DETAILED ACTION
Examiner acknowledges receipt of the reply filed 8/28/2026, in response to the restriction requirement mailed 6/03/2026.
Claims 1-7, 9, and 11-15 are pending. Claims 8 and 10 have been cancelled. Claims 3-7, 9, and 11-15 are withdrawn from further consideration for the reasons set forth below.
Claims 1 and 2 are being examined on the merits in this office 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 .
Election/Restrictions
Applicant's election of Group 1 (claims 1-2) with traverse in the reply filed on 8/28/2026 is acknowledged. The traversal is on the ground(s) for the following reasons. Applicant states: Although Zuo et al. disclose that an expression vector harboring a nucleic acid encoding an atonal-associated factor in combination with a co-transcription factor can be introduced into inner ear for the treatment of hearing loss, Zuo et al. do not teach the specific technical solution of combining IKZF2 and Atoh1 (reply filed 8/28/2026 at p. 5). Applicant asserts that Zuo et al “list dozens of genes” including IKZF2 and Atoh1. Applicant asserts “In the absence of any specific teaching, those skilled in the art could not have readily arrived at combining these two specific genes for treating hearing loss from the dozens of genes disclosed by Zuo et al”. Applicant further asserts “surprising synergistic effect” of the combination of IKZF2 and Atoh1 on the regeneration of cochlear outer hair cells, referring to Example 2 (p. 6). Applicant asserts “merely based on the disclosure of Zuo et al. and without experimental verification, that the combination of Atoh1 and Ikzf2 would synergistically promote the trans-differentiation of cochlear supporting cells into OHC-like cells, thereby regenerating cochlear outer hair cells upon damage thereto and treating or preventing hearing impairment”.
This is not found persuasive.
Zuo et al expressly taught a combination of Atoh1 and Ikzf2 (e.g., claims 1, 4, 10, 13, para [0065]). Evidence of secondary considerations, such as unexpected results or commercial success, is irrelevant to 35 U.S.C. 102 rejections and thus cannot overcome a rejection so based. In re Wiggins, 488 F.2d 538, 543, 179 USPQ 421, 425 (CCPA 1973). See M.P.E.P. § 2131.04.
An initial review of the specification did not reveal the term “synergy” or any analogous terms or synonyms.
Example 2 states:
The effects of different treatment methods on the production of OHC-like cells were compared. That is, three different treatments were made in the adult cochlea supporting cells: expressing Atoh1 alone, expressing Ikzf2 alone, and expressing Atoh1 and Ikzf2 at the same time. Compared with the control group (FIG. 2A-A′″), overexpressing Atoh1 alone (FIG. 2B-B′″) or overexpressing Ikzf2 alone (FIG. 2C-C′″ and FIG. 2D-D′″) could not produce new Prestin+ outer hair cells. However, overexpressing Atoh1 and Ikzf2 at the same time (FIG. 2E-E′″ and FIG. 2F-F′″) could produce a small amount of new Prestin+ outer hair cells. Quantitative analysis of OHC-like cells in mice overexpressing Atoh1 and Ikzf2 at the same time (Fgfr3-Atoh1-Ikzf2) (FIG. 2G) revealed that new cells were visible throughout the cochlea, however the number was small and varied significantly. Summing up, for the three different reprogramming methods, it was found that only by simultaneously activating Atoh1 and Ikzf2 can OHC-like cells be produced (FIG. 2H).
Evidence of “synergy” is questionable when Ikzf2 alone and Atoh1 alone did not yield any outer hair cells. Moreover, the specification indicates the yield of outer cells produced in mice overexpressing both Ikzf2 and Atoh1 “was small and varied significantly”. Thus, the statistical relevance of the findings is unclear.
Lack of unity of invention was further identified at pp. 7-10 of the restriction requirement- relating to Markush grouping of claimed alternatives. Applicant did not address this part of the restriction requirement.
It is further noted the restriction requirement identified groups of inventions I-VII, as set forth in the restriction mailed 6/3/2026. 37 CFR 1.475 (b)- see restriction mailed 6/3/2026 at pp. 2-4 - limits unity of invention to a single product and as single method of use group. Applicants have 2 product groups and 5 method of use groups, thus, unity is lacking and restriction is proper.
