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 07/21/2026. Claims 1-8, 10, 12, 14-18 are currently pending. Claims 6, 8, 10, 12 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 1-5, 7, 14-18 are examined herein. The Election of Species requirement mailed on 02/16/2026 is still deemed proper. Applicant elected species “(b) A polynucleotide sequence encoding Tppp3 or a fragment thereof” without traverse in the reply filed on 03/25/2026.
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.
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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US2022/014949, filed on 02/02/2022, and it has PRO 63/145,161 filed on 02/03/2021.
Claim Rejections - 35 USC § 112 Enablement
Claims 1-5, 7, 14-18 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 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
Claims 1-5, 7, 14-18 are directed to a method of treating glaucoma or other optic neuropathies, which share common pathogenic process involving degeneration of retinal ganglion cells (RGCs), the method comprising: delivering to a RGC in the eye of a subject, a composition comprising a polynucleotide sequence that encodes Tppp3. Thus, the methods require a reliable implementation of: 1) obtaining a composition comprising a polynucleotide sequence that encodes Tppp3; 2) obtaining a subject in need thereof; 3) administering said composition comprising a polynucleotide sequence according to claim 1 to a subject in need thereof.
Breadth of the Claims
Claims 1-5, 7, 14-18 are broadly directed to a method of treating glaucoma or other optic neuropathies which share a set of common pathogenic processes converging on RGC degeneration. The method comprises: delivering to a retinal ganglion cell (RGC) in the eye of a subject, a composition comprising a polynucleotide sequence that encodes Tppp3. According to the specification, a polynucleotide sequence may encompass polynucleotides having “any three-dimensional structure, and may perform any function, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, siRNA, shRNA, guide RNA, anti-sense RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, control regions, isolated RNA of any sequence, nucleic acid probes, and primers. … may be linear or circular” (Page 5, ¶[0022]).
Guidance of the Specification
The specification is silent on the role of Tppp3 in glaucoma or any optic neuropathy. The examples only examined the expression of Tppp3 in normal mice, albeit of different developmental stages. There is no mechanistic investigation or evidence of a causal link between Tppp3 expression with any of the aforementioned optic neuropathies. All overexpression and shRNA knockdown experiments were performed on in vitro cultured RGCs from mice.
Although the specification discloses noticeable reduction in the expression of Tppp3 in crushed optic nerve (Page 24, ¶[0083]; FIG. 2E), this is not evidence that boosting Tppp3 expression reverses damages due to optic nerve crush or any other types of optic neuropathies this experimental model is used to mimic. PHOSITAs would not be able to interpret this correlation indicates therapeutic potential.
The specification concedes that “The biological basis of glaucoma is poorly understood and the factors contributing to its progression have not been fully characterized” (Page 1, ¶[0002]), yet relies on the “axon outgrowth” phenomenon observed in vitro as an evidence of therapeutic potential to treat optic neuropathies. However, while the Tppp3 overexpression experiment on cultured RGCs seems to stimulate RGC axon outgrowth (FIG. 3E), a positive impact on RGC axonal outgrowth is yet to be proven as a reliable indication for therapeutic efficacy in the clinical stage because there is currently no FDA approved therapy for optic neuropathies that enable RGC axon regeneration (see state of art below). Even if, hypothetically, an observation of a stimulatory effect on RGC axon outgrowth did indicate therapeutic potential for optic neuropathies in vivo, the shRNA experiment would still have been inconclusive as the levels of axon outgrow appear to be at the same levels as the control group with no statistically significant improvement (FIG. 3F). Incidentally, there is no disclosure as to how the inhibitory agents that reduce the expression levels of Tppp3 can be logically used to help treat or prevent glaucoma or any other optic neuropathy. Even for Tppp3 expression vectors, there is zero guidance regarding the injection dosage, frequency, and outcome evaluation criteria etc.
