)
Choi, Youn and Hu make obvious a biomaterial and method of transplantation of said biomaterial comprising methyl cellulose, hyaluronic acid, gellan gum and hypoxia preconditioned WJ-MSC as described above and incorporated herein in its entirety.
However, regarding claims 6 and 14, Choi, Youn and Hu do not explicitly teach wherein the human umbilical cord mesenchymal stem cells include a suspension of micro-spheroids having 50-200 cells with sizes ranging from 50 to 200 μm.
Genovese teaches encapsulating MSC spheroids which can be 100 μm to 150 μm in size and have can have 150 cells/spheroid to 600 cells/spheroid in hydrogels to treat traumatic injury (p. 1133, 1st column; Abstract; Figure 1C). Genovese additionally teaches that it has been shown that MSCs injected with a biomaterial carrier material, exhibit better viability and retention in the transplanted tissue (p.1132, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to obtain the WJ-MSC of Choi in a spheroid containing 150-600 cells through methods known in the art as taught by Genovese to combine with a HAMC hydrogel solution to produce an injectable biomaterial with a reasonable expectation of success. An artisan would be utilizing known methods in the prior art to yield predictable results (i.e. combining cells with HAMC hydrogels for transplantation) (MPEP 2143; Rationale A). Moreover, Genovese teaches that it has been shown that MSCs injected with a biomaterial carrier material, exhibit better viability and retention in the transplanted tissue (p.1132, 1st column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Choi (supra) in view of Youn (supra) and Hu (supra) as applied to claims 1 and 10 above, and in further view of Beegle (Stem Cells. 2015 Jun;33(6):1818-28; previously cited)
Choi, Youn and Hu make obvious a biomaterial and method of transplantation of said biomaterial comprising methyl cellulose, hyaluronic acid, gellan gum and hypoxia preconditioned WJ-MSC as described above and incorporated herein in its entirety. Moreover, Hu teaches utilizing hypoxic conditions of 0.5% oxygen.
Regarding claims 12, Choi, Youn and Hu do not teach oxygen concentrations between 1% and 6%.
Beegle teaches utilizing hypoxic conditions from 1%-10% oxygen compared to the atmospheric 20% (p. 1819, 1st column). Moreover, 1% is an optimal hypoxic level to favor cell survival (p. 1826, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the method of Choi, Youn and Hu from utilizing 0.5% oxygen to instead utilize 1% oxygen as taught by Beegle with a reasonable expectation of success. An artisan would have been motivated to do so as Beegle teaches 1% oxygen is an optimal hypoxic level to favor cell survival (p. 1826, 2nd column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
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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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631