Patent Application 17733744 - COMPOSITIONS AND METHODS FOR TREATING

Title: COMPOSITIONS AND METHODS FOR TREATING SENSORINEURAL HEARING LOSS USING OTOFERLIN DUAL VECTOR SYSTEMS

Application Information

Invention Title: COMPOSITIONS AND METHODS FOR TREATING SENSORINEURAL HEARING LOSS USING OTOFERLIN DUAL VECTOR SYSTEMS
Application Number: 17733744
Submission Date: 2025-04-10T00:00:00.000Z
Effective Filing Date: 2022-04-29T00:00:00.000Z
Filing Date: 2022-04-29T00:00:00.000Z
National Class: 514
National Sub-Class: 04400R
Examiner Employee Number: 82053
Art Unit: 1638
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 1

Cited Patents

The following patents were cited in the rejection:

Office Action Text

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 .

Detailed Action
This action is in response to the papers filed July 11, 2022.

Amendments
Applicant's amendments, filed July 11, 2022, is acknowledged. Applicant has cancelled Claims 9-10, 12, 15-16, 19-20, 23-27, 29, 32-33, and 36, and amended Claims 3-5, 8, 11, 13-14, 17-18, 21-22, 28, 30-31, and 34-35.
Claims 1-8, 11, 13-14, 17-18, 21-22, 28, 30-31, and 34-35 are pending and under consideration.

Priority
This application is a continuation of PCT/US2020/58265 filed on October 30, 2020. Applicant’s claim for the benefit of a prior-filed application provisional applications:
63/023,058 filed on May 11, 2020;
62/971,504 filed on February 7, 2020;
62/965,776 filed on January 24, 2020; and
62/928,290 filed on October 30, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is/are acknowledged.

The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 62/971,504, 62/965,776, and 62/928,290 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The specifications and original claims are silent to the instantly recited subdomains of the respective SEQ ID NO’s recited in Claims 28, 30, and 31.
Rather, support is found in 63/023,058 filed on May 11, 2020 (e.g. Table 4, e.g. pgs 74-83).
Accordingly, the effective priority date of the instant application is granted as May 11, 2020.

If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.

Information Disclosure Statement
Applicant has filed Information Disclosure Statements on July 11, 2022 and July 19, 2024 that have been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.

Allowable Subject Matter
1. Claims 28 and 30-31 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The recited coordinates of Claims 28 and 31 correspond to the instantly recited coordinates of Claim 30.

With respect to Claims 28 and 30-31, the claims are directed to the first AAV vector comprises a polynucleotide sequence comprising the sequence of nucleotides 2272 to 6041 (3769nts) of SEQ ID NO: 60, which also reads upon nucleotides 235-4004 of SEQ ID NO:66 and nucleotides 182-3949 of SEQ ID NO:62.
Per Table 4 (pgs 76-83), this encodes a Myo15 promoter, a Kozak sequence, an N-terminal portion of human OTOF-5, an AP splice donor sequence, and an AP recombinogenic head sequence.
The claims are directed to a region of a second rAAV vector comprising instant nucleotides 2267-6476 (4209 nucleotides) of SEQ ID NO:61, which also reads upon nucleotides 223-4438 of SEQ ID NO:67 and nucleotides 187-4396 of SEQ ID NO:63.
Per Table 4 (pgs 84-92), this encodes an AP recombinogenic head sequence, a spice acceptor sequence, a C-terminal portion of human OTOF-5, and a bGH polyA sequence.

Dyka et al WO 20/093018 (effective filing date of November 1, 2018; of record in IDS) is closest prior art for having disclosed a second rAAV vector comprising a nucleotide sequence (SEQ ID NO:16) that is 100% identical to instant nucleotides 2267-6476 (4209 nucleotides) of SEQ ID NO:61, which also reads upon nucleotides 223-4438 of SEQ ID NO:67 and nucleotides 187-4396 of SEQ ID NO:63.
While the first rAAV vector of Dyka et al encodes a nucleic acid sequence (SEQ ID NO:14) that is identical to nucleotides 3235-6041 of SEQ ID NO:60, Dyka et al do not disclose the first AAV vector polynucleotide sequence comprises nucleotides 2272-3234 of SEQ ID NO:60, which corresponds to the Myo15 promoter.
Thus, the first AAV vector comprising a polynucleotide sequence comprising the sequence of nucleotides 2272 to 6041 (3769nts) of SEQ ID NO: 60 appears to be free of the prior art.
Similarly, the first AAV vector comprising a polynucleotide sequence comprising the sequence of nucleotides 235-4004 (3769nts) of SEQ ID NO: 66 and/or nucleotides 182-3949 (3767nts) of SEQ ID NO: 62 also appear to be free of the prior art.

Claim Objections
2. Claims 1, 3, 22, 28, and 30-31 are objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The multiple ‘wherein’ clauses should be separated by line indention.
The multiple first regions (Claim 3) should be separated by line indention.
The multiple second regions (Claim 3) should be separated by line indention.
The first nucleic acid/vector embodiments (Claims 3, 22, 28, and 30-31) should be separated from the second nucleic acid/vector embodiments by line indentation.
Appropriate correction is required.

3. Claims 5-7 are objected to because of the following informalities:
These claims each identify “AP gene fragment”. However, the claims do not first identify the AP by its complete name prior to using its acronym. The abbreviation should be spelled out in the first appearance of the claims and should be followed by the abbreviation in parentheses, e.g. Otoferlin (OTOF), as recited in Claim 1.
Appropriate correction is required.

Claim Rejections - 35 USC § 112
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.

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.

4. Claim(s) 34-35 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 34 recites a method of increasing OTOF expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the dual vector system of claim 1.
Claim 35 recites a method of treating a subject having or at risk of developing sensorineural hearing loss or auditory neuropathy, the method comprising administering to the subject a therapeutically effective amount of the dual vector system of claim 1.

