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 03/25/2026. Claims 1-18 are currently pending. Claims 6, 8, 10, 12 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 1-5, 7, 9, 11, 13-18 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.
Election/Restrictions
Applicant's election without traverse of species “(b) A polynucleotide sequence encoding Tppp3 or a fragment thereof” in the reply filed on 03/25/2026 is acknowledged. It is interpreted as an election of one of the required species: (b) A polynucleotide sequence encoding Tppp3 or a fragment thereof or a complimentary sequence to Tppp3 sequence.
Claims 6, 8, 10, 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species (a) and (c), there being no allowable generic or linking claim.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
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.
Specification
The disclosure is objected to because of the following informalities: The description in the specification of Figure 1 refer to colors in the Brief Description of Drawings, i.e. ¶[0009] the recitation of a “Red arrow”. The drawings have not been filed in color, and there is no petition for color drawings filed. Therefore, the specification should not refer to colors in the drawings that are filed as black and white drawings. Since these references to colors are not necessary based on the context of the figures, removing these references would remedy the object.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 Written Description
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 1-5, 7, 9, 11, 13-18 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claims 1-5, 7, 9, 11, 13-18 are directed to a method of treating glaucoma or other optic neuropathies, the method comprising: delivering to a retinal ganglion cell in the eye of a subject, a composition comprising a polynucleotide sequence that (i) encodes Tppp3; (ii) is a large genus of a fragment of Tppp3, or (iii) is complementary to Tppp3 sequence. The recitation of “fragment” was repeated for a total of 3 times (Page 2, ¶[0005], twice; Page 5, ¶[0022], once) with no definition regarding what a “fragment” is, or how it is determined to qualify as a “fragment” of Tppp3.
Neither the claims nor the specification provides definition regarding what a “fragment” is. No example of any polynucleotide encoding “a fragment of Tppp3” protein was provided. Under the broadest reasonable interpretation (BRI), a single amino acid could be interpreted to be a “fragment” of Tppp3, or it could encompass fragments of DNA sequences that lose the ability to be transcribed into mRNA, or transcribed mRNAs failing to be translated into functional peptides. The species specifically disclosed are not representative of the genus because the genus is highly variant in structure.
Regarding the state of the art, Orosz (A New Protein Superfamily: TPPP-Like Proteins. PLoS ONE 7(11):e49276. Published 11/14/2012) teaches that diverse long-, short- and truncated TPPPs are still poorly understood and are often associated with neurological disorders (Page 12, left column, 2nd¶). 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). Moreover, Bystrenova (Amyloid fragments and their toxicity on neural cells. Regen Biomater. 2019 Mar;6(2):121-127) teaches that “supramolecular structure rather than the identity of the protein, is the key of cellular toxicity and of the underlying specific cell death mechanism” (Page 126, right column, lines 6-8). Even with swift developments in powerful artificial intelligence-based prediction algorithms in the protein science space, de Crécy-Lagard (Limitations of Current Machine-Learning Models in Predicting Enzymatic Functions for Uncharacterized Proteins. bioRxiv [Preprint]. 2025 Jun 6:2024.07.01.601547) teaches that “…current ML methods not only fail to make novel predictions but also make basic logic errors in their predictions” (Page 1, line 20-23), highlighting the unpredictability of undefined fragments of a protein with uncertain functions. Lastly, Carelli (Optic neuropathies: the tip of the neurodegeneration iceberg. Hum Mol Genet. 2017 Oct 1;26(R2): R139-R150) teaches “different layers, from molecular to anatomical, ... may target differently cell types and anatomical settings” (Page R139, Abstract, lines 9-14), further confounding the proposed therapeutic role of Tppp3 sequences or fragments by the instant application.
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 1 is overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Therefore, claim 1 does not meet the written description requirement.
Claims 2-5, 7, 9, 11, 13-18 are also rejected for depending from claim 1 yet unable to remedy the lack of written description therein.
Claim Rejections - 35 USC § 112 Enablement
Claims 1-5, 7, 9, 11, 13-18 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, 9, 11, 13-18 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 (i) encodes Tppp3; (ii) is a large genus of a fragment of Tppp3, or (iii) is complementary to Tppp3 sequence. Thus, the methods require a reliable implementation of: 1) obtaining a composition comprising a polynucleotide sequence that (i) encodes Tppp3; (ii) is a large genus of a fragment of Tppp3, or (iii) is complementary to Tppp3 sequence; 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, 9, 11, 13-18 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 (i) encodes Tppp3; (ii) is a large genus of a fragment of Tppp3, or (iii) is complementary to Tppp3 sequences. According to the specification, a polynucleotide sequence that is complementary to Tppp3 sequences 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 what a “fragment” is. There is no specific structure, sequence, or size disclosed. There is no example of using such polynucleotide that “is a fragment of Tppp3”. The specification is also silent on the function of said “fragment” with no indication whether a fragment of the Tppp3 protein is required because under BRI, no protein-encoding function is required.
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.
The specification is silent on how antisense oligonucleotide, siRNA, shRNA, or similar nucleic acid-based therapeutics targeting Tppp3 in RGCs could treat or prevent the development of reginal disorders, as no example was given, nor was there any hypothesis given. There is no in vivo experiment of any kind to draw causal relationship between the expression levels of Tppp3 with any of the above-mentioned retinal disorders.
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), an 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 appears 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.
Furthermore, the specification is silent on how to identify polynucleotides that are fragments of Tppp3 sequences for treating glaucoma or other optic neuropathies.
State of the Art
The teachings of Orosz (2012), Lord (2025), and Carelli (2017) have been discussed above. 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 15, 28-29, 35, and 37 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 roles of Tppp3 sequence fragments 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.
3) There is no logical support for using antisense or CRISPR technologies against Tppp3 as a treatment for glaucoma or any optic neuropathy based on the disclosure because the only effect of Tppp3 observed is the in vitro overexpression experiments, which seems to support axon outgrowth. How would inhibition of such an effect treat or prevent glaucoma or any other optic neuropathy is not explained.
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) Identify a suitable polynucleotide that is a Tppp3 sequence fragment; 2) 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, as there is no instruction as to how to use antisense polynucleotides against Tppp3 sequences to carry out the claimed invention. In absence of such information in the specification as well as in the state of the art, one skilled in the art 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 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 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.
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 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
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