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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/07/2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 03/07/2025. Claims 11-28 are currently pending. Accordingly, claims 11-28 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.
Claim Objections
Claim 14 is objected to because of the following informalities: NT4/5 is an abbreviation but the claim lacks the full unabbreviated term, as is shown for neurotrophin 3 (NT3). Appropriate correction is required.
Claim 26 does not end in a period. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Scope of Enablement
Claims 11-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of promoting or enhancing auditory neuron innervation of adult human auditory hair cells, the method comprising administering an antibody capable of binding and inhibiting RGMa, does not reasonably provide enablement for the method comprising administration of any of nucleic acid or antibody inhibitor of neogenin. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
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
Breadth of the Claims
Guidance of the Specification
State of the Art
Experimentation Required
Claim 11 is drawn to a method of promoting or enhancing auditory neuron innervation of adult human auditory hair cells by administering an inhibitor of neogenin. The recited inhibitor of neogenin is an inhibitory nucleic acid that specifically reduces expression of neogenin. The broadest reasonable interpretation of the term “inhibitory nucleic acid” encompasses any nucleic acid which may have the function or effect of reducing expression of neogenin. The functional limitation of reducing expression of neogenin is interpreted as encompassing both knockdown and knockout of gene expression (i.e., the reduction of gene expression to zero or to undetectable levels). Regarding the breadth of the genus of the inhibitor, while skill in the art is high, the invention is in the class of invention that the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” (Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001)), and the genus of nucleic acids capable of inhibiting expression of a target gene is broad, varied, and unpredictable.
Rayburn & Zhang (Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible? Drug Discovery Today. Volume 13, Numbers 11/12. June 2008.) review the landscape of nucleic-acid-based therapeutics such as antisense oligonucleotides, ribozymes, RNA interference, aptamers and other types of gene therapy, stating, “These strategies, while working by different mechanisms, are all based upon the principle that administration, or plasmid-driven expression, of exogenous DNA or RNA can be used to regulate the type and extent of expression of targeted gene products.” (p. 516 bottom right to p. 517 left). In addition to antisense oligonucleotides, Rayburn & Zhang list a wide variety of nucleic acid structures for RNA interference, ranging from siRNA to shRNA, miRNA and piRNA (§RNA interference). They also note, in regards to antisense oligonucleotides specifically, “Several major hurdles remain to be overcome, including problems with efficacy, off-target effects, delivery and side effects.” (Abstract).
The genus of nucleic acid technologies for reducing gene expression is vast and both structurally and functionally varied, as described above. Regarding siRNA alone, Endy (Endy et al. Laboratory Fundamentals in Biological Engineering. Module 2.1: siRNA Design. MIT OpenCourseWare. Fall 2007.) indicates that, prior to the filing date of the instant invention, there were unknowns about what made one siRNA more effective than one another, such that only half of siRNAs designed by researchers typically worked well, and choosing which region of the messenger RNA to target was mostly guesswork (§Part 1: siRNA Design). Therefore, the genus of siRNAs alone encompasses significant variability and unpredictability in their structure and their ability to specifically reduce target expression.
It is also relevant to note that the claims are interpreted to encompass reducing neogenin expression by gene knockout. Rago (Rago et al. Genetic knockouts and knockins in human somatic cells. Nature Protocols volume 2, pages2734–2746 (2007.) describes the using of exogenous DNA constructs to knock out genes via homologous recombination (Abstract, Figure 1). These require particular functional and structural elements such as homology regions, selectable marker genes, splice acceptors, internal ribosomal entry sites, LoxP recognition sites, etc. Rago’s disclosures also only pertain to human somatic cell lines, but do not address how to achieve knockout in vivo, which would be required by in vivo applications of the claimed method.
Even ribozymes have been used to knock down expression of target genes. Dallas (Dallas et al. Hairpin ribozyme-antisense RNA constructs can act as molecular lassos. 6752–6766 Nucleic Acids Research, 2008, Vol. 36, No. 21.) describes RNA Lassos, which bind to and circularize around target RNAs, blocking transcription of the target mRNA (Abstract). These are structurally distinct from antisense oligonucleotides, siRNAs, DNA constructs for homologous recombination, etc.
In summary, the genus of nucleic acids which can reduce expression of a target gene is vast, structurally and functionally diverse, and face many ongoing hurdles and unknowns. Even within the narrower genus of siRNA, the technology is unpredictable, requiring guesswork and empirical validation to confirm their effectiveness.
