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. Application Status This action is written in response to applicant’s correspondence received 02/17/2026 . Claims 1-12 are currently pending. Claim s 1-7 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 8-12 are examined herein. Election/Restrictions Applicant ’s elect ion of Group II, ( claims 8-12 ) in the reply filed on 02/17/2026 is acknowledged. However, the election of species requirement requires an election of the following species: “ a microRNA-122 (miR-122), a miR-122 mimic and an inhibitor of a microRNA-451 (miR-451) ”, therefore, Applicant’s election of the species “ miR-451 ” in the reply filed on 02/17/2026 is treated as an election of the species “ an inhibitor of a microRNA-451 (miR-451) ”. The restriction requirement mailed on 12/17/2025 i s still deemed proper and is therefore made FINAL. Claim s 1-7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group I , there being no allowable generic or linking claim. Information Disclosure Statement The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Priority This application is a 371 of PCT/US2021/060054 filed on 11/19/2021 . Applicant’s claim for the benefit of the following prior-filed application s under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged : PRO 63/155,396 , filed on 03/02/2021 ; PRO 63/158,004 , filed on 03/08/2021 ; PRO 63/216,199 , filed on 06/29/2021 ; PRO 63/225,932 , filed on 07/26/2021 . Drawings The drawings are objected to because: 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG." In the current case, the view numbers for Figures 1-18 are preceded by the word "FIGURE" instead of the abbreviation "FIG.". Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Specification The disclosure is objected to because of the following informalities: Th ere are 4 references to color “ red ” in the BRIEF DESCRIPTION OF DRAWINGS section: "(Fig. 3I-3Q) with a red line (inside white box)" ( Page 7, line 1 ) "For Fig. 12G-12L,... a red line (in white box)" ( Page 9, line 2 ) "In Fig. 14G-14L,... a red line (in white box)" ( Page 9, line 17 ) "In Fig. 17G-17L, ... a red line (in white box)" ( Page 10, line 8 ) However, the figures are in black and white. Since these references to the color “red” are inconsequential to the disclosure, replacing “red” with “black” would remedy the informalities. Appropriate correction is required. The disclosure is objected to because of the following informalities: The recitation of “ ( Error! Reference source not found.A ) ” on page 38, lines 30-31 appears to be in error. Appropriate correction is required. Claim Rejections - 35 USC § 112 Enablement Claims 8-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation ( United States v. Telectronics ., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman , 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands , 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below: Nature of the Invention Claim 8 directs to a method of inhibiting or treating osteoarthritis in a subject in need thereof . Thus, the method requires a reliable implementation of: 1) administering a therapeutically sufficient amount of a pharmaceutical composition comprising an inhibitor of microRNA-451 (miR-451) ; 2) inhibiting or treating osteoarthritis in a subject in need thereof . Breadth of the Claims Claim 8 broadly directs to inhibitin g or treating osteoarthritis in any subject in need thereof , these terms are broad because there is no evidence that osteoarthritis in different species universally shows increased tissue levels in IL-1ß and miR-451 . despite the further limitations in dependent claim s 9-12 , there are still a wide spectrum of osteoarthritis types in need thereof that do not show increased tissue IL-1ß or miR-451 . Guidance of the Specification 1) The disclosure relies on an artificial OA model using rodents with ALCT injury in the knee joints to provide prophetic guidance on how to “ treat” OA despite evidence of failure : T he instant specification confirms that there is no benefit for administering a miR-451 inhibitor to subjects in need thereof after OA had already developed , therefore, “treating” osteoarthritis using an inhibitor of miR-451 (i.e. 451 PI) is proven not enabled . “ 451-PI had preventative effects on OA progression when administered at the time of injury . However, no therapeutic