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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 1/05/2026 is acknowledged. The requirement is still deemed proper and is therefore made FINAL.
Claims 24-26 and 29-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election without traverse of a single method in the reply filed on 1/05/2026 is also acknowledged.
The elected species read upon claims 1-5 and 7-19. Claims 6 and 20-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
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 enhancement of any therapeutic outcome 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 pending claim 1 and pending 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 enhancement of any therapeutic outcome 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 pending claim 1 and pending 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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 10-14 are rejected under 35 U.S.C. 112(b) 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.
Claim 1 is drawn to “[a] method for enhancing a therapeutic outcome in a subject having a musculoskeletal condition or disorder, comprising administering at least one senolytic agent and/or at least one anti-fibrotic agent”.
Claims 7-8 are drawn to “[t]he method of claim, wherein the at least one senolytic agent is Fisetin” (claim 7) and “wherein the at least one antifibrotic agent is losartan” (claim 8).
Claims 10-14 each depend from claims 7 or 8, wherein:
the senolytic agent is administered “before treatment” (claim 10);
the senolytic agent is administered “before and after treatment” (claim 11);
the antifibrotic agent is administered “after treatment” (claim 12);
the senolytic agent is administered “before treatment” and the antifibrotic agent is administered “after treatment” (claim 13); and
the senolytic agent is administered “before and after treatment” and the antifibrotic agent is administered “after treatment” (claim 14).
The recitation of “treatment” in claims 10-14 lack antecedent basis, rendering the claims indefinite. In particular, it is unclear when the agents are administered in the method for enhancing a therapeutic outcome. In claim 10, for example, is the senolytic agent administered before whatever treatment precipitates “a therapeutic outcome” as recited by claim 1? Or, is the senolytic agent administered before treatment with another senolytic agent and/or treatment with at least one antifibrotic agent?
Accordingly, claims 10-14 are rejected as indefinite.
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 1-3 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Utsunomiya et al (Orthop J Sports Med 7(7)(suppl 5):2 pages, published July 2019).
Claim 1 is drawn to a method for enhancing a therapeutic outcome (more specifically, cartilage healing related to the outcome of surgical treatment (claim 2)) in a subject having a musculoskeletal condition or disorder (more specifically, an osteochondral defect (claim 3)), the method comprising administering the antifibrotic agent losartan (claim 8).
Utsunomiya et al teach “[b]iologically regulated BMS by blocking TGF-β1 (oral intake of losartan) provided superior cartilage repair [of “[a]n osteochondral defect... made in the patellar groove of... white rabbits” (Methods)]... compared to outcomes from BMS only” (Conclusion).
That is, Utsunomiya et al teach enhancing cartilage healing related to the outcome of bone marrow stimulation (BMS) – i.e., a surgical treatment – in a subject having an osteochondral defect, the method comprising administering losartan to said subject.
Accordingly, claims 1-3 and 8 are anticipated.
Claims 18 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Utsunomiya et al (Orthop J Sports Med 7(7)(suppl 5):2 pages, published July 2019) as applied to claims 1-3 and 8 above, as evidenced by Research Models New Zealand White Rabbit (available online at https://www.criver.com/resources/new-zealand-white-rabbit-data-sheet, accessed 1/23/2026).
Claim 18 is drawn to the method of claim 8, wherein the at least one anti-fibrotic agent is administered at a dosage of about 10 mg/day to about 200 mg/day.
Utsunomiya et al teach administering a “10 mg/kg/day dose of losaratan” to “New Zealand White rabbits” (Abstract) which, given a weight range of 2 to 6 kg (as evidenced by Research Models New Zealand White Rabbit), equates to about 20 to 60 mg/day.
Accordingly, claim 18 is also anticipated.
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).
Claim 1 is drawn to a method for enhancing a therapeutic outcome (more specifically, cartilage healing related to BMAC treatment (as elected by Applicant) which reads on claims 2 and 4-5) in a subject having a musculoskeletal condition or disorder (more specifically, an osteochondral defect (as elected by Applicant) which reads on claim 3), the method comprising administering at least one senolytic agent and/or at least one antifibrotic agent to the subject (more specifically, the senolytic agent fisetin and the antifibrotic agent losartan (as elected by Applicant) which reads on claims 7-9).
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” (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 1-5 and 7-9 are 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 1-5, 7-9 and 15-19 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hannon et al (The Journal of Arthroscopic & Related Surgery 32:339-347, 2016 – Abstract only) in view of Li et al (Folia Biologica (Krakow) 67(4):177-189, published December 30, 2019), Kawaguchi et al (Acta Orthopaedica 80(5):606-611, 2009), Sahu et al (BMC Musculoskeletal Disorders 20:193, published May 4, 2019) and Utsunomiya et al (Orthop J Sports Med 7(7)(suppl 5):2 pages, published July 2019).
Claim 1 is drawn to a method for enhancing a therapeutic outcome (more specifically, cartilage healing related to BMAC treatment (as elected by Applicant) which reads on claims 2 and 4-5) in a subject having a musculoskeletal condition or disorder (more specifically, an osteochondral defect (as elected by Applicant) which reads on claim 3), the method comprising administering at least one senolytic agent and/or at least one antifibrotic agent to the subject (more specifically, the senolytic agent fisetin and the antifibrotic agent losartan (as elected by Applicant) which reads on claims 7-9).
As thus summarized, the elected invention reads on claims 1-5 and 7-9.
Hannon et al teach that “arthroscopic bone marrow stimulation (BMS) [i.e., microfracture] with and without concentrated bone marrow aspirate (cBMA) as a biological adjunct to the surgical treatment of osteochondral lesions (OCLs) of the talus” resulted in a “MOCART [magnetic resonance observation of cartilage repair tissue] in the cBMA/BMS group [that] was significantly higher than that in the BMS-alone group” (Abstract).
As such, Hannon et al teach BMAC treatment of a subject having an osteochondral defect to provide the therapeutic outcome of cartilage healing.
However, Hannon et al do not teach enhancing said therapeutic outcome (i.e., enhancing said cartilage healing) by further administering fisetin and losartan to said subject.
Regarding the further administration of fisetin: as taught by Li et al, “[f]isetin attenuates cartilage destruction in adjuvant-induced arthritis” (Title), specifically demonstrating that, compared to “control group showing... cartilage destruction along with bone erosion” (Page 182, Figure 3A), “animals treated with... fisetin showed less cartilage destruction” (Page 182, Column 2; see also Page 183, Column 2: “[r]educed cartilage and subchondral bone destruction... was consistently more intense following the... fisetin treatment. Additionally, the fisetin treatment demonstrated a prominent constructive effect on articular bone and tissue erosion along with pannus formation”). As further taught by Li et al, treatment with fisetin resulted in the “suppression of... TNF-α expression” (Page 183, Column 2) and a “reduction in IL-6 expressions” (Page 185, Column 1).
As taught by Kawaguchi et al, “[b]locking of tumor necrosis factor activity promotes natural repair of osteochondral defects” (Title).
And as taught by Sahu et al, “[c]ontinuous low-intensity ultrasound attenuates IL-6 and TNFα-induced catabolic effects and repairs chondral fissures in bovine osteochondral explants” (Title).
Accordingly, it would have been obvious, based on Li et al, Kawaguchi et al, and Sahu et al to modify the method of Hannon et al so as to further include the administration of fisetin. A person of ordinary skill in the art would have reasonably expected that fisetin would find use in promoting cartilage healing in a subject having an osteochondral defect considering that:
Li et al teach that fisetin promotes cartilage healing in the related condition of adjuvant-induced arthritis; and
Li et al additionally teach that fisetin suppresses TNF-α and IL-6 expression which, as further taught by Kawaguchi et al and Sahu et al, promotes treatment of osteochondral defects.
As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
Regarding the further administration of losartan: as taught by Utsunomiya et al, in rabbits suffering from osteochondral defects, “[b]iologically regulated BMS by blocking TGF-β1 (oral intake of losartan) provided superior cartilage repair... compared to outcomes from BMS only” (Conclusion).
Accordingly, it would have been obvious, based on Utsunomiya et al to also modify the method of Hannon et al so as to further include the administration of losartan.
As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
For all the foregoing reasons, claims 1-5 and 7-9 are rejected as prima facie obvious.
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).
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))).
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 15-19 are also rejected as prima facie obvious.
Conclusion
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611