The requirement is still deemed proper for these reasons and is therefore made FINAL.
Claims 3-7, 9, and 11-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 8/28/2026.
Examiner acknowledges Applicants election of the following species:
IKZF2 protein (SEQ ID NO: 1,3)
Atoh1 protein (SEQ ID NO:2, 4)
Applicant’s election of the following species in the reply filed on 8/28/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, [with specific regard to the election of species] the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1 and 2 read on the elected species.
Priority
The filing receipt dated 5/21/2026 provides the following information:
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Drawings
The drawings are objected to for the following reasons.
Figs 1A-1C and 1E- the font and images are too blurry and/or pixelated to decipher. The images are too clearly distinguish.
The same applies to Figs 2A-2F, 2H, 3A, 3B, 4A-4G, 5A-5C, and 6B-6G.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The Fig 3 figure legend refers to “green residual fragments”, red lines and blue lines. Fig 6 refers to blue dashed lines.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “Present invention provides,” etc.
The use of the term Tween, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. See as-filed specification at p. 15.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See as-filed specification at p. 10.
Claim Objections
Claims 1 and 2 are objected to because of the following informalities:
Claim 1 should be split into two separate claims. The claim is drawn to a method of (i) regenerating cochlea outer hair cells, and/or (ii) treating or preventing hearing impairment by using a combination of active ingredients. As set forth in the preamble, the claim is drawn to two distinct methods, affecting distinct patient populations, achieving different end points (cochlea outer hair cell growth vs treating/preventing hearing impairment).
Claim 2 should be amended to recite “impairment is related to [[the]] degeneration and/or damage of cochlea outer hair cells (OHCs).
Appropriate correction is required.
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 1 and 2 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.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01.
Claim 1 recites: A method of (i) regenerating cochlea outer hair cells, and/or (ii) treating or preventing hearing impairment by using a combination of active ingredients; wherein the combination of active ingredients comprises: (a) IKAROS Family Zinc Finger 2 (Ikzf2) protein, a coding sequence thereof, or a promoting agent thereof, or a combination thereof; and (b) Atonal bHLH transcription factor 1 (Atoh1) protein, a coding sequence thereof, or a promoting agent thereof, or a combination thereof.
The omitted steps are: a step of administering the combination of active ingredients to a subject.
Instant claim 1 merely recites “using” a combination of active ingredients to regenerate cochlea hair cell growth and/or treat/prevent hearing impairment. The term “using” provides no probative guidance to the skilled artisan as how the claimed method is achieved. Claim 2 depends from claim 1, and is rejected for the same reasons.
To overcome this rejection, the claim should be amended to recite an active step of administering the combination of active agents to a subject in need thereof.
Claim 2 recites the limitation "the degeneration”. There is insufficient antecedent basis for this limitation in the claim.
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 and 2 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “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. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP 2163.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gostelli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
In the instant case, instant claim 1 is drawn to a method of (i) regenerating cochlea outer hair cells, and/or (ii) treating or preventing hearing impairment by using a combination of active ingredients; wherein the combination of active ingredients comprises: (a) IKAROS Family Zinc Finger 2 (Ikzf2) protein, a coding sequence thereof, or a promoting agent thereof, or a combination thereof; and (b) Atonal bHLH transcription factor 1 (Atoh1) protein, a coding sequence thereof, or a promoting agent thereof, or a combination thereof.
The specification indicates that Ikzf2 (IKAROS Family Zinc Finger 2) is a zinc finger protein (also known as Helios). Ikzf2 is essentially a transcription factor distributed in the nucleus, and its main function is to initiate the expression of specific genes (e.g., outer hair cells (OHCs) of the cochlea). Embodiments includes SEQ ID NO: 1 (human) and SEQ ID NO: 5 (mouse) (pp. 10-11). Atoh1 (atonal bHLH transcription factor 1) is a nuclear transcription factor of the bHLH family (also known as math1). Atoh1 is also essentially a transcription factor distributed in the nucleus, and its main function is to initiate the expression of specific genes. In the mouse cochlea, Atoh1 begins to express in the middle embryonic cochlea, and its main function is to allow the progenitor cells of the cochlear auditory epithelium to develop into hair cells. Embodiments includes SEQ ID NO: 2 (human) and SEQ ID NO: 6 (mouse) (p. 11).