State of the Art
Lord (Diverse Roles of Tubulin Polymerization Promoting Protein 3 (TPPP3) in Human Health and Disease. Cells. 2025 Oct 10;14(20):1573) teaches that, despite recent discoveries about the diverse roles of TPPP3 in physiology and diseases, “there still remain large gaps that need to be filled” (Page 13, First 2 lines). In short, the roles of Tppp3 in optic neuropathies are not understood and are unpredictable, aside from the admission in the specification that “The biological basis of glaucoma is poorly understood and the factors contributing to its progression have not been fully characterized” (Page 1, ¶[0002]). Despite the development in regenerative medicine in recent decades, there is currently no FDA approved therapeutics targeting RGC axon regeneration to treat glaucoma or optic neuropathy. Gokoffski (Optic Nerve Regeneration: How Will We Get There? J Neuroophthalmol. 2020 Jun;40(2):234-242) teaches that only very few stem cell-based retinal axon regeneration studies are actively on Clinicaltrials.gov (Page 239, Table 1), highlighting the challenge and the lack of success in the art. Fawcett (The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult? Neurochem Res. 2020 Jan;45(1):144-158) further summarizes the sobering facts regarding the state of art in axon regeneration in mature neural cell types in the central nervous system, while concluding on a hypothetical scenario “From a practical perspective it seems sensible to work both on the axons, restoring transport and trafficking of the key molecules, and on the transcriptional programme in cell bodies. If we can arrange for expression of the right molecules and then get them to the right place, then axons will regenerate” (Page 154, last 6 lines). In fact, the first ever gene therapy approved by FDA to rejuvenate RGCs using three of the four Yamanaka factors, transcription factors OCT-4, SOX-2, and KLF-4 (OSK), for phase I clinical trial targeting open-angle glaucoma and other optic neuropathies was just announced by Life Biosciences in 2026 (Life Biosciences _2026_ Announces FDA Clearance of IND Application for ER-100.pdf, listed in PTO-892; https://www.lifebiosciences.com/life-biosciences-announces-fda-clearance-of-ind-application-for-er-100-in-optic-neuropathies/).
Fawcett (2019) summarizes the state of the art: “Axon regeneration in the CNS is inhibited by many extrinsic and intrinsic factors. Because these act in parallel, no single intervention has been sufficient to enable full regeneration of damaged axons in the adult mammalian CNS” (Page 144, Abstract, lines 1-2). In view of the state of the art, any in vitro “evidence” of axon regeneration has no bearing in determining the in vivo impact in the central nervous system (CNS).
The Level of Predictability in the Art
The unpredictability of the claimed methods in claims 1-5, 7, 14-18 is high because:
1) Absence of success in the field of retinal ganglion cell axon regeneration. Numerous promising experimental strategies appear to promote axon in vitro fail to succeed in clinical stage, confirmed by Gokoffski (2020) and Fawcett (2020).
2) Without working example to support the in vivo roles of Tppp3 or any meaningful effect of either Tppp3 overexpression or knockdown in vivo, the limited observations for Tppp3 overexpression in vitro in cultured mouse RGCs and non-statistically significant effects of shRNA RNAi do not prove anything in glaucoma or any optic neuropathy.
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 determine the effective dose, delivery routes, and duration of the claimed treatment, particularly when the guidance from specification is absent. One of ordinary skill in the art would not be able to use the information provided by the instant specification to carry out the full scope of the invention as claimed. With the striking absence of such information in the specification, as well as in the state of the art, skilled artisans would reasonably require an undue quantity of experimentation to practice the full scope of the claimed method. Therefore, this requirement amounts to undue burden of experimentation, also rendering the teachings in the specification highly unpredictable because of vast number of unknowns regarding essential parameters needed for reduction to practice, preventing one skilled in the art to make and use the claimed invention.
Taken 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.
