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 02/25/2026. Claims 1-19 are currently pending.
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.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application
filed in EP19305496.2 on 04/16/2019.
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 1-19 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 claims contain 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
The claimed invention directs to similar in vivo methods of preventing, inhibiting or reversing collagen type I and/or III expression in the ligament flavum (LF) of a patient suffering from LF fibrosis, LF hypertrophy (LFH), or spinal stenosis, by enhancing the degradation of mRNA transcripts from the collagen type I and/or III genes in the LF cell or tissue. Thus, the methods require a reliable implementation of: i) preventing, inhibiting or reversing collagen type I and/or III gene expression in the LF cells or tissue; ii) evaluating the efficacy of required amount of the reagent; in iii) any patient.
The Breadth of the Claims
The scope of the independent claim 1 limits the method to delivering species of “a MIR29A reagent”. However, the specification still teaches broad genera of structures that encompass viral particles comprising recombinant viral genome and non-viral nucleic acid encapsulated in a variety of nanocarriers, and the format of the MIR29A reagent encompasses siRNAs, shRNA, etc.: (Specification, pages 3-5; ¶[0017]-[0024], ¶[0029]-[0033], ¶[0048]-[0050]).
Furthermore, the varieties of clinical indications that the claimed method is directed to encompass collagen type I and/or III expression elevation, LF fibrosis, LFH, and spinal stenosis in vivo with no evidence supporting a causal link between collagen expression in the LF cells with these associated but not identical disorders in a patient, which are still poorly understood.
Guidance of the Specification
The specification is silent as to what MIR29A reagent to introduce under which conditions in order to treat LF fibrosis, LFH, or spinal stenosis in a patient by targeting collagen type I and/or III, particularly in the presented 5 Examples, which only offered: an organotypic culture system that does not show results of treatment by any MIR29A reagent that knocks down the collagen type I and/or III expression; an animal model for LFH proposed based on a public scientific publication; a proposed clinical trial with no patient recruitment or data collection at the time of filing; a couple of in vitro experiments using MIR29A inhibitor or lentiviral vector encoding a MIR29A reagent, only to confirm known facts in the art.
Example 1 (Specification, page 34, paragraphs [00148] – [00150]) is a correlation study among patient-derived LF tissue thickness measurements, collagen 1, collagen 3, and MIR29a expression levels based on the disclosure on page 34 of specification, ¶[00148], “The correlations among collagen I, collagen III, and microRNA-29a levels were analyzed using Pearson's correlation coefficients. p < 0.05 was considered statistically significant”. However, the findings seem to only confirm what’s already known in the literature, e.g. Zhang (Detection of miR-29a in plasma of patients with lumbar spinal stenosis and the clinical significance”, Molecular Medicine Reports, 2018, pp. 223-229, vol. 18; Included on IDS filed on 11/30/2023) teaches that “Pearson correlation analysis was used to analyze the correlations between the expression levels of microRNA (miR)-29a ...” and “in plasma and intervertebral disc tissue of patients with LSS were significantly lower in patients with LSS compared with in patients with LDH, as well as healthy controls… miR-29a may be considered to be a potential biomarker of LSS” (Page 223, Abstract).
Example 2 (Specification, page 35, paragraphs [00151] – [00164]) is a clinical trial proposal and the study has not happened yet as of the effective filing date. It does not quality as an example.
Example 3 (Specification, page 39, paragraphs [00165]) confirms that an antisense microRNA-29a inhibitor increases collagen I and III expression, albeit in patient-derived non-hypertrophic LF tissue after ex vivo transfection. It also confirms that overexpression of microRNA-29a using lentiviral vector transduction led to reduced expression of collagen I (but not collagen III) in cultured LF cells. Neither of the above reagents or approaches can be used in human patients in vivo at the clinical stage. Hence, providing a lentiviral vector expressing microRNA-29a to cultured cells is not a working example of administering microRNA-29a to LF tissue in a patient as claimed.
Example 4 (Specification, page 40, paragraphs [00166] – [00170]) merely provides a 3D organotypic culture model of LFH using patient-derived LF tissue or cells in an in vitro culture environment, with no functional assay assessing the therapeutic potential of a microRNA-29a performed at the time of filing. Hence, this is not a working example.