The examples are limited to teaching the protein sequence and expression vectors encoding the Ikzf2 and Atoh1 proteins
The specification does not explicitly or implicitly define the claim term “promoting agent”.
The term “promoting agent” is construed as a compound that can promote/increase either directly or indirectly expression of Ikzf2 and Atoh1 gene, mRNA or protein levels. A compound could directly or indirectly effect functional activity along a functional pathway. A “promoting agent” can be of any chemical or physical composition, e.g., nucleotide, peptide, protein, lipid, small molecule, combination thereof, etc.
No examples of a promoting agent of Ikzf2 or a promoting agent of Atoh1 were disclosed in the specification.
With regard to the term “promoter”, the specification is limited to disclosing expression vector promoters (pp. 13-14). Examiner notes that an expression vector promoter is a specific regulatory DNA sequence within an expression vector that binds RNA polymerase to initiate the transcription of an inserted gene into messenger RNA.
The specification does not provide any written description for the claimed “promoting agents” since the claims do not describe a single structural feature. The specification does not clearly define or provide examples of what qualify as “promoting agents” of the claimed invention.
As stated earlier, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. Here, the specification fails to provide any probative guidance as to what compounds fall within the instant claim scope of ““promoting agent” of Ikzf2 or Atoh1, much less what compounds have functional utility in the claimed method of regenerating cochlea outer hair cells, and/or treating or preventing hearing impairment.
The specification is limited to teaching full-length Ikzf2 or Atoh1 mouse and human protein/nucleic acid sequences.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1 and 2 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 treating hearing impairment comprising administering a combination of Ikzf2 protein/coding sequence and Atoh1 protein/coding sequence to a subject in need thereof, does not reasonably provide enablement for treatment with “promoting agent” Ikzf2 or Atoh1. The specification is not enablement for preventing hearing impairment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed more recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
With regard to enablement of a claim drawn generally to treatment of impairment of a body organ’s functions, see In re Schmidt, 153 USPQ 640, 653.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(1) Breadth of claims. Claim 1 is directed to a method of (i) regenerating cochlea outer hair cells, and/or (ii) treating or preventing hearing impairment by using a combination of active ingredients; wherein the combination of active ingredients comprises: (a) IKAROS Family Zinc Finger 2 (Ikzf2) protein, a coding sequence thereof, or a promoting agent thereof, or a combination thereof; and (b) Atonal bHLH transcription factor 1 (Atoh1) protein, a coding sequence thereof, or a promoting agent thereof, or a combination thereof.
The claims do not expressly state that the combination of active agents (Ikzf2 and Atoh1) is actually administered to a subject. See separate but related 112b rejection.
The specification indicates that Ikzf2 (IKAROS Family Zinc Finger 2) is a zinc finger protein (also known as Helios). Ikzf2 is essentially a transcription factor distributed in the nucleus, and its main function is to initiate the expression of specific genes (e.g., outer hair cells (OHCs) of the cochlea). Embodiments includes SEQ ID NO: 1 (human) and SEQ ID NO: 5 (mouse) (pp. 10-11). Atoh1 (atonal bHLH transcription factor 1) is a nuclear transcription factor of the bHLH family (also known as math1). Atoh1 is also essentially a transcription factor distributed in the nucleus, and its main function is to initiate the expression of specific genes. In the mouse cochlea, Atoh1 begins to express in the middle embryonic cochlea, and its main function is to allow the progenitor cells of the cochlear auditory epithelium to develop into hair cells. Embodiments includes SEQ ID NO: 2 (human) and SEQ ID NO: 6 (mouse) (p. 11).
The specification does not explicitly or implicitly define the claim term “promoting agent”.
The specification states at p. 10: As used herein, the terms “hearing impairment”, “hearing disorder” and “hearing injury” refer to hearing dysfunction due to degeneration and/or damage of cochlea outer hair cells.
(2) The nature of the invention and predictability in the art: The invention is directed toward and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
(3) Direction or Guidance: That provided is very limited. As noted, the specification is limited to discloses full-length Ikzf2 and Atoh1 (human and mouse protein/nucleic acid sequences). No “promoting agents”- as relating to Ikzf2 and Atoh1- were disclosed.