Response to Arguments
Applicant's arguments filed on 07/21/2026 have been fully considered but they are not persuasive. Applicant argues on page 6-7 of the Remarks filed on 07/21/2026:
“With respect to enablement, … However, the specification specifically discloses the examination of the expression of Tppp3 during optic nerve crush, which is a common model for glaucoma and other optic neuropathies. Optic nerve crush results in the death of retinal ganglion cells, which is an important aspect of glaucoma and other optic neuropathies. Specifically, paragraph 83 states "Pou2f2 and Tppp3 proteins can be detected in optic nerve and were significant reduced by optic nerve crush." Thus, the specification clearly provides a link to Tppp3 expression and optic neuropathies as shown through optic nerve crush”
This argument has been fully considered but it is not persuasive. The observation that Tppp3 expression was reduced in the optic nerve crush model is inconclusive. The specification fails to indicate whether the mouse optic nerve crush was performed in vivo or ex vivo. The instant FIG. 3B demonstrates that a reduction in Tppp3 mRNA levels can be seen in a naturally occurring developmental process. There is no evidence presented in the specification that increasing Tppp3 expression reverses tissue damages resulting from optic neuropathies. The effect on RGC neurite outgrowth was not observed under conditions associated with any optic neuropathy (FIG. 3E). See Fawcett (2019) cited in the office action above.
“Additionally, Rao et al. (Acta Neuropathol Commun. 2024 Dec 29;12(1):204), a publication that resulted from the present application, discloses in vivo data …, indicating the protective role of Tppp3 in RGCs (Figs. 3D and E)." (pg. 9 1st column 2nd paragraph) ....
The in vivo data provided in the experiments disclosed in Rao et al. are all in line with the teachings of the specification. Accordingly, Applicant submits that a person of ordinary skill in the art could make or use the instantly claimed invention without undue experimentation. As such, claims 1-5, 7, 9, 11, and 13-18 are enabled by the specification at least for the reasons discussed above”.
This argument has been considered but is not persuasive. The Office notes that the reference Rao (Acta Neuropathol Commun. 2024 Dec 29;12(1):204) postdates the effective filing date of the instant application, an affidavit or declaration under 37 CFR 1.132 is required for post-filing evidence submitted to traverse the rejection or objection, see MPEP §716. Even assuming, arguendo, an affidavit or declaration under 37 CFR 1.132 was filed along with the submitted evidence, Rao (2024) fails to provide support for enablement for the following two reasons:
1), Rao only provides evidence for over-expressing TPPP3 in the test subjects’ retina 2 weeks prior to ONC injury (Page 5, left col, last ¶), which is not in scope with the claimed invention of “A method of treating glaucoma or other optic neuropthies…” (Claim 1), as the subjects did not have glaucoma or any form of optic neuropathies at the time of receiving the treatment;
2) Rao does not provide any evidence of “preventing or reducing glaucoma or other optic neuropathies” (Claim 1). Figure 3B shows increased neurite outgrowth from the side of ONC injury (*), a tissue level effect, but Figure 3C shows no difference between the overexpression group and the control group in terms of the distance of neurite outgrowth, nor does it show “axon regeneration over long distances in the CNS to recover functionality after injury” (Rao, Page 1, right col, 1st ¶, last 3 lines), an “unmet need” identified by Rao, yet Rao also fails to meet. The tissue level effects of “neuroprotection” is not in scope with the claimed “method of treating glaucoma …”.
Anterograde tracing of axon outgrowth for tissue analysis is simply not applicable in human patients. Since the disclosure does not teach any measures to evaluate the effect of the claimed invention in human subjects without invasive tissue dissection, which inevitably leads to complete blindness, undue experimentation is required of one of ordinary skill in the art.
The evidence provided by Rao is not commensurate in scope with the claimed invention. See MPEP §2164.05. Thus, the rejection of claims 1-5, 7, 14-18 under 35 U.S.C §112(a) as failing to comply with the enablement requirement 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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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