Example 5 (Specification, page 42, paragraphs [00171] – [00179]) only recites the method of creation of a model for LFH in rats based on a public scientific article by Wang (The increased motion of lumbar induces ligamentum flavum hypertrophy in a rat model. BMC Musculoskelet Disord. 2021 Apr 6;22(1):334; Listed in IDS filed on 11/30/2023). Hence, this is not a working example.
To one skilled in the art, these are not seen as working examples of treating LF fibrosis, LFH, or spinal stenosis, but rather preparatory experimental steps toward an assessment study that has yet to happen for the claimed inventions. There is no recitation of evidence for successful inhibition, reversal, or alleviation of collagen type I or III expression in the LF cells of an in vivo model of the diseases.
The State of the Prior Art
With regard to the state of the art, there is no consensus on which type of microRNA reagent for knocking down collagen expression would be effective to treat LF fibrosis, LFH, or spinal stenosis. The Specification (Page. 1, ¶[0003]) states that “Spinal stenosis of the lumbar spine has numerous etiologies, but a significant contributor is ligamentum flavum hypertrophy… Current evidence suggests non-operative measures have mixed efficacies”, which is confirmed by Katz (Diagnosis and Management of Lumbar Spinal Stenosis: A Review. JAMA. 2022 May 3;327(17):1688-1699). Katz (2022) teaches that clinical therapeutic benefits of the only injectable non-surgical experimental therapeutics for lumbar spinal stenosis, steroid injection, remains unestablished based on current observations. The claimed invention thus belongs to a group of treatment measures lacking historical success in patients.
There are several reports on using MIR29 family of microRNAs to treat fibrosis-based diseases in other organs. Several clinical trials have been completed or are on-going to test the safety and efficacy of MIR29 reagents to treat fibrosis or pathogenic scar formation in the eye and lung, while numerous preclinical studies have been carried out to test the therapeutic potential of MIR29 family of microRNAs for other organs targeting fibrosis. However, to date, there has been no FDA approved microRNA-based therapeutics in the market (Nat Biotechnol 42, 1623–1624, 2024). A MIR29b mimic-based therapeutic for fibrosis was discontinued after completing Phase II clinical trial showing tolerable safety profile and moderate efficacy based on a recent journal editorial (Nat Biotechnol 42, 1623–1624, 2024). It would be highly unpredictable whether “knocking down” collagen type I and/or III would be sufficient to prevent, inhibit or reverse collagen production-fibrotic diseases in any patient.
Despite the recent success in siRNA or RNAi-based therapeutics in other diseases, there has been no siRNA- or other RNAi reagent-based therapeutics under clinical investigations that target the collagen type I and/or III expression in the LF.
The Level of Predictability in the Art
As stated in the State of the Art, the level of predictability in the art is dependent on many factors including the type of disease model, reagent formulation, the therapeutic target, and the environmental conditions (e.g. species of animal or the personal profile of the patient). The state of the art requires experimentation including analysis of a representative amount of effective reagent and environmental conditions in order to treat LF fibrosis, LFH, and spinal stenosis. Therefore, the methods to be followed to achieve the limitations of the instant claims are highly unpredictable. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species whether other species will work. Based on the state of microRNA therapeutics, even with seemingly acceptable safety and efficacy clinical study outcomes may eventually falter without FDA approval.
Moreover, the causal link between LF fibrosis, LFH, or spinal stenosis, and collagen type I and/or III expression is not fully established. Two recent reviews, Sun (Ligamentum flavum fibrosis and hypertrophy: Molecular pathways, cellular mechanisms, and future directions. FASEB J. 2020 Aug;34(8):9854-9868) and Byvaltsev (Molecular and Genetic Mechanisms of Spinal Stenosis Formation: Systematic Review. Int J Mol Sci. 2022 Nov 3;23(21):13479), both teach that fibrosis is a common manifestation for diverse clinical indications with distinct signaling regulation and gene networks involved in distinct organ systems, particularly in the ligamentum flavum of patients suffering from LF fibrosis, LFH, or spinal stenosis. While microRNAs have been shown to have wide ranging biological impacts, there are major gaps of knowledge in the field regarding the delivery strategies, effective dosing, off-targeting, and in vivo impact in human patients. The instant claims and the Specification do not bridge any of these gaps.
