DETAILED ACTION
Notice of 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 .
Status of the Claims
The amendments filed 7/24/2026 have been entered.
Priority
Provisional Application No. 63/063,271, filed 8/08/2020, provides support for a method of “improv[ing] the beneficial effect of Bone Marrow Stem Cells for Osteoarthritis” comprising administering “senolytic and anti-fibrotic agents”, specifically naming fisetin and losartan (Page 14), as embraced by pending claims 1 and 7-8.
However, provisional Application No. 63/063,271 does not provide support for the broad improvement of any therapeutic outcome of BMSC, BMC or BMAC treatment in a subject having any musculoskeletal condition or disorder (e.g., enhancing cartilage healing due to microfracture treatment of osteochondral defects, generically, and so on) as further embraced by claim 1 and claims 2-5 and 7-19 dependent thereon.
Provisional Application No. 63/157,174, filed 3/5/2021, provides support for a method of “improv[ing] the beneficial effect of bone marrow derived stem cells (derived from bone marrow aspirate concentrate) for improving outcomes in patients with knee osteoarthritis” comprising administering “a senolytic agent (Fisetin) and an anti-fibrotic agent (Losartan), used independently or in combination” (Abstract), as embraced by pending claims 1 and 7-8, further disclosing that “[t]he senolytic treatment (Fisetin 20 mg/kg/day...) regimen will be in cycles of 2 days on and 28 days off, administered before and for 3 months” and the “Losartan treatment... 25 mg/day... will be administered for a period of 30 days starting at the time of BMSC treatment” (Page 2)
However, provisional Application No. 63/157,174 does not provide support for the broad improvement of any therapeutic outcome of BMSC, BMC or BMAC treatment in a subject having any musculoskeletal condition or disorder (e.g., enhancing cartilage healing due to microfracture treatment of osteochondral defects, generically, and so on) as further embraced by claim 1 and claims 2-5 and 7-19 dependent thereon.
As such, the effective filing date of pending claims 1-5 and 7-19 is determined to be 7/30/2021, based on PCT/US2021/04369.
Response to Arguments
Applicant’s arguments, filed 7/24/2026, have been fully considered.
Applicant first argues that, as amended, “claim 1 is entitled to the benefit of the priority applications at least to the extent directed to improving BMSC, BMS, and/or BMAC treatment with senolyltic and/or anti-fibrotic agents” (Applicant Arguments, Page 6).
The argument it not found persuasive. At minimum, the claims continue to embrace methods of improving an outcome of BMSC, BMC, or BMAC in a subject suffering from any musculoskeletal condition or disorder (e.g., carpal tunnel syndrome, tendinitis, lower back pain, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, bursitis, fibromyalgia, gout, etc.) whereas the priority documents are limited to methods for improving the beneficial effect of Bone Marrow Stem Cells for Osteoarthritis.
Applicant next traverses the rejection of claims 10-14 under 35 U.S.C. 112(b). The rejection has been WITHDRAWN in view of Applicant’s amendments to the claims. Claims 2 and 4-5 are NEWLY rejected in view of Applicant’s amendments to the claims.
Applicant additionally traverses the rejection of claims as being anticipated by Utsunomiya et al (Orthop J Sports Med 7(7)(suppl 5):2 pages, published July 2019; of record) (Applicant Arguments, Pages 7-8)
The rejection is WITHDRAWN in view of Applicant’s amendments to the claims.
Applicant next traverses the rejection of claims as being anticipated by Huard et al (US 2021/0046123; of record) (Applicant Arguments, Page 7). However, Applicant does not provide any basis for this traversal.
As such, the rejection is MAINTAINED.
Applicant next traverses the rejection of claims under 35 U.S.C. 103(a) as being unpatentable based primarily on Hannon et al (The Journal of Arthroscopic & Related Surgery 32:339-347, 2016 – Abstract only) (Applicant Arguments, Page 8).
The rejection has been WITHDRAWN as superfluous in view of the rejection of claims based on Huard et al.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 4-5 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 is drawn to “[a] a method for improving an outcome of bone marrow stem cell (BMSC), bone marrow concentrate (BMC), or bone marrow aspirate concentrate (BMAC) treatment in a subject having a musculoskeletal condition or disorder, the method comprising administering at least one senolytic agent and/or at least one anti-fibrotic agent before, after, or concurrent with the BMSC, BMC, or BMAC treatment”.