Regarding the claimed outcomes of neogenin inhibition, De Vries & Cooper (of record) show that neogenin is an axon guidance receptor (Fig. 1) with many ligands, and further establish that, “The functional outcome of neogenin activation is dictated by both the nature of the ligand as well as the developmental context.” (Abstract). They go on to note that, “Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons.” This indicates that neogenin can have opposing effects on axon growth depending on the ligand. Lastly, De Vries & Cooper note that, “While neognin signaling cascades or poorly understood, the opposing responses of neogenin to RGMa and netrin-1 in the context of axon guidance indicates that neogenin signaling is complex and subject to tight spatiotemporal regulation.”
In summary, the prior art shows that neogenin’s role in axon guidance was poorly understood, and insofar as it was understood, it was known to be a multifunctional receptor which played complex and even opposing roles in axon guidance depending on which ligand it bound. Based on that disclosure, it would have been difficult for the skilled artisan to predict, with a reasonable expectation of success, that neogenin inhibition would have resulted in auditory innervation.
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art (MPEP 2164.03). Given the lack of knowledge in the state of art and lack of predictability in the art regarding inhibitory nucleic acids and neogenin’s role in axon guidance, as discussed above, we turn to the specification for guidance.
However, the specification provides little guidance which would enable the ordinary artisan to make and use the claimed inhibitor and method, respectively. The specification does not reduce to practice the inhibition of neogenin using inhibitory nucleic acids or, in fact, any other chemical moiety, such as antibodies. The specification only discloses working example of using antibodies to inhibit RGMa to promote auditory innervation (see e.g., Example 4, p. 32-33), but does not disclose a method of promoting innervation using any RGMa-inhibiting nucleic acids.
The specification also does not supply guidance regarding the effective route, duration and quantity of administration of the inhibitor needed to achieve the claimed outcome, or how these parameters may be determined. In absence of this guidance, the routine practitioner would have to resort to a substantial amount of undue experimentation involving a wide range of amounts, durations and routes of administration to make and use the invention as claimed.
The specification does disclose that siRNA against RGMa and neogenin have been previously described and are commercially available, as are methods for reducing their expression using the siRNA (p. 18 ln 9-15). However, this is not enabling in the absence of a working example because the claims are not drawn to merely inhibiting expression of neogenin or to a nucleic acid inhibitor of neogenin. Instead, the claims are drawn to methods of promoting or enhancing auditory innervation via neogenin inhibition. Thus, they require not only the inhibitor itself, but a specific outcome of its use/administration. The specification does not provide a working example of a method leading to that outcome. Therefore, the guidance offered by the specification is merely prophetic and is not clearly enabling for the claimed outcomes.
In order to practice the claimed invention, an undue amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to design inhibitory nucleic acids throughout the claimed genus of all antisense oligonucleotide, siRNA, miRNA, piRNA, aptamers, ribozymes, etc., all to target any region of the neogenin gene or mRNA. Then the artisan would need to test the entire genus of inhibitory nucleic acids to determine whether inhibition of neogenin by any or all approaches promoted or enhanced auditory neuron innervation. Given the breadth, variability and unpredictability of the genus of claimed inhibitors, the specificity of the outcome, the unpredictability in the state of the art regarding neogenin’s functions, and the lack of any working examples in the specification, it is the conclusion that one of ordinary skill would not, without undue experimentation, have been able to make and use the full scope of the claimed invention from the disclosures in the specification coupled with information known in the art.
Regarding the dependent claims:
Claim 12 limits the nucleic acid to antisense or siRNA. However, as discussed above, there is significant unpredictability and variability even within the narrower scope of siRNA.
Claims 13-14 add steps of administering additional agents, which do not overcome the lack of enablement as it pertains to the inhibitor and outcome of neogenin inhibition.
Claims 15-28 recite in vivo applications of the method as well as further limiting the inhibitory nucleic acid, specifying characteristics of the subject, adding administration of further agents, etc., but do not overcome the lack of enablement as it pertains to the inhibitor and outcome of neogenin inhibition.
Written Description
Claims 11-28 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.
As discussed above, the claimed invention encompasses methods of promoting or enhancing auditory neuron innervation of adult human auditory hair cells in vitro or in vivo, or treating a human subject who has hearing loss or a balance disorder as a result of a loss or decrease in innervation of said cells, using a nucleic acid which reduces expression of neogenin.
Also as discussed above, the breadth of the claimed genus of nucleic acid inhibitors is vast and structurally and functionally diverse, encompassing anything from antisense oligonucleotides to ribozymes or gene editing nucleases. Each of these species functions according to different mechanisms to reduce gene expression.