With respect to reduction to practice, Katz (2022; see full citation above in state of the prior art) teaches that “Lumbar spinal stenosis affects approximately 103 million people worldwide and 11% of older adults in the US. First-line therapy is activity modification, analgesia, and physical therapy. Long-term benefits from epidural steroid injections have not been established. Selected patients with continued pain and activity limitation may be candidates for decompressive surgery”. The state of the art indicates that there is a high level of unpredictability in the outcome of the claimed inventions. Thus, it is noted that the prior art teaches that no injectable medicine, including the widely used steroids, has established therapeutic efficacy. In view of the unpredictability in injectable therapeutics as seen in the art for LF diseases, a working example in the specification is more than necessary.
Thus, the state of art indicates highly unpredictable outcome for the claimed invention without any tangible supporting data to one with ordinary skill in the art.
The Quantity of Experimentation necessarily Needed
In light of the high level of unpredictability in the art, and the limited amount of direction provided by the inventor, and the noticeable absence of working examples detailed above, the quantity of experimentation necessarily needed to use the invention (i.e. the claimed method), especially with respect to reducing collagen type I and/or III expression to alleviate LF fibrosis, LFH, or spinal stenosis, based on the disclosure is considerably high. For example, it would be necessary for one skilled in the art to identify optimal sequence of said reagents, determine optimal dosing schemes, identify effective administration routes, and optimize timepoints to use the invention to treat clinical indications of LF fibrosis, LFH, or spinal stenosis. There would be an unreasonable amount of experimentation required by a person of ordinary skill in the art.
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, it is the conclusion that an unreasonable amount of experimentation would be required to use the invention as claimed.
Response to Arguments
Applicants argue that:
Remarks 02/25/2026 page 7:
“…As amended, the claims are directed to specific MIR29A … sequences set forth in SEQ ID NOs: 3, 4, and 21, and are therefore directed to specific, structurally defined molecular species rather than a genus.”
The argument above has been considered; however, it is unpersuasive regarding the §112(a) Enablement rejection. The further narrowing down of the recited “reagent” to “a MIR29A reagent” still results in a broad genus as evidenced by the disclosure in the specification (Pages 3-5, ¶[0017]-[0024], ¶[0029]-[0033], ¶[0048]-[0050]). see The Breadth of Claims above in the §112 Enablement rejection.
Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing relevant factors outlined in the §112(a) Enablement rejection above. In summary, the Nature of Invention is a method of treating in patient, the Breadth of the Claims still encompasses broad structures after amendment, the Guidance of the Specification remains insufficient, the State of the Art still demonstrates lack of success in the field, which is further confounded by the lack of predictability in the art, especially when the causal link between the target diseases in a patient and the observed effects in cultured cells in vitro is still missing. It would require undue experimentation for ordinarily skilled artisans to use the invention as claimed. The evidence for failing to comply with the enablement requirement remains substantial.
Remarks 02/25/2026 page 8:
“…, the specification provides experimental data directly examining ligamentum flavum tissue demonstrating a mechanistic relationship between MIR29A expression and collagen regulation within the target tissue.”
The argument above has been considered, but it is not persuasive. The “correlative” characteristic of the disclosed experimental results was directly quoted from the applicant’s own disclosure. See Guidance of the Specification above, Example 1. The instant specification teaches on page 34, ¶[00148], “The correlations among collagen I, collagen III, and microRNA-29a levels were analyzed using Pearson's correlation coefficients. p < 0.05 was considered statistically significant”. Furthermore, the argument “experimental data directly examining ligamentum flavum tissue demonstrating a mechanistic relationship between MIR29A expression and collagen regulation within the target tissue” is not supported by evidence. The only mechanistic investigation between MIR29A expression and collagen regulation experiments was performed on cultured non-hypertrophic LF cells in Examples 2 & 3 (Page 37, ¶[00159]; Page 38, ¶[00160]; Page 6, ¶[0057] FIG. 6; Page 39, ¶[00165]). The “correlative” experiments were performed using patient derived LF tissue in Example 1. There is no experimental data presented that “directly” examined the relationship between MIR29A expression and collagen regulation “within the target tissue”.
Remarks 02/25/2026 page 8:
“The Office Action cites Zhang et al. as evidence that MIR29A findings are merely correlative. … In contrast, the present application focuses directly on ligamentum flavum tissue and demonstrates a relationship between MIR29A and collagen expression within the relevant target tissue.”
The argument above has been considered, but it is not persuasive. The “correlative” characteristic of the disclosed experimental results and the mechanistic investigation using non-hypertrophic LF cells in vitro in the instant specification do not distinguish the observations from the prior art Zhang. No “relationship between MIR29A and collagen expression within the relevant target tissue” was demonstrated in the instant specification.
Remarks 02/25/2026 page 8:
“… the scientific literature supports the biological and therapeutic relevance of collagen type I and type III regulation in ligamentum flavum fibrosis and hypertrophy. As shown in the attached Appendix, multiple studies have …
For example, human ligamentum flavum tissue studies have demonstrated increased collagen type I and type III expression in hypertrophied ligamentum flavum specimens, with expression levels correlating with ligament thickness. See Appendix, Chen et al. and Wang et al…. See Appendix, Wang et al.”
The argument above has been considered, but it is unpersuasive. Applicant's arguments rely on facts that are not supported by evidence. Chen (Hypertrophy of ligamentum flavum in lumbar spine stenosis is associated with increased miR-155 level. Dis Markers. 2014;2014:786543; Included in IDS filed on 11/30/2023) has been considered. However, Chen (2014) demonstrates the same deficiency as the instant application, in that only cultured cells were used in vitro, in culture dishes, to demonstrate any potential therapeutic impact of manipulating collagen expression in these LF fibroblasts using microRNAs or sponges for microRNAs. Furthermore, Chen focuses on MIR155, which is a distinct molecule with seemingly opposite roles of those of MIR29A in LF tissues derived from patients suffering from lumbar spinal stenosis or lumbar disc herniation. Chen does not disclose any relationships between MIR155 and MIR29A, hence, there is no support for the instant claims from Chen. Wang (Decorin: a potential therapeutic candidate for ligamentum flavum hypertrophy by antagonizing TGF-β1. Exp Mol Med. 2023 Jul;55(7):1413-1423) was NOT considered, as there is no Affidavit or Declaration from the applicant on file under 37 CFR 1.132 to support the citation of a post-filing art in order to traverse the rejection in the argument. See MPEP § 716.01.
Remarks 02/25/2026 Page 8-9:
“Further, MIR29A has been widely recognized as a regulator of fibrosis and collagen expression across multiple tissue types. …. See Appendix, Wawrose et al.
Importantly, …. See Appendix, Wawrose et al. …. These results …”
The argument above has been considered, but it is not persuasive. Applicant's arguments rely on facts that are not supported by evidence. Wawrose (MicroRNA-29a: a novel target for non-operative management of symptomatic lumbar spinal stenosis. Eur Spine J. 2024 Mar;33(3):892-899) was NOT considered, as there is no Affidavit or Declaration from the applicant on file under 37 CFR 1.132 to support the citation of a post-filing art in order to traverse the rejection in the argument. See MPEP § 716.01. The assertion from the applicant that “These results confirm the mechanistic relationship between MIR29A and collagen expression in the relevant target tissue and establish the feasibility of using MIR29A to modulate collagen expression in ligamentum flavum cells” has insufficient factual support, hence is unpersuasive. See §112(a) Enablement rejection.
Remarks 02/25/2026 page 9-10:
“…. The specification, together with the knowledge in the art and supporting literature provided in the Appendix, enables one of ordinary skill in the art to make and use these MIR29A molecules for regulating collagen expression in ligamentum flavum tissue without undue experimentation. Accordingly, Applicant respectfully submits that the claimed invention is enabled.”
The argument above has been considered. However, it is unpersuasive. The instant claims direct to “a method of treating spinal stenosis in a patient, treating hypertrophic LF in a patient, and/or reducing expression of type I and/or III collagen, and/or treating fibrosis in LF of a patient”. The assertion from application “The specification, together with the knowledge in the art and supporting literature provided in the Appendix, enables one of ordinary skill in the art to make and use these MIR29A molecules for regulating collagen expression in ligamentum flavum tissue without undue experimentation” has insufficient support in the specification. See §112(a) Enablement rejection.
Applicant’s response is not sufficient to rebut the lack of enablement rejection with evidence. Accordingly, Applicant’s arguments have been considered but are not persuasive, and the rejection under 35 U.S.C. §112(a) Enablement is maintained.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. 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.
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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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