The claim denotes that there is an amount of the pharmaceutical composition that upon administration to the subject is not, in fact, “a therapeutically effective amount”.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject [parameter 1] human or non-human animal to be treated;
the structure/function of the OTOF-5 polypeptide expressed from the vector(s) [parameter 2];
the regulatory element(s) driving expression of the OTOF-5 polypeptide [parameter 3];
the AAV capsid serotype(s) [parameter 4]; and
the administration route [parameter 5];
the dosage administered [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particles that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” so as to necessarily and predictably:
increase OTOF expression in a subject in need thereof;
treating a subject having sensorineural hearing loss;
treating a subject having auditory neuropathy;
treating a subject at risk of developing sensorineural hearing loss; and/or
treating a subject at risk of developing auditory neuropathy.

Parameter 1
The claims are broad for reasonably encompassing an enormous genus of animal subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, rabbits, mice, and rats (e.g pg 12, line 8; pg 17, lines 34-36)
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
The claims fail to recite, and the specification fails to disclose, a first subject who is “in need”, as opposed to a second subject who is not “in need”. Rather, “in need” appears to be an arbitrary and subjective determination.
The Examiner notes that while the specification disclose a mouse model system in which the endogenous OTOF gene is mutated (e.g. pg 142, line 29) or the subject has “deafness secondary to genetically driven OTOF deficiency” (e.g. pg 142, line 12-13), instant claims fail to recite and require the subject to comprise one or mutations in their endogenous OTOF-5 gene, nor even deafness.

Parameter 2
The claims are broad for reasonably encompassing an enormously vast genus of structurally and functionally undisclosed OTOF-5 polypeptides, e.g “or a variant thereof”.
The specification discloses the OTOF-5 amino acid sequence may comprises a multitude of amino acid substitutions, insertions, and/or deletions relative to a reference SEQ ID NO, e.g. SEQ ID NO:1 (e.g. pg 6, line 30-pg7, line 18).
SEQ ID NO:1 is composed of 1997 amino acids.
40% identity allows for 1198 substitutions, deletions, and/or insertions.
50% identity allows for 998 substitutions, deletions, and/or insertions.
60% identity allows for 799 substitutions, deletions, and/or insertions.
70% identity allows for 599 substitutions, deletions, and/or insertions.
80% identity allows for 399 substitutions, deletions, and/or insertions.
90% identity allows for 200 substitutions, deletions, and/or insertions.
95% identity allows for 100 substitutions, deletions, and/or insertions.

20^1198 = an infinite number of structurally and functionally undisclosed variants of SEQ ID NO:1.
20^100 = 1x10^130 structurally and functionally undisclosed variants of SEQ ID NO:1.
(www.calculator.net/exponent-calculator; last visited March 31, 2025)

Parameter 3
The claims are broad for encompassing an enormous genus of structurally and functionally undisclosed Myo15 promoters, e.g. “functional portion or derivative thereof”, that are to be operably linked to the enormously vast genus of about 1x10^130 to infinite structurally and functionally undisclosed variants of SEQ ID NO:1.
Claim 4 recites SEQ ID NO:21, which is 965 nucleotides in length.
40% identity allows for 579 substitutions, deletions, and/or insertions.
50% identity allows for 482 substitutions, deletions, and/or insertions.
60% identity allows for 386 substitutions, deletions, and/or insertions.
70% identity allows for 193 substitutions, deletions, and/or insertions.
80% identity allows for 193 substitutions, deletions, and/or insertions.
90% identity allows for 96 substitutions, deletions, and/or insertions.
95% identity allows for 48 substitutions, deletions, and/or insertions.
4^579 = an infinite number of structurally and functionally undisclosed variants of SEQ ID NO:1.
4^193 = 7x10^116 structurally and functionally undisclosed variants of SEQ ID NO:1.
4^48 = 7x10^28 structurally and functionally undisclosed variants of SEQ ID NO:1.

Parameter 4
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).

Parameter 5
The claims are broad for encompassing an enormous genus of distinctly different anatomical routes by which the AAV vectors are to be administered to the subject.
The specification discloses such routes include, but are not limited to, intravenous, parenteral, intradermal, transdermal, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intraarterial, intravascular, inhalation, perfusion, lavage, or oral administration (e.g. pg 139, lines 4-10).
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
The Examiner notes that while the specification disclose “direct delivery to the inner ear” (e.g. pg 139, lines 9-10) and/or “injection through the round window membrane” (e.g. pg 142, lines 29-30), instant claims fail to recite and require the rAAV vectors to be delivered to the inner ear, nor that the increased OTOF-5 expression be in the cells of the inner ear.
It would be remedial for Applicant to amend Claims 34-35 to positively recite the step of administering to the subject’s ear an rAAV viral genome dosage of…, for example.

Parameter 6
The claimed methods are recited at a high level of generality for failing to recite the rAAV vector(s) dosage(s) that is to be administered.
The claims would reasonably encompass as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
The phrase “therapeutically effective amount” itself denotes that there is an amount of the rAAV vector system that, upon administration to the enormous genus of subjects via the enormous genus of anatomically distinct routes does not, in fact, necessarily and predictably achieve “a therapeutically effective amount”.
The claims fail to recite the objective minimal amount of the rAAV vector system that is to be administered that is necessarily, sufficiently, and predictably a “therapeutically effective amount”.

Parameter 7
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
For example:
The specification discloses the “therapeutically effective amount” is sufficient to “effect beneficial or desired results” (e.g. pg 12, line 9), which itself is an arbitrary and subjective determination, and “depends upon the context in which it is being applied” (pg 12, line 10), which itself is variable parameter.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
While pg 9, lines 31-35 discloses the system increases OTOF expression in a cell (e.g., a cochlear hair cell), improves hearing (e.g., as assessed by standard tests, such as audiometry, auditory brainstem response (ABR), electrocochleography (ECOG), and otoacoustic emissions), prevents or reduces hearing loss, delays the development of hearing loss, slows the progression of hearing loss, improves speech discrimination, or improves hair cell function, as discussed above, neither Claim 34 nor Claim 35 recite and/or require the system to be expressed in cochlear hair cells.
Claim 35 neither recites nor requires the therapeutically effective amount to improve hearing (e.g., as assessed by standard tests, such as audiometry, auditory brainstem response (ABR), electrocochleography (ECOG), and otoacoustic emissions), prevent or reduce hearing loss, delay the development of hearing loss, slow the progression of hearing loss, improve speech discrimination, or improve hair cell function.

