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 on 06/30/2026. Claims 1-12 are currently pending. Claims 1-7 were withdrawn from prosecution as being drawn to nonelected
subject matter and are now cancelled. New claims 13-16 are added. Accordingly, claims 8-16 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not
persuasive to place the claims in condition for allowance for the reasons that follow.
Election/Restrictions
Applicant’s election 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 is still deemed proper and is therefore made FINAL.
Claims 1-7 were withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being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, and are now cancelled.
New claims 13-16 are added. Accordingly, claims 8-16 are examined herein.
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 applications 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.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, 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.
Regarding claim 13, the recitation “osteoarthritis associated with inflammation-related IL-1ß expression” creates ambiguity as to whether infringement and practice of the claimed method require determination of the IL-1ß expression status, rendering the claim scope unclear. It is unclear what degree, threshold, or type of relationship between the recited osteoarthritis and IL-1ß expression is required to satisfy this limitation. The specification does not provide an objective standard by which a person having ordinary skill in the art (PHOSITA) could determine the metes and bounds of this claim.
Claim 13 is further rejected for the recitation “acute injury”. There is no definition of what an “acute injury” requires in the claims or the specification. Since the timing of the claimed method depends on the definition of “acute”, which is a degree/relative term in a clinical context, the specification fails to provide any standard for measuring that degree such that persons having ordinary skill in the art (PHOSITAs) cannot determine the metes and bounds of the claim. See MPEP §2173.05(b).
Claims 14-16 are also rejected for depending from the rejected claim 13 and failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8-16 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 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 osteoarthritis in a subject in need thereof.
Claim 13 directs to a method of inhibiting osteoarthritis associated with inflammation-related IL-1ß expression in a subset of subjects in need thereof, wherein the subject has sustained an acute injury to the at least one affected joint. 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 osteoarthritis in a subject in need thereof.
Breadth of the Claims
Claim 8 broadly directs to inhibiting 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 claims 9-12, there are still a wide spectrum of osteoarthritis types in need thereof that do not show concurrent increase in tissue IL-1ß and miR-451.
The deletion of “treating” in the claim does not reduce the breadth of the claim because under the broadest reasonable interpretation, “inhibiting” already encompasses embodiments of therapeutic effects of “treating” because inhibiting the progression or worsening of established osteoarthritis is an equivalent intervention of “treating” under the broadest reasonable interpretation (BRI), in addition to prophylactic inhibition of the onset of osteroarthritis.
Claim 13 similarly encompasses both prophylactic embodiments prior to the development of osteoarthritis and therapeutic embodiments that require the establishment of osteoarthritis. Although claim 13 encompasses a subset of osteoarthritis types and a subset of subjects in need thereof, the breadth of the claim remains broad. The recitation “associated with inflammation-related IL-1ß expression” does not explicitly exclude osteoarthritis embodiments that do not show increased IL-1ß or mir-451 expression. Despite the further limitations in dependent claims 14-16, there is still a broad genus compassing osteoarthritis types that without concurrent increase in tissue IL-1ß and 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 “inhibit” OA despite evidence of failure:
The 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, “inhibiting” developed osteoarthritis using an inhibitor of miR-451 (i.e. 451 PI) is proven not enabled by applicant disclosure.
“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 24-29).
“…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 therapeutic effect without an 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 from such a result that miR-451 does not play a role in OA progression without IL-1ß elevation.
3) This is a new ground of rejection for claims 13-16, necessitated by the amendment of adding claims 13-16. For the new claims 13-16, the new limitations “associated with inflammation-related IL-1ß expression” and “wherein the subject has sustained an acute injury…” require precise information about the IL-1ß expression levels and the timing of the injury of the subject in need thereof. The specification only provides examples using rats, but the only measurement of IL-1ß expression levels is from a single time point, a terminal (Day 70) measurement compared to the pre-ACLT surgery baseline (Day 0), see data in FIG. 4. This single data point does not establish IL-1ß expression levels, kinetics, or timing at any point during the “acute” phase of injury now recited in claim 13, nor does it establish when, if ever, IL-1ß expression becomes “elevated” relative to the injury event. Because the only measured timepoint (Day 70) falls well outside any ordinary understanding of “acute injury”, the specification provides no data within the claimed acute window from which a person of ordinary skill in the art could practice the full scope of claim 13 without undue experimentation.
Furthermore, since at Day 70, the terminal time point when osteoarthritis is supposedly established in the rat model, the levels of IL-1ß still appear elevated. This evidence provided by the applicant contradicts any correlation between the increased levels of IL-1ß and the effect of miR-451 inhibition the other data presented by the applicant. There is no explanation provided as to why the increased IL-1ß levels after the onset of osteoarthritis no longer support the beneficial role of miR-451 inhibition (FIG. 11A). Hence, the therapeutic role of miR-451 based on IL-1ß levels is unpredictable. There is no guidance in the disclosure regarding at which clinical stage the increased levels of IL-1ß stops supporting the beneficial effects of miR-451 inhibition. PHOSITAs cannot determine the threshold.
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 evidence for clinical contribution of IL-1ß in human subjects suffering from osteoarthritis, Vincent (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 10-11).
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.
The above cited prior arts, along with the teachings of the instant specification, collectively indicate that the roles of miR-451 in OA are not well understood, discordant under different disease conditions, and unpredictable when extrapolating discoveries in a rodent ACLT model to human injuries. Therefore the reliance on IL-1ß for prophylactic benefits renders the prophylactic inhibition of OA using an inhibitor for miR-451 with undefined dynamic relationship to IL-1ß is unlikely to succeed in humans because it depends on increased levels in IL-1ß, but therapeutic targeting of IL-1 itself in clinical trials has been consistent failures. In addition, the correlation between the benefits of miR-415 inhibition and an increase in IL-1ß is unpredictable over the course of osteoarthritis development in rat models.