effect was detected when 451-PI was administered after OA had developed ” ( Page 48, Conclusion, lines 2-4 ). “ While prophylactic administration of miR-451 inhibitor was efficacious, therapeutic administration after OA had already developed did not reduce or reverse OA severity . .. . A longer duration of [ miR -] 451-PI treatment after OA is contemplated and may achieve the desired therapeutic effects … " ( Page 13, lines 24-2 9 ). “… miR-451 inhibition after OA onset (therapeutic cohort) does not appear to reduce OA severity. A longer duration of 451-PI treatment after OA has developed is contemplated and may improve the outcome ” (Page 46, lines 8-12 ). 2) The specification establishes an IL-1ß requirement for increased miR-451 levels to play a role in osteoarthritis progression through creating an in vitro artificial inflammatory condition associated with OA by stimulating in vitro cultured chondrocytes using IL-1ß . An increase in miR-451 expression was identified using and an artificial knee injury model in rats . Neither phenomenon is universally observed in osteoarthritis , but confirms that miR-451 has no role in inflammation without increase in IL-1ß . “… miR-451 expression was elevated in the cartilage of OA in Sprague Dawley rats, indicating that inhibiting miR-451 is a target for alleviating OA …” ( Page 13, lines 14- 15 ). "... elevated levels of miR-451 expression were found in OA knees of Sprague Dawley rats 10 weeks following anterior cruciate ligament transection (ACLT) compared to sham knees ..." ( Page 37, lines 25-26 ). " Other studies (no citation given) have found elevated serum 10 cytokines including IL-1ß , IL-4, IL-5, IL-6, IL-12, IL-18, MIP-la, IFN-α, VEGF " ( Page 25, lines 7-10 ). Regarding the in vitro chondrocyte cell culture study, " Since IL- lß signaling is a major contributor of OA, a well-established model of creating an osteoarthritic phenotype in vitro is to stimulate cell cultures with this cytokine . This study first established that both these microRNAs (miR-122 and miR-451) were elevated in OA in the bilateral ACLT model " ( Page 26, lines 21-25 ). " Transfection with miR-451 in the presence of IL-1ß stimulation led to exacerbated production in MMP-13 and PGE2, even more so than levels with IL- lß stimulation alone. Interestingly, this microRNA did not encourage these responses in the absence of IL-1ß " (Page 27, lines 2-5). “ … miR-451 is potentially targeting an anti-inflammatory molecule that interferes with the IL-1ß signaling pathway , but not the TNF-a signaling pathway ” ( Page 13, 2nd ¶, lines 12-13 ). “ This Example demonstrates that … miR-451 chondrodestructive role, causing an exacerbated inflammatory response in the presence of IL-1ß …” ( Page 27, lines 11-13 ). “ The elevated presence of both IL-1ß and miR-451 in OA makes this a novel target for OA therapies ” ( Page 45, lines 12-13 ). Hence, the link between miR-451 with the OA progression is solely established by an in vitro modeling study using IL-1ß stimulation to establish an in vitro OA model. This artificial OA model in a dish ONLY used IL-1ß as stimulation to prove that an inhibitor of miR-451 relieves the IL-1ß-dependent inflammation responses hypothesized to drive OA progression . However, without IL-1ß elevation or stimulation, the specification teaches that miR-451 “ does not encourage ” exacerbated production in MMP-13 and PGE2, one skilled in the art would conclude form such an result that miR-451 does not play a role in OA progression without IL-1ß elevation . State of the Art 1) The instant specification teaches the lack of a cure and effective treatments after OA onset/development : “...80% of anterior ligament injured knees will develop radiographic evidence of OA 5 to 15 years following the initial injury . Currently, there is no cure ” ( Page 1, lines 22-25 ). “ …reversing OA after it has developed has never been achieved to date … " ( Page 13, line 27 ). 2) Regarding the lack of clinical evidence of IL-1ß in human subjects suffering from osteoarthritis, Vincent ( IL-1 in osteoarthritis: time for a critical review of the literature. F1000Res. 2019 Jun 21;8:F1000 Faculty Rev-934 ) teaches that “… interleukin-1 (IL-1) as a target in osteoarthritis (OA) has been an attractive one for many years. … However, … Agnostic transcriptomic and genomic analyses do not identify IL-1 as a key pathway . In vivo models show a conflicting role for this molecule; ... Recently, a number of large double-blind randomized controlled clinical studies targeting IL-1 have failed …”. Vincent (2019) further teaches that “ Randomised clinical trials in OA are conclusively telling us that this is not a target in OA despite all our hopes … ” ( Page 5, Conclusion, lines 10- 1 1 ) . 3) Regarding the role of miR-451 in chondrocytes in osteoarthritis, since chondrocytes are required for osteogenesis, chondrocyte apoptosis is a contributor to osteoarthritis, and the “sponge”-based absorption/removal of miR-451 was observed to correlate with chondrocyte apoptosis by Tang et al. ( LncRNA p21 promotes chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR 451. Mol Med Rep. 2018 Dec;18(6):5295-5301; Hereinafter , Tang ) suggests that the absence of miR-451 is associated with osteoarthritis ( Tang , 2018; page 5295, Title ) . This suggests that it is unpredictable whether inhibiting miR-451 would be effective for treating osteoarthritis . 4) Regarding other known roles of miR-451 in bone tissue, Liu et al. ( MiR-451 suppresses proliferation, migration and promotes apoptosis of the human osteosarcoma by targeting macrophage migration inhibitory factor. Biomed Pharmacother . 2017 Mar;87:621-627 ) teaches that miR-451 plays a suppressive role on the proliferation of osteosarcoma cells in the bone, however, osteosarcoma is a distinct disease from OA , hence, the complex roles of miR-451 in bone tissue remains unclear . Th e above cited prior arts , along with the teachings of the instant specification, collectively indicate that the role of miR-451 in OA is not well understood , and the reliance on IL-1ß for prophylactic benefits renders the prophylactic inhibition of OA using an inhibitor for miR-451 unlikely to succeed in humans because therapeutic targeting IL-1 in clinical trials has been consistent failures . The Level of Predictability in the Art The unpredictability of the claimed methods in claims 8 -12 is high because : Without firm evidence that the chondrocytes in human subjects suffering from OA or an injury to the joint actually have increased IL-1ß and elevated expression of miR-451 in the affected joint chondrocytes, the effect of an miR-451 inhibitor is unpredictable based on the disclosures above regarding the elevation of IL-1ß and miR-451 levels in the ACLT rat models in the instant specification and the opposite observations of Tang (2018) , as well as the lack of clear clinical evidence of elevated IL-1ß levels in the cartilage of human patients suffering from OA as summarized by Vincent (2019). Experimentation Required In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one skill ed in the art to : 1) A scertain the levels of miR-451 and IL-1ß levels in the chondrocyte of an injured joint cartilage tissue before administering a miR-451 inhibitor for prophylactic inhibition of OA; 2) Determine the effective duration of the prophylactic inhibition period given the instant specification’s teaching that there is a huge variation in human population regarding how long it takes to develop radiographic evidence of OA after traumatic injury in the knee joint ( 5 to 15 years ; Page 1, lines 22-25 ) , particularly when the guidance from specification is prophetic . Therefore, this requirement amounts to undue burden of experimentation and also renders following the teachings in the specification highly unpredictable because of vast number of uncertainties and unknowns regarding essential parameters needed for reduction to practice , preventing one skilled in the art to use the claimed invention. Tak en into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to use the invention as claimed. Regarding claims 9-12 , these claims are also rejected for depending from a rejected claim 8 but failing to remedy the lack of enablement in scope with the claimed inventions therein. Conclusion No claims are allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached FILLIN "Work schedule?" \* MERGEFORMAT Mon- Thr 7:30am to 4:30pm Fri 10am to 2pm ET . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Neil P Hammell can be reached on FILLIN "SPE Phone?" \* MERGEFORMAT (571) 270-5919 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /DELPHINUS DOU YI YU/ Examiner, Art Unit 1636 /NEIL P HAMMELL/ Supervisory Patent Examiner, Art Unit 1636