If there are multiple phenotypic results by which “therapeutically effective amount” and/or “treating” is determined, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.

The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to improve hearing, but does not achieve improved speech discrimination, in a subject, e.g. rabbit, as opposed to a second rAAV dosage administered via a second administration route, e.g. intravenously, that is necessarily and predictably able to achieve some arbitrary and subjective “beneficial therapeutic effects” yet is unable to reduce or inhibit auditory neuropathy in a subject, e.g. monkey, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intramuscularly, that is necessarily and predictably able to achieve improve hair cell function in a subject, e.g. guinea pig, but is unable to inhibit delay hearing loss or sensorineural hearing loss in a subject, e.g. chicken, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intracisternally, that is necessarily and predictably able to achieve cochlear hair cell expression, but is unable to inhibit prevent, inhibit, or otherwise delay developing sensorineural hearing loss in a subject, e.g. human, for example.
The instant claim as a whole does not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
Appropriate correction is required.

When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).

5. Claim(s) 3 and 34-35 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.
Claim 3 recites the phrases “at least 85% identity to” and “a functional portion or derivative thereof”.
Claim 34 recites a method of increasing OTOF expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the dual vector system of claim 1.
Claim 35 recites a method of treating a subject having or at risk of developing sensorineural hearing loss or auditory neuropathy, the method comprising administering to the subject a therapeutically effective amount of the dual vector system of claim 1.
The claim denotes that there is an amount of the pharmaceutical composition that upon administration to the subject is not, in fact, “a therapeutically effective amount”.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject [parameter 1] human or non-human animal to be treated;
the structure/function of the OTOF-5 polypeptide expressed from the vector(s) [parameter 2];
the regulatory element(s) driving expression of the OTOF-5 polypeptide [parameter 3];
the AAV capsid serotype(s) [parameter 4]; and
the administration route [parameter 5];
the dosage administered [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particles that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” so as to necessarily and predictably:
increase OTOF expression in a subject in need thereof;
treating a subject having sensorineural hearing loss;
treating a subject having auditory neuropathy;
treating a subject at risk of developing sensorineural hearing loss; and/or
treating a subject at risk of developing auditory neuropathy.

Parameter 1
The claims are broad for reasonably encompassing an enormous genus of animal subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, rabbits, mice, and rats (e.g pg 12, line 8; pg 17, lines 34-36)
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
The claims fail to recite, and the specification fails to disclose, a first subject who is “in need”, as opposed to a second subject who is not “in need”. Rather, “in need” appears to be an arbitrary and subjective determination.
The Examiner notes that while the specification disclose a mouse model system in which the endogenous OTOF gene is mutated (e.g. pg 142, line 29) or the subject has “deafness secondary to genetically driven OTOF deficiency” (e.g. pg 142, line 12-13), instant claims fail to recite and require the subject to comprise one or mutations in their endogenous OTOF-5 gene, nor even deafness.

Parameter 2
The claims are broad for reasonably encompassing an enormously vast genus of structurally and functionally undisclosed OTOF-5 polypeptides, e.g “or a variant thereof”.
The specification discloses the OTOF-5 amino acid sequence may comprises a multitude of amino acid substitutions, insertions, and/or deletions relative to a reference SEQ ID NO, e.g. SEQ ID NO:1 (e.g. pg 6, line 30-pg7, line 18).
SEQ ID NO:1 is composed of 1997 amino acids.
40% identity allows for 1198 substitutions, deletions, and/or insertions.
50% identity allows for 998 substitutions, deletions, and/or insertions.
60% identity allows for 799 substitutions, deletions, and/or insertions.
70% identity allows for 599 substitutions, deletions, and/or insertions.
80% identity allows for 399 substitutions, deletions, and/or insertions.
90% identity allows for 200 substitutions, deletions, and/or insertions.
95% identity allows for 100 substitutions, deletions, and/or insertions.

20^1198 = an infinite number structurally and functionally undisclosed variants of SEQ ID NO:1.
20^100 = 1x10^130 structurally and functionally undisclosed variants of SEQ ID NO:1.
(www.calculator.net/exponent-calculator; last visited March 31, 2025)

Parameter 3
The claims are broad for encompassing an enormous genus of structurally and functionally undisclosed Myo15 promoters, e.g. “functional portion or derivative thereof”, that are to be operably linked to the enormously vast genus of about 1x10^130 to infinite structurally and functionally undisclosed variants of SEQ ID NO:1.
Claim 3 recites “at least 85% identity to” or “a functional portion or derivative thereof” SEQ ID NO:7, which is 454 nucleotides in length.
85% identity allows for 68 substitutions, deletions, and/or insertions.
4^40 = 9x10^40 structurally and functionally undisclosed variants of SEQ ID NO:7.
Fragments and portions reads on nucleic acid fragments as little as 5, 10, 15, or 20 nucleotides, which encompasses an enormously vast genus of structurally and functionally undisclosed fragments of SEQ ID NO:7 of variable lengths.

Claim 3 recites “at least 85% identity to” or “a functional portion or derivative thereof” SEQ ID NO:8, which is 1157 nucleotides in length.
85% identity allows for 174 substitutions, deletions, and/or insertions.
4^174 = 5x10^104 structurally and functionally undisclosed variants of SEQ ID NO:8.
Fragments and portions reads on nucleic acid fragments as little as 5, 10, 15, or 20 nucleotides, which encompasses an enormously vast genus of structurally and functionally undisclosed fragments of SEQ ID NO:8 of variable lengths.