In order to prevent a hearing impairment, the skilled artisan must be able to first predict and identify subjects that are at risk for developing hearing impairment, as well as required amounts of Ikzf2 and Atoh1, dosing regimen and route(s) of administration in order to prevent development of hearing impairment in a subject. For instance, preventing hearing impairment would need to occur before a subject could hear in the first instance, e.g. at birth.
(4) State of the Prior Art:
Ječmenica (Childs Nerv Syst 31:515-519 (2015)) teach that three out of 1000 newborns are affected by a hearing loss, one of these being profound congenital deafness, whereas in the population of children treated in the intensive care unit, the incidence is 1:50 (abstract). A large number of pathological conditions, (genetic, infectious, and metabolic) can manifest themselves in a conductive or sensorineural hearing loss. Nonsyndromic autosomal recessive hearing loss is found in 56 % of cases, syndromic recessive in 30 %, nonsyndromic autosomal dominant in 12 %, and nonsyndromic related to the X chromosome and mitochondrial in 2 % of the cases. Id.
From audiological aspect, deafness signifies the absence of auditory function [1]. Normal hearing requires anatomical integrity and functional compliance of all parts of the auditory system: the outer, middle, and inner ear; the cochlear nerve; and the central auditory pathways [2]. According to the site of the lesion, HI can be conductive, sensorineural, mixed, central, and psychogenic (p. 815). Conductive HI is the result of insufficient functioning of the conduction part, outer and middle ear. Sensorineural hearing impairment (SNHI) is the result of damaged membranous labyrinth, the organ of Corti, or some of the structures in volved in the transmission of sound to the temporal cortex. Mixed HI involves dysfunction of both parts of the hearing organ, conductive and perceptive. With regard to duration, a HI may be transient or permanent, in relation to behavior, progressive or non-progressive. Id. Autosomal recessive HI is usually a consequence of mutations in genes Connexin 26, 30, and 31; GJB 2 (C×26); GJB3 (C× 31); and GJB 6 (C×30) encoding the transmembrane protein which determines the creation of connections between the intermediate space and the opening of K+ channel. These mutations result in high levels of toxic K+ in hearing cells which causes irreversible damage (p. 516). So far, over 400 syndromes with hearing impairment have been described covering HI of different nature and location (p, 517). Mitochondrial diseases commonly affect the nerve and muscle tissue; therefore, these patients often have damaged auditory pathway (p. 518).
Hudspeth (Nature reviews neuroscience 15:600-614 (2014)) teach that uniquely among human senses, hearing is not simply a passive response to stimulation. Our auditory system is instead enhanced by an active process in cochlear hair cells that amplifies acoustic signals several hundred-fold, sharpens frequency selectivity and broadens the ear’s dynamic range (abstract). The receptor for sound in the human ear is the organ of Corti, a strip of sensory epithelium running some 33 mm along the spiral cochlea. The key components of the organ of Corti are hair cells, the sensory receptors of the inner ear. Cochlear hair cells are of two types, each of which has distinct functions in the transduction process. Each of the 3,500 inner hair cells, which are arranged in a single row, forms synapses with an average of ten afferent nerve terminals. The associated axons in turn carry auditory information into the cochlear nucleus of the brainstem. Although the 12,000 outer hair cells in three rows also make sparse contacts on afferent fibers, their principal role is mechanical: outer hair cells mediate the cochlear active process (FIG. 1) (pp. 600-601).
Chessum et al (Nature 563:696-700 (2018)) teach that the sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning. Both cell types are thought to arise from common progenitors. Ikzf2 (which encodes Helios) is an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm (abstract).
Lee et al (Chonnam Med J 53:37-46 (2017)) teach that cochlear sensory hair cells (HCs) are crucial for hearing as mechanoreceptors of the auditory systems. Transcription factor Atoh1 is the key player during HC development and regeneration (abstract). Atoh1 and its related signaling pathways (Notch, fibroblast growth factor, and Wnt/β-catenin signaling) involved in the development of cochlear sensory HCs. Id. The inner HCs are arranged in a single row and outer HCs are arranged in three rows (Fig. 1). Inner HCs excite type I spiral ganglion neurons. A single inner HC makes synaptic connection with numerous type I afferent nerve fibers. Outer HCs enhance the responsiveness of the sensory epithelium to specific frequencies and detect low intensity sound. They are innervated by type II afferent nerve fibers. A single afferent nerve fiber can innervate many outer HCs (p. 37).