The specification does not disclose any specific structures of those inhibitors or reduce to practice the inhibition of neogenin using those structures, much less a representative number of species. Nor does the specification disclose any correlation between a common structure, such as an antisense nucleotide sequence, and the function of reducing expression of neogenin. As a result, one of ordinary skill would be unable to envision the entire genus of inhibitory nucleic acids capable of specifically reducing expression neogenin based on the instant disclosure.
Also regarding claims 13, 17 and 24, these claims broadly recite agents that promote proliferation, differentiation or survival of sensory neurons. Specific examples of such agents are recited in e.g., claim 25. According to Wurdak (Wurdak et al. A small molecule accelerates neuronal differentiation in the adult rat. Proc Natl Acad Sci U S A. 2010 Sep 7;107(38):16542–16547.), there is a, “lack of knowledge about the molecular mechanisms controlling adult neurogenesis under normal and pathophysiological conditions” (p. 16542). While it, “may be possible to develop neurogenic agents for pharmacological intervention” (Id.), the speculative nature of the statement indicates that those agents were not particularly extent or well-understood at the time. Known agents included fluoxetine, an antidepressant; an anticonvulsant, valproate; and a series of experimental small molecules such as KHS101, a neuropathiazol. These represent a structurally and functionally diverse genus with many unknown species and a lack of correlation between a common structure and the shared function of promoting proliferation, differentiation or survival of neurons. As a result, one of ordinary skill would be unable to envision the entire genus of such agents based on the instant disclosure.
Also regarding claim 27, the claim recites “other known or suspected ototoxic agents”. The genus of ototoxic agents is vast, and is even vaster when including all suspected agents. For example, Steyger (Steyger. Mechanisms Involved in Ototoxicity. Semin Hear. 2011 August ; 32(3): 217–228.) notes that, “The mechanisms of ototoxicity are as diverse as the pharmacological properties of each ototoxin” (Abstract), and that, “each of these compounds have little or no pharmaceutical or chemical overlap” (p. 1 last para). The specification only lists radiation, antibiotics such as gentamicin and streptomycin, chemotherapeutic agents such as cisplatin, anti-inflammatory drugs such as sodium salicylate, or heavy metals such as lead, cadmium, or bismuth. However, as Steyger points out, the genus of ototoxic agents, both known and unknown, is vast and has little pharmaceutical or chemical overlap, i.e., a correlation between a common structure and the function of ototoxicity. Additionally, it is not clear how one may determine if a suspected agent does or does not cause ototoxicity, given that there is little to no correlation between structure and function that would allow the ordinary artisan to make that determination. Note: while Steyger post-dates the priority filing date of the instantly claimed invention, the reference is provided because it shows the factual characteristics and properties of the agents. MPEP 2124.
Based on the breadth of the claims, the limited amount of guidance provided by the specification and the art, the high degree of variation among members of the claimed genus, and the lack of a disclosed correlation between any nucleic acid structure and the function of reducing neogenin expression, one of ordinary skill in the art would conclude that Applicant was not in possession of the invention as broadly claimed.
Response to Arguments
Applicant's arguments filed 03/07/2025 have been fully considered but they are not persuasive for the reasons that follow.
Applicant points out that De Vries & Cooper is focused on the role of neogenin during nervous system development, in contrast to the amended claims (p. 6). However, this is not persuasive because it does not address the lack of predictability regarding the role of neogenin in axon guidance. In fact, a search of the prior art did not location literature indicating that the role of neogenin, netrin-1, and RGMa in the adult nervous system was well-understood. This would weigh against the skilled artisan’s ability to predict the effect of neogenin inhibition in adult auditory hair cells, and further indicate that more guidance would have been required to fully enable the artisan to practice the claimed method.
Applicant also submits a publication demonstrating that inhibition of neogenin using an inhibitory nucleic acid promotes regeneration of axons (p. 7). However, the publication, Chen et al., post-dates the filing date of the instant application. Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. Information published for the first time after the filing date generally cannot be used to show what was known at the time of filing.
Additionally, in contrast to the generic breadth of the claims, Chen discloses the administration of a specific antisense morpholino (p. 433, left) to improve neuronal survival in the spinal cord, and therefore does not enable the full scope of what is claimed.
Furthermore, other than contemplating administering a genus of nucleic acid inhibitors to reduce expression of neogenin or RGMa, as described above, the specification of the applications does not disclose how to use the claimed invention. See Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: "Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea that a siRNA inhibitor of neogenin may promote innervation does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention." Applicant cannot rely on the knowledge of one skilled in the art to supply information on the novel aspects of the claimed invention.
Conclusion
No claims are allowed.
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636