Claim 4 recites SEQ ID NO:21, which is 965 nucleotides in length.
40% identity allows for 579 substitutions, deletions, and/or insertions.
50% identity allows for 482 substitutions, deletions, and/or insertions.
60% identity allows for 386 substitutions, deletions, and/or insertions.
70% identity allows for 193 substitutions, deletions, and/or insertions.
80% identity allows for 193 substitutions, deletions, and/or insertions.
90% identity allows for 96 substitutions, deletions, and/or insertions.
95% identity allows for 48 substitutions, deletions, and/or insertions.
4^579 = an infinite number structurally and functionally undisclosed variants of SEQ ID NO:21.
4^193 = 7x10^116 structurally and functionally undisclosed variants of SEQ ID NO:1.
4^48 = 7x10^28 structurally and functionally undisclosed variants of SEQ ID NO:1.

Parameter 4
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).

Parameter 5
The claims are broad for encompassing an enormous genus of distinctly different anatomical routes by which the AAV vectors are to be administered to the subject.
The specification discloses such routes include, but are not limited to, intravenous, parenteral, intradermal, transdermal, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intraarterial, intravascular, inhalation, perfusion, lavage, or oral administration (e.g. pg 139, lines 4-10).
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
The Examiner notes that while the specification disclose “direct delivery to the inner ear” (e.g. pg 139, lines 9-10) and/or “injection through the round window membrane” (e.g. pg 142, lines 29-30), instant claims fail to recite and require the rAAV vectors to be delivered to the inner ear, nor that the increased OTOF-5 expression be in the cells of the inner ear.
It would be remedial for Applicant to amend Claims 34-35 to positively recite the step of administering to the subject’s ear an rAAV viral genome dosage of…, for example.

Parameter 6
The claimed methods are recited at a high level of generality for failing to recite the rAAV vector(s) dosage(s) that is to be administered.
The claims would reasonably encompass as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
The phrase “therapeutically effective amount” itself denotes that there is an amount of the rAAV vector system that, upon administration to the enormous genus of subjects via the enormous genus of anatomically distinct routes does not, in fact, necessarily and predictably achieve “a therapeutically effective amount”.

Parameter 7
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
For example:
The specification discloses the “therapeutically effective amount” is sufficient to “effect beneficial or desired results” (e.g. pg 12, line 9), which itself is an arbitrary and subjective determination, and “depends upon the context in which it is being applied” (pg 12, line 10), which itself is variable parameter.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
While pg 9, lines 31-35 discloses the system increases OTOF expression in a cell (e.g., a cochlear hair cell), improves hearing (e.g., as assessed by standard tests, such as audiometry, auditory brainstem response (ABR), electrocochleography (ECOG), and otoacoustic emissions), prevents or reduces hearing loss, delays the development of hearing loss, slows the progression of hearing loss, improves speech discrimination, or improves hair cell function, as discussed above, neither Claim 34 nor Claim 35 recite and/or require the system to be expressed in cochlear hair cells.
Claim 35 neither recites nor requires the therapeutically effective amount to improve hearing (e.g., as assessed by standard tests, such as audiometry, auditory brainstem response (ABR), electrocochleography (ECOG), and otoacoustic emissions), prevent or reduce hearing loss, delay the development of hearing loss, slow the progression of hearing loss, improve speech discrimination, or improve hair cell function.

Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).

Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of essentially infinite structurally and functionally undisclosed OTOF-5 polypeptide variants being operably linked to the enormously vast genus of essentially infinite structurally and functionally undisclosed Myo15 promoter variants, that upon administration to the enormous genus of human and non-human animals will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result(s), thereby achieving a real-world, clinically meaningful result of treating and/or preventing sensorineural hearing loss and/or auditory neuropathy, including but not limited to, improves hearing (e.g., as assessed by standard tests, such as audiometry, auditory brainstem response (ABR), electrocochleography (ECOG), and otoacoustic emissions), prevents or reduces hearing loss, delays the development of hearing loss, slows the progression of hearing loss, improves speech discrimination, or improves hair cell function.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.

A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)

The claims fail to recite, and the specification fails to disclose, a first functional portion or derivative of SEQ ID NO:7, being only about 5, 10, 15, or 20 nucleotides in length that necessarily and predictably has Myo15 promoter activity.
The claims fail to recite, and the specification fails to disclose, a first functional portion or derivative of SEQ ID NO:8, being only about 5, 10, 15, or 20 nucleotides in length that necessarily and predictably has Myo15 promoter activity.
The claims fail to recite, and the specification fails to disclose, a first SEQ ID NO:7 variant of the enormously vast genus of about 9x10^40 structurally and functionally undisclosed SEQ ID NO:7 variants, that does not have Myo15 promoter activity, as opposed to a second SEQ ID NO:7 variant of the enormously vast genus of about 9x10^40 structurally and functionally undisclosed SEQ ID NO:7 variants, that necessarily and predictably has Myo15 promoter activity, for example.
The claims fail to recite, and the specification fails to disclose, a first SEQ ID NO:8 variant of the enormously vast genus of about 5x10^104 structurally and functionally undisclosed SEQ ID NO:8 variants, that does not have Myo15 promoter activity, as opposed to a second SEQ ID NO:8 variant of the enormously vast genus of about 5x10^104 structurally and functionally undisclosed SEQ ID NO:8 variants, that necessarily and predictably has Myo15 promoter activity, for example.

The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to improve hearing, but does not achieve improved speech discrimination, in a subject, e.g. rabbit, as opposed to a second rAAV dosage administered via a second administration route, e.g. intravenously, that is necessarily and predictably able to achieve some arbitrary and subjective “beneficial therapeutic effects” yet is unable to reduce or inhibit auditory neuropathy in a subject, e.g. monkey, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intramuscularly, that is necessarily and predictably able to achieve improve hair cell function in a subject, e.g. guinea pig, but is unable to inhibit delay hearing loss or sensorineural hearing loss in a subject, e.g. chicken, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intracisternally, that is necessarily and predictably able to achieve cochlear hair cell expression, but is unable to inhibit prevent, inhibit, or otherwise delay developing sensorineural hearing loss in a subject, e.g. human, for example.