The Level of Predictability in the Art
The unpredictability of the claimed methods in claims 8-16 is high because:
Without firm evidence that the chondrocytes in human subjects suffering from OA or an injury to the joint actually have 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. The contradictory prior art teachings of Tang (2018), as well as the lack of clear clinical benefit in targeting elevated IL-1ß levels in the cartilage of human patients suffering from OA as summarized by Vincent (2019), along with applicant’s own data contradicting the correlation between an increase in IL-1ß and any potential benefits of miR-451 inhibition in the rat model based on time frame established by the applicant’s own data in terms of intervention timelines (FIG. 4F and FIG. 11A).
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 skilled in the art to: 1) Ascertain 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 inhibition of OA; 2) Determine the effective dosing and timing of the inhibition regimen 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 injury (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. Vast number of unknowns prevent one skilled in the art to use the claimed invention.
Conclusion of 35 U.S.C. 112(a) Enablement Analysis
After applying the Wands factors and analysis to claims 8 and 13, taking 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, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 8 and 13 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a skilled artisan to use the invention commensurate in scope with these claims.
Claims 9-12, 14-16 are also rejected for depending from a rejected claim 8 or 13 but failing to remedy the lack of enablement in scope with the claimed inventions therein.
Response to Arguments
Applicants argue that:
“Claims 8-12 were rejected under 35 U.S.C. 112(a) as not being enabled by the specification. The Examiner takes the position that evidence in the instant specification Confirms[sic] there is no benefit for administering an miR-451 inhibitor after OA has already developed. Without agreeing with this position, claim 8 is now amended to cancel "treating", thus limiting the method to inhibiting OA. Examples 1 and 2 in the specification provide evidence that early intervention following an injury can inhibit OA from developing, as now claimed in claims 8-12.”
This argument is considered but is not persuasive. Under the broadest reasonable interpretation (BRI), “inhibiting osteoarthritis” encompasses embodiments of inhibiting the progression or worsening of established osteoarthritis, which already involve the establishment of osteoarthritis. Applicant’s own examples demonstrate that there is no therapeutic benefit for miR-451 inhibitor for these embodiments. For the remaining scope, wherein embodiments do not yet have osteoarthritis established, the office action above provides detailed analysis in view of the amendment and the submitted evidence, Scott (2022).
“The Examiner cites Vincent as teaching a lack of clinical evidence of IL-1ß playing a role in human subjects suffering from OA.... However, the Vincent publication implicitly establishes that IL-1 is elevated in synovial joints early after injury in human subjects… the presence of IL-1 in relevant human tissues, particularly following injury, is not disputed by evidence presented by Vincent … Example 2 provides direct evidence that inhibition of miR-451 and miR-122 inhibited cytokine pathways that increase MMP-13 and PGE2 in the presence of IL-1ß.”
This argument is considered but is not persuasive because the previous office action does not dispute “that IL-1 is elevated in synovial joints early after injury in human subjects… the presence of IL-1 in relevant human tissues, particularly following injury”. The previous office action mailed on 04/03/2026 cited Vincent (F1000Res. 2019;8:F1000 Faculty Rev-934) to highlight the lack of evidence for clinical benefit of targeting IL-1 in human subjects suffering from osteoarthritis. See State of Art section above for the reiterated office action. This reference is cited to support the unpredictability of the role of miR-451 on osteoarthritis progression because the specification attempts to establish an IL-1ß dependency for miR-451’s role in osteoarthritis, however, applicant presented evidence that contradicts the intended correlation (FIG. 4F and FIG. 11A). See the Guidance of the Specifiction section above.
“The Examiner cites Tang and further takes the position that the role of miR- 451 is not well understood. However, Applicant respectfully points out that Tang merely "suggests" that the absence of miR-451 is associated with OA and that the Examiner improperly concludes from this that it is unpredictable whether inhibiting miR-451 would be effective for treating OA… The data in the present specification has been published in a highly-prestigious peer-reviewed journal (Scott et al….”
This argument has been considered but is not persuasive. The reference Scott (Sci Rep. 2022;12 (1):16068) submitted without an accompanying declaration under 37 CFR 1.132, has been fully considered. A declaration is not required to evaluate this submission because the reference’s technical content is substantively duplicative of subject matter already disclosed in the specification as filed, i.e. all figures, including Figures 1-5 and Supplementary Figures 1-4 of Scott are identical to FIGs. 11-18 of the instant specification, and does not present any additional working example, data, or teaching directed to the deficiencies identified above. As the reference adds no enabling content beyond what was already before the office, it does not overcome the rejections set forth above. The Office additionally notes the reference postdates the effective filing date of the instant application, such that it could not in any event supply enablement lacking as of filing. See MPEP §2164.05(a).
“Liu teaches that miR-451 suppresses various processes involved in osteosarcoma by targeting macrophage inhibitory factor. Applicant agrees with the Examiner that osteosarcoma is a distinct disease from OA and thus asserts that the prior art of Liu is irrelevant to inhibiting the development of OA.”
This argument has been considered. This reference has been removed from the reasoning in the office action. See State of the Art above.
“Should the Examiner find the application to be other than in condition for allowance, the Examiner is requested to contact the undersigned atjackie@wcf-ip.com or at the local telephone number listed below to discuss any other changes deemed necessary in a telephonic or personal interview.”
Due to time constraints, there was no opportunity to initiate an interview. Upon receiving the office action, applicant is encouraged to follow the guidelines below to schedule an examiner interview at the earliest convenience if deemed beneficial to advance prosecution.
Conclusion
No claims are allowable.
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.
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 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, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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