Claims 2 and 4-5 are drawn to “[t]he method of claim 1, wherein the outcome is related to the outcome of... non-surgical treatment of the musculoskeletal condition or disorder” (claim 2), wherein “the non-surgical treatment comprises administration of an orthobiologic to the subject” (claim 4), more specifically “administration of bone marrow stem cells to the subject” (claim 5).
Claims 2 and 4-5 fail to further limit claim 1 because the method of claim 1, which comprises BMSC, BMC, or BMAC treatment, already involves improving the outcome of administration of bone marrow stem cells to the subject.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5 and 7-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huard et al (US 2021/0046123; of record).
As amended, claim 1 is drawn to a method for improving an outcome of bone marrow stem cell (BMSC), bone marrow concentrate (BMC), or bone marrow aspirate concentrate (BMAC) treatment in a subject having a musculoskeletal condition or disorder (more specifically, a bone injury, condition, or disorder (claim 3)), the method comprising administering at least one senolytic agent (more specifically, fisetin (claims 7 and 9) and/or at least one antifibrotic agent (more specifically, losartan (claims 8-9)) before, after, or concurrent with the BMSC, BMC, or BMAC treatment.
Huard et al teach treatment of rabbits having “osteochondral defect (OD) in the patella grove” with “[m]icrofracture procedures” followed by “BMAC... injected intra-articularly in the left knee” (Paragraph 0131) and further treated with “losartan and Fisetin... to determine the effect of Fisetin... with losartan and BMAC, for cartilage repair” – i.e., to determine “the synergistic effect of adding BMAC and losartan to Fisetin” (Paragraph 0129), wherein “data showed that the augmentation of BMAC, or Fisetin and Losartan, to microfracture accelerated cartilage regeneration in a rabbit osteochondral defect model” (Paragraph 0132).
Accordingly, claims 1, 3 and 7-9 are anticipated.
Claims 2 and 4-5 are drawn to “[t]he method of claim 1, wherein the outcome is related to the outcome of... non-surgical treatment of the musculoskeletal condition or disorder” (claim 2), wherein “the non-surgical treatment comprises administration of an orthobiologic to the subject” (claim 4), more specifically “administration of bone marrow stem cells to the subject” (claim 5).
As discussed above, claims 2 and 4-5 fail to further limit claim 1 because the method of claim 1, which comprises BMSC, BMC, or BMAC treatment, already involves improving the outcome of administration of bone marrow stem cells to the subject.
Accordingly, claims 2 and 4-5 are also anticipated.
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.
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 10-17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Huard et al (US 2021/0046123; of record).
Claims 10-14 are drawn to the method of claim 7, wherein:
the senolytic agent is administered to the subject in cycles of about 2 days on/about 28 days off before and after the BMSC, BMS, and/or BMAC treatment (claims 10-11 and 14); and
the anti-fibrotic agent is administered for at least about 30 days after the BMSC, BMS, and/or BMAC treatment (claims 12-14).
As taught by Huard et al, “[t]he present invention includes methods comprising administering to a subject at least one senolyltic agent... at a dosing frequency of more than once”, in particular wherein “[f]isetin is administered orally 2 daily doses back-to-back, followed by 28 days off routinely for years or decades” (Paragraph 0056) – further disclosing “the treatment of patients with senolyltic agents before stem cell harvesting in order to eliminate preexisting senescent cells in the body” (Paragraph 0073) – as well as “administering to the subject a second therapeutic agent in combination with the at least one senolyltic agent... administered before, after, or concurrent with the senolyltic agent” (Paragraph 0059)
As such, Huard et al generically teach a dosing regimen which overlaps the instantly claimed dosing regimen. And, as stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
For the same reasons, it would have been customary to determine the optimal dosing regimen of Huard et al to arrive at the instantly claimed dosing regimen. It would have been obvious to do so in order to best achieve the desired results with a reasonable expectation of success.
Accordingly, claims 10-14 are rejected as prima facie obvious.
Claims 15-17 are drawn to the method of claims 7-8 wherein:
the senolytic agent is administered at a dosage of about 1000 mg/day (claim 15); and/or
the senolytic agent is administered at a dosage of about 10 mg/kg/day to about 100 mg/kg/day (claim 16), more specifically about 20 mg/kg/day (claim 17); As taught by Huard et al, “[a] therapeutically effective amount of a senolyltic agent can be... about 1000 mg” wherein in some embodiments “the senolyltic agent is Fisetin and is administered to a human subject at about 1 mg/kg to about 100 mg/kg” (Paragraph 0061).
As taught by Huard et al, “[a] therapeutically effective amount of a senolyltic agent can be... about 1000 mg” and, in some embodiments, “the senolyltic agent is Fisetin and is administered to a human subject at about 1 mg/kg to about 100 mg/kg” (Paragraph 0061).
Accordingly, claims 15-17 are also rejected as prima facie obvious.
Claims 18-19 are rejected under 35 U.S.C. 103(a) as being unpatentable over Huard et al (US 2021/0046123; of record) in view of Li et al (Folia Biologica (Krakow) 67(4):177-189, published December 30, 2019; of record).
Claims 18-19 are drawn to the method of claims 7-8 wherein:
the anti-fibrotic agent is administered at a dosage of about 10 mg/kg/day to about 200 mg/kg/day (claim 18), more specifically about 25 mg/kg/day (claim 19).
As discussed above, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the concentration of active ingredient to administer for the treatment of a condition is clearly a result-effective variable. Indeed, as indicated by the court in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015), every ordinary artisan in medicine performs “merely routine optimization of drug dosage to maximize therapeutic effect”. And, as demonstrated by Li et al, which teach administration of fisetin at a dosage of 25 mg/kg/day, 50 mg/kg/day and 100 mg/kg/day (Page 179, Column 1), “[a]nimals treated with 25 mg/kg of fisetin displayed a modest inflammation with less diffused joint space, whereas animals treated with 50 mg/kg of fisetin showed less cartilage destruction and diminished swelling with a partial diffusion of the joint space. A diminished joint space with no joint swelling or bone erosion was observed in the 100 mg/kg fisetin-treated groups” (Page 182, Column 2). Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal dosage of fisetin and losartan to administer in order to best achieve the desired results.
As such, claims 18-19 are also rejected as prima facie obvious.
Claims 10-19 are ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Huard et al (US 2021/0046123; of record) as applied to claims 1-5 and 7-9 above, in further view of NCT04815902 (3/22/2021).
Claims 10-14 are drawn to the method of claim 7, wherein:
the senolytic agent is administered to the subject in cycles of about 2 days on/about 28 days off before and after the BMSC, BMS, and/or BMAC treatment (claims 10-11 and 14); and
the anti-fibrotic agent is administered for at least about 30 days after the BMSC, BMS, and/or BMAC treatment (claims 12-14).
And claims 15-19 are drawn to the method of claims 7-8 wherein:
the senolytic agent is administered at a dosage of about 1000 mg/day (claim 15);
the senolytic agent is administered at a dosage of about 10 mg/kg/day to about 100 mg/kg/day (claim 16), more specifically about 20 mg/kg/day (claim 17); and/or
the anti-fibrotic agent is administered at a dosage of about 10 mg/kg/day to about 200 mg/kg/day (claim 18), more specifically about 25 mg/kg/day (claim 19).
The teachings of Huard et al have been set forth above.
NCT04815902, disclosing the “[u]se of senolyltic and anti-fibrotic agents to improve the beneficial effect of bone marrowy stem cells for OA” (Brief Title), in particular “to improve beneficial effect demonstrated by the active control which is to be injection of autologous bone marrow aspirate concentrate (BMAC) into an osteoarthritic knee” (Brief Summary), teach administration of “fisetin 20 mg/kg taken a total of 4 days prior to BMA concentrate injection (-32 and -31 and -3 and -2) then again after BMA concentrate injection... (32 & 33, 61 & 62 and 90 & 91)” as well as “Losartan 12.5 mg, BID beginning the first day after BMA concentrate injection and continuing for 30 days” (Arms, Experimental).
Accordingly, based further on NCT04815902, it would have been prima facie obvious to select the instantly claimed dosing regimen from within the generic disclosure of Huard et al for the treatment of an osteochondral defect with a reasonable expectation of success.
As such, claims 10-19 are rejected as prima facie obvious.
Conclusion
The new ground(s) of rejection presented in this Office action are necessitated by Applicant’s amendments to the claims. 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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