"The claimed invention as a whole may not be adequately described if the claims require an essential or critical element which is not adequately described in the specification and which is not conventional in the art", "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus", "in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus''. MPEP §2163

An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).

Possession may also be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was ''ready for patenting'' such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 1 19 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998), Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997)*, Amgen, Inc. v. Chugai Pharmaceutical, 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by ''whatever characteristics sufficiently distinguish it'').

Therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. See Fiers v. Revel, 25 USPQ2d 1602 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.

Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).

Based on the applicant's specification, those of ordinary skill in the art cannot envision the detailed combinations of the broad genus of rAAV vectors whose genomes encode the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptides operably linked to an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoters to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes at an enormous genus of unrecited dosages so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), thereby achieving a real-world, clinically meaningful result of treating and/or preventing sensorineural hearing loss and/or auditory neuropathy, as required by the independent claims.
At best, the specification discloses the use of AAV serotype 2, whereby said AAV2 vector encodes a Myo15 promoter (SEQ ID NO:21) operably linked to the hOTOF-5 cDNA (SEQ ID NO:1), administered to the ear via injection through the round window at a dose of 4x10^10 vector genomes/ear, of a mouse subject comprising loss-of-function mutations of the endogenous OTOF-5 gene (e.g. Example 3).

In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, the breadth of the claims reasonably encompasses:
an enormous genus of human and non-human animal subjects [parameter 1] to be treated;
an enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptide variants to be expressed from the vector(s) [parameter 2];
an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoter variants driving expression of the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptide variants [parameter 3];
an enormous genus of AAV capsid serotype(s) [parameter 4]; and
an enormous genus of anatomically distinct administration routes [parameter 5];
an enormous genus of first and second rAAV virus particle dosages to be administered [parameter 6]; and
a broad genus of different phenotypic responses to be achieved [parameter 7].
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particles that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” so as to necessarily and predictably:
increase OTOF expression in a subject in need thereof;
treating a subject having sensorineural hearing loss;
treating a subject having auditory neuropathy;
treating a subject at risk of developing sensorineural hearing loss; and/or
treating a subject at risk of developing auditory neuropathy, as required by the independent claims.

In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
In the instant case, Applicant seeks to monopolize an entire class of treating sensorineural hearing loss and/or auditory neuropathy without satisfying the real-world scientific and clinical nexus of the broad genus of rAAV vectors whose genomes encode the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptides operably linked to an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoters to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes at an enormous genus of unrecited dosages so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s) of treating and/or preventing sensorineural hearing loss and/or auditory neuropathy, as required by the independent claims.

“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.

The claims fail to recite the objective minimal amount of the rAAV vector system that is to be administered that is necessarily, sufficiently, and predictably a “therapeutically effective amount”.

Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.

6. Claims 3 and 34-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while being enabling for a method of treating a mouse subject suffering from loss-of-function mutations in their endogenous OTOF-5 gene and having sensorineural hearing loss or auditory neuropathy comprising the step of administering to the subject’s ear via injection through the round window at least 4x10^10 vector genomes/ear of an AAV serotype 2 virus whose genome encodes a Myo15 promoter comprising or consisting of SEQ ID NO:21 operably linked to the hOTOF-5 nucleic acid encoding the amino acid sequence of SEQ ID NO:1,
does not reasonably provide enablement for a nexus between an enormous genus of AAV vector serotypes, the enormous genus of rAAV vector dosages, an enormously vast, essentially infinite genus of structurally and functionally undisclosed OTOF-5 polypeptide variants operably linked to an enormously vast, essentially infinite genus of structurally and functionally undisclosed Myo15 promoter variants, the enormous genus of anatomically distinct administration routes, and the enormous genus of human and non-human animal subjects so as to necessarily and predictably achieve a clinically meaningful, real-world therapeutic results of:
treating a subject having sensorineural hearing loss;
treating a subject having auditory neuropathy;
treating and/or preventing the development of sensorineural hearing loss in a subject at risk; and/or
treating and/or preventing the development of auditory neuropathy in a subject at risk, as required by the independent claims.
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.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.

The nature of the invention involves one of the most complex and unpredictable areas of medicine molecular biology - gene therapy treatment.
The invention is in a class of invention which 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).

The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
Considering the mode of administration, the specification simply requires administration of the AAV to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Fumoto et al (Targeted Gene Delivery: Importance of Administration Routes, INTECH, Novel Gene Therapy Approaches, pg 3-31; editors Wei and Good, publisher Books on Demand, 2013) details these obstacles wherein direct injection is to date the best procedure (pg 11, Table 3, Figure 3, “Direct injection of rAAV vector…exhibited faster and stronger transgene expression than intravenous and intraportal injections”).
To date, no single mode of gene transfer has provided a viable option for successful gene therapy protocols Daya et al (Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; pg 590-591, joining ¶). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (Daya et al, pg 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product. Even the use of targeting methods and tissue specific promoters have done little to overcome the numerous obstacles related to gene delivery. Even use of tissue specific promoters and capsids targeting has not successfully overcome these obstacles. Taken together with the large breadth of target tissues and diseases claimed, in light of the difficulties to overcome even one of these barriers, one could not perform the full breadth of the claims.
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg 386, col. 2).
Ghoraba et al (Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses, Clinical Opthalmology 16: 1753-1771, 2022) is considered relevant post-filing art for having taught that the associated immune and inflammatory reactions to gene therapy, including rAAV-based gene therapies, may render such treatment ineffective or harmful, which are of particular concerns for the eyes due to their susceptibility to inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors (Abstract). Intravitreal administration, while convenient, is unable to transduce the outer retina layers, which is the main target of most retinal diseases due to defects in the RPE or photoreceptor cells (e.g. pg 1762, Intravitreal Delivery). Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response. The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies (pg 1763, para 1).
Acland et al (U.S. 2004/0022766) is considered relevant prior art for having disclosed a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid [0023], and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5' inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a coding sequence encoding a human Lebercilin [0031].
Acland et al disclosed [0057] “[T]he use of subretinal injection as the route of delivery is a critical component of this method, as intravitreal administration does not enable the same therapeutic effects. The vector and carrier cannot diffuse across the multiple cell layers in the retina to reach the RPE, when intravitreal injection is used. Similarly, intravenous delivery is unacceptable because the material does not penetrate the blood-brain (blood-retina) barrier. Because the virus does not diffuse well, topical administration is similarly not preferred for this method.”

Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022; last visited September 27, 2024) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”

The gene therapy art is unpredictable, as manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells, routes of administration, the transient and unpredictable expression of the transgenes in target cells, the specific genes to be used for a treatment, the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method.
Based on the applicant's specification, those of ordinary skill in the art cannot envision the detailed combinations of the broad genus of rAAV vectors whose genomes encode the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptides operably linked to an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoters to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes at an enormous genus of unrecited dosages so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), thereby achieving a real-world, clinically meaningful result of treating and/or preventing sensorineural hearing loss and/or auditory neuropathy, as required by the independent claims.
At best, the specification discloses the use of AAV serotype 2, whereby said AAV2 vector encodes a Myo15 promoter (SEQ ID NO:21) operably linked to the hOTOF-5 cDNA (SEQ ID NO:1), administered to the ear via injection through the round window at a dose of 4x10^10 vector genomes/ear, of a mouse subject comprising loss-of-function mutations of the endogenous OTOF-5 gene (e.g. Example 3).

The specification fails to make up for deficiencies of the global scientific community, and thus the ordinary artisans must determine for themselves that which Applicant fails to disclose.

The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the broadly claimed genus of rAAV serotypes may be administered by the broadly encompassed administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating, prohibiting, and/or preventing sensorineural hearing loss or auditory neuropathy in the enormous genus of animal subjects with a dual rAAV vector system encoding an enormously vast genus of structurally and functionally undisclosed Myo15 promoter variants and fragments operably linked to the enormously vast genus of structurally and functionally undisclosed OTOF-5 polypeptides.
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to extrapolate the results provided in the instant specification of administering directly to the cochlear inner ear cells the AAV2 vectors encoding OTOF-5 to the larger genus of AAV capsid serotypes having different cellular tropisms, the enormous genus of anatomically different administration routes, and the enormous genus of rAAV dosages reasonably encompassed by the claims. Neither the specification nor the claims provide the appropriate nucleic acid vector or viral dosage to be administered in the plurality of possible intravenous, intracranial, intraperitoneal, intramuscular, subcutaneous, intramuscular, intrarectal, intravaginal, intrathecal, intratracheal, intradermal, or transdermal injection, by oral or nasal administration means that would reasonably be expected by the ordinary artisan to necessarily and predictably achieve a clinically meaningful, real-world therapeutic result of treating, prohibiting, and/or preventing sensorineural hearing loss or auditory neuropathy in the enormous genus of animal subjects.
The gene therapy art is extremely unpredictable. The unpredictability is manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells (the enormous genus of possible AAV serotypes disclosed), routes of administration (as disclosed, do not even require direct administration to the cochlea inner ear cells), the transient and unpredictable expression of the transgenes in target cells (the genus of disclosed possible promoters and/or regulatory sequences), and the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Those of ordinary skill in the art would immediately recognize that the instant specification fails to establish the nexus between the broad genus of AAV vectors, the enormous genus of AAV vector dosages, and the corresponding enormous genus of anatomically distinct administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the enormous genus of human and non-human animal subjects encompassed by the claimed methods.
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023; last visited September 27, 2024) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.

The specification fails to make up for the deficiencies of the global scientific community.

Based on the applicant's specification, those of ordinary skill in the art cannot envision the detailed combinations of the broad genus of rAAV vectors whose genomes encode the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptides operably linked to an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoters to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes at an enormous genus of unrecited dosages so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), thereby achieving a real-world, clinically meaningful result of treating and/or preventing sensorineural hearing loss and/or auditory neuropathy, as required by the independent claims.
At best, the specification discloses the use of AAV serotype 2, whereby said AAV2 vector encodes a Myo15 promoter (SEQ ID NO:21) operably linked to the hOTOF-5 cDNA (SEQ ID NO:1), administered to the ear via injection through the round window at a dose of 4x10^10 vector genomes/ear, of a mouse subject comprising loss-of-function mutations of the endogenous OTOF-5 gene (e.g. Example 3).

In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, the breadth of the claims reasonably encompasses:
an enormous genus of human and non-human animal subjects [parameter 1] to be treated;
an enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptide variants to be expressed from the vector(s) [parameter 2];
an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoter variants driving expression of the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptide variants [parameter 3];
an enormous genus of AAV capsid serotype(s) [parameter 4]; and
an enormous genus of anatomically distinct administration routes [parameter 5];
an enormous genus of first and second rAAV virus particle dosages to be administered [parameter 6]; and
a broad genus of different phenotypic responses to be achieved [parameter 7].
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particles that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” so as to necessarily and predictably:
increase OTOF expression in a subject in need thereof;
treating a subject having sensorineural hearing loss;
treating a subject having auditory neuropathy;
treating a subject at risk of developing sensorineural hearing loss; and/or
treating a subject at risk of developing auditory neuropathy, as required by the independent claims.