Mulvaney et al (JARO 13:281-293 (2012)) teach Atoh1 (also known as Math1, Hath1, and Cath1 in mouse, human, and chicken, respectively) is a proneural basic helix–loop–helix (bHLH) transcription factor that is required in a variety of developmental
contexts. Atoh1 is involved in differentiation of neurons, secretory cells in the gut, and mechanoreceptors including auditory hair cells. Atoh1 regulates neurosensory development in the ear as well as neurogenesis in the cerebellum. Atoh1 activity in the cochlea is both necessary and sufficient to drive auditory hair cell differentiation, in
keeping with its known role as a regulator of various genes that are markers of terminal differentiation (abstract). Damage to hair cells from any of multiple causes (age,
toxic drugs, noise, and disease) is a common cause of hearing loss. Having identified Atoh1 as an important factor in HC differentiation there is much potential for exploring Atoh1-mediated HC regeneration (p. 291).
The instant claims further encompass blunt force trauma to the ear/cochlea.
(5) Working Examples: Example 1 discloses ectopic overexpression of Ikzf2 in inner hair cells. Example 2 discloses ectopic overexpression of Ikzf2 and Atoh1 in adult mice generate outer hair like cells. Examples 3-4 discloses stimulates a human hearing impaired mouse model. Knock-in mice were treated with diphtheria toxin (DT) which killed the cochlea outer hair cells. Hearing threshold increased following DT treatment. Overexpressing atoh1 and Ikzf2 yielded a large number of prestin+ OHC-like cells. Example 5 discloses that cilia structure disappeared int eh outer hair cell killing model, but reappear in the model of adult supporting cells overexpressing Ikzf2 and Atoh1. Example 6 discloses that OHC-like cells are similar to wild type outer hair cells of P1 mice progeny.
Examiner expressly notes that there are no examples of preventing hearing impairment in the specification. In order to prevent, the skilled artisan must first be able to identify subjects at risk for developing hearing impairment, much less provide effective amounts and dosing regimen in a manner to prevent. It is noted proteins were not administered exogenously. Data related to proteins expressed from expression vectors. Additionally, the specification did not reduce to practice much less disclose a “promoting agent” of either Atoh1 or Ikzf2.
(6) Skill of those in the art:
MPEP 2141.03 states (in part)" A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. V. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. At 1396, 82 USPQ2d at 1396. The "hypothetical person having ordinary skill in the art' to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner's definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(7) The quantity of experimentation needed: given the fact that, historically, the development of new drugs has been difficult and time consuming, and especially in view of factors 1-6, the quantity of experimentation needed is expected to be substantial and undue.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 and 2 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zuo et al (U.S. 2019/0358293), as evidenced by Chessum et al (Nature 563:696-700 (2018)).
Zuo et al. teach methods and compositions using a nucleic acid molecule encoding an atonal-associated factor in combination with a co-transcription factor and/or inhibitor of a gene silencing complex to change the sensory perception of an animal (abstract). Claim 1 method of improving the sensory perception [e.g., hearing impairment/loss] of an animal comprising administering to the inner ear of an animal in need thereof an expression vector harboring a nucleic acid molecule encoding an atonal-associated factor in combination with at least one co-transcription factor and/or inhibitor of a gene silencing complex (see also para [0003], [0006], [0057], [0085]- [0087], [0091]). Atonal-associated factors include Atonal Homolog 1 (Atoh1). Co- transcription factors include lkzf2 (paras. [0005]-[0007], [0057], [0065], claims 1, 4, 10 and 13). Paragraph [0065] teaches co-expression of Atoh1 and lkzf2.
Accordingly, the limitations of claim 1 are satisfied.
Regarding claim 2, Zuo teach that hearing loss can be associated with damage of sensory hair cells (e.g., para [0006], [0089], [0091], [0105], [0155]). As evidenced by Chessum et al, sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning.
Conclusion
No claims are allowed.
Claims 1-7, 9, and 11-15 are pending. Claims 1-7, 9, and 11-15 are withdrawn.
Claims 1 and 2 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654
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