In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
In the instant case, Applicant seeks to monopolize an entire class of treating sensorineural hearing loss and/or auditory neuropathy without satisfying the real-world scientific and clinical nexus of the broad genus of rAAV vectors whose genomes encode the enormously vast, essentially infinite, genus of structurally and functionally undisclosed OTOF-5 polypeptides operably linked to an enormously vast, essentially infinite, genus of structurally and functionally undisclosed Myo15 promoters to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes at an enormous genus of unrecited dosages so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s) of treating and/or preventing sensorineural hearing loss and/or auditory neuropathy, as required by the independent claims.

“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.

The claims fail to recite the objective minimal amount of the rAAV vector system that is to be administered that is necessarily, sufficiently, and predictably a “therapeutically effective amount”.

The specification fails to make up for the deficiencies of the global scientific community.

Accordingly, limiting the claims to a method of treating a mouse subject suffering from loss-of-function mutations in their endogenous OTOF-5 gene and having sensorineural hearing loss or auditory neuropathy comprising the step of administering to the subject’s ear via injection through the round window at least 4x10^10 vector genomes/ear of an AAV serotype 2 virus whose genome encodes a Myo15 promoter consisting of SEQ ID NO:21 operably linked to the hOTOF-5 nucleic acid encoding the amino acid sequence of SEQ ID NO:1, is proper.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.

Claim Rejections - 35 USC § 103
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 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.

The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.

This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.

7. Claims 1-2, 5-8, 11, 13-14, 17-18, 21-22, and 34-35 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Alemi (2012; of record in IDS) in view of Auricchio et al (U.S. 2016/0076054), Simons et al (WO 18/039375; of record in IDS), Boye et al (WO 18/204734; of record in IDS), and Petit et al (U.S. 2018/0055908).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Alemi is considered relevant prior art for having taught a dual rAAV vector system, wherein:
a first adeno-associated virus (AAV) vector comprises:
a promoter operably linked to a first coding polynucleotide that encodes an N-terminal portion of an otoferlin protein,
a splice donor signal sequence positioned 3' of the first coding polynucleotide, and
a first recombinogenic region positioned 3' of the splice donor signal sequence; and
a second AAV vector comprises:
a second recombinogenic region,
a splice acceptor signal sequence positioned 3' of the second recombinogenic region,
a second coding polynucleotide that encodes a C-terminal portion of the otoferlin protein positioned 3' of the splice acceptor signal sequence, and
a poly(A) sequence positioned 3' of the second coding polynucleotide;
wherein the first coding polynucleotide and the second coding polynucleotide that encode the therapeutic protein do not overlap (e.g. “5’ half”, “3’ half”), and
wherein neither the first nor second AAV vector encodes the full-length therapeutic protein.

Auricchio et al is considered relevant prior art for having disclosed a dual rAAV vector system, wherein:
a first adeno-associated virus (AAV) vector comprises:
a promoter operably linked to a first coding polynucleotide that encodes an N-terminal portion of a therapeutic protein,
a splice donor signal sequence positioned 3' of the first coding polynucleotide, and
a first recombinogenic region positioned 3' of the splice donor signal sequence; and
a second AAV vector comprises:
a second recombinogenic region,
a splice acceptor signal sequence positioned 3' of the second recombinogenic region,
a second coding polynucleotide that encodes a C-terminal portion of the therapeutic protein positioned 3' of the splice acceptor signal sequence, and
a poly(A) sequence positioned 3' of the second coding polynucleotide;
wherein the first coding polynucleotide and the second coding polynucleotide that encode the therapeutic protein do not overlap, and
wherein neither the first nor second AAV vector encodes the full-length therapeutic protein (e.g. Figure 1, hybrid AP or hybrid AK).

Neither Alemi nor Auricchio et al teach/disclose wherein the therapeutic protein is OTOF isoform 5.
However, prior to the effective filing date of the instantly claimed invention, Simons et al is considered relevant prior art for having disclosed a dual rAAV vector system, wherein:
a first adeno-associated virus (AAV) vector comprises:
a promoter operably linked to a first coding polynucleotide that encodes an N-terminal portion of OTOF isoform 5 (e.g. pg 94, line 6, isoform e; pg 95, lines 23-25, NM_001287489.1),
a splice donor signal sequence positioned 3' of the first coding polynucleotide, and
a first recombinogenic region positioned 3' of the splice donor signal sequence; and
a second AAV vector comprises:
a second recombinogenic region,
a splice acceptor signal sequence positioned 3' of the second recombinogenic region,
a second coding polynucleotide that encodes a C-terminal portion of OTOF isoform 5 protein positioned 3' of the splice acceptor signal sequence, and
a poly(A) sequence positioned 3' of the second coding polynucleotide;
wherein the first coding polynucleotide and the second coding polynucleotide that encode the therapeutic protein- do not overlap, and
wherein neither the first nor second AAV vector encodes the full-length therapeutic protein (e.g. Figures 1-2).
Simons et al disclosed Otoferlin expression in the inner ear hair cells (e.g. pg 135, lines 22-23), whereby the promoter is capable of driving expression of the protein in choclear hair cells (e.g. pg 161, lines 28-29), e.g. a Myo7A or Myo6 promoter (e.g. pg 164, lines 21-23).

Boye et al is considered relevant prior art for having disclosed a dual rAAV vector system, wherein:
a first adeno-associated virus (AAV) vector comprises:
a promoter operably linked to a first coding polynucleotide that encodes an N-terminal portion of OTOF isoform 5 (e.g. pg 7, line 13, NM_001287489.1),
a splice donor signal sequence positioned 3' of the first coding polynucleotide, and
a first recombinogenic region positioned 3' of the splice donor signal sequence; and
a second AAV vector comprises:
a second recombinogenic region,
a splice acceptor signal sequence positioned 3' of the second recombinogenic region,
a second coding polynucleotide that encodes a C-terminal portion of OTOF isoform 5 protein positioned 3' of the splice acceptor signal sequence, and
a poly(A) sequence positioned 3' of the second coding polynucleotide;
wherein the first coding polynucleotide and the second coding polynucleotide that encode the therapeutic protein do not overlap, and
wherein neither the first nor second AAV vector encodes the full-length therapeutic protein (e.g. Figures 1A-1B, 2).
Boye et al disclosed Otoferlin expression in the OTOF KO-rescued mice inner ear hair cells (e.g. pg 4, Figure 8 legend).

Neither Alemi, Auricchio et al, Simons et al, nor Boye et al teach/disclose wherein the promoter is a Myo15 promoter.
However, prior to the effective filing date of the instantly claimed invention, Petit et al is considered relevant prior art for having disclosed the use of a Myo15 promoter (e.g. [0210] to drive expression of a desired protein in auditory neurons or hair cells (e.g. [0267]), as the Myo15 promoter is “specific for auditory hair cells” [0364].

Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, rAAV expression vectors, and gene therapy methods. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 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 ___, 82 USPQ2d at 1396.

Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first promoter driving expression of an otoferlin transgene, as taught/disclosed by Alemi, Simons et al, and Boye et al, with a second promoter, to wit, a Myo15 promoter, as disclosed by Petit et al, in a recombinant AAV vector system expressing otoferlin isoform 5 with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
An artisan would be motivated to substitute a first promoter driving expression of an otoferlin transgene with a second promoter, to wit, a Myo15 promoter, as disclosed by Petit et al, in a recombinant AAV vector system expressing otoferlin isoform 5 because:
a) Alemi taught a desire to express OTOF from the dual rAAV vector system in the inner hair cells in vivo;
b) Simons et al disclosed Otoferlin expression in the inner ear hair cells (e.g. pg 135, lines 22-23), whereby the promoter is capable of driving expression of the protein in choclear hair cells (e.g. pg 161, lines 28-29), e.g. a Myo7A or Myo6 promoter (e.g. pg 164, lines 21-23);
c) Boye et al successfully demonstrated Otoferlin expression in the OTOF KO-rescued mice inner ear hair cells (e.g. pg 4, Figure 8 legend); and
d) Petit et al disclosed the use of a Myo15 promoter (e.g. [0210] to drive expression of a desired protein in auditory neurons or hair cells (e.g. [0267]), as the Myo15 promoter is “specific for auditory hair cells” [0364].
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 5, Aurrichio et al disclosed wherein the first recombinogenic region and/or the second recombinogenic region is an AP gene fragment (e.g. Figure 1, hybrid AP).
Simons et al disclosed wherein the first recombinogenic region and/or the second recombinogenic region is an AP gene fragment (e.g. pg 218, Example 19; Figures 1-2).
Boye et al disclosed wherein the first recombinogenic region and/or the second recombinogenic region is an AP gene fragment (e.g. Figure 1A, 1B, 2).
With respect to Claims 6-7, Boye et al disclosed SEQ ID NO:3, which is 100% identical to instant SEQ ID NO:51 (search results available in SLIC).
With respect to Claim 22, Aurrichio et al disclosed wherein
the first vector comprises a first inverted terminal repeat (ITR) sequence 5' of the promoter and a second ITR sequence 3' of the recombinogenic region, and
the second vector comprises a first ITR sequence 5' of the recombinogenic region and a second ITR sequence 3' of the poly(A) sequence (e.g. Figure 1, hybrid AP).
Simons et al disclosed wherein
the first vector comprises a first inverted terminal repeat (ITR) sequence 5' of the promoter and a second ITR sequence 3' of the recombinogenic region, and
the second vector comprises a first ITR sequence 5' of the recombinogenic region and a second ITR sequence 3' of the poly(A) sequence (e.g. Figures 1-2).
Boye et al disclosed wherein
the first vector comprises a first inverted terminal repeat (ITR) sequence 5' of the promoter and a second ITR sequence 3' of the recombinogenic region, and
the second vector comprises a first ITR sequence 5' of the recombinogenic region and a second ITR sequence 3' of the poly(A) sequence (e.g. Figures 1A, 1B, 2).
With respect to Claim 2, Aurrichio et al disclosed wherein the first AAV vector and the second AAV vector comprise an AAV1 capsid (e.g. [0137], AAV2/1, meaning AAV2 genome, AAV1 capsid).
Simons et al disclosed wherein the first AAV vector and the second AAV vector comprise an AAV1 capsid (e.g. pg 182, line 29; pg 197, line 5).
Boye et al disclosed wherein the first AAV vector and the second AAV vector comprise an AAV1 capsid (e.g. pg 15, line 5).
With respect to Claim 8, Simons et al disclosed the OTOF polynucleotide encodes OTOF isoform 5 (e.g. pg 94, line 6, isoform e; pg 95, lines 23-25, NM_001287489.1), which is considered to be the same or substantially the same (syn. variant thereof) of instant SEQ ID NO:1.
Boye et al disclosed the OTOF polynucleotide encodes OTOF isoform 5 (e.g. pg 7, line 13, NM_001287489.1), which is considered to be the same or substantially the same (syn. variant thereof) of instant SEQ ID NO:1.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Instant specification fails to disclose an element of criticality for the OTOF-5 encoded by instant SEQ ID NO:1, as opposed to the OTOF-5 amino acid sequence previously recognized by the ordinary artisans, e.g. NM_001287489.1.
Nevertheless, Simons et al SEQ ID NO:5 is 100% identical to instant SEQ ID NO:1 (search results available in SLIC).
With respect to Claim 11, instant specification discloses that SEQ ID NO:2 is the nucleotide sequence of NM_001287489.1 (e.g. Table 2, pgs 25-26).
Nevertheless, Simons et al SEQ ID NO:11 is 100% identical to instant SEQ ID NO:2 (search results available in SLIC).
With respect to Claims 13-14, 17-18, and 21, Alemi taught the first vector encoded 2.8kb of the “5’ half” of the OTOF cDNA, and the second vector encoded 3.2kb of the “3’ half” of the OTOF cDNA.
SEQ ID NO:1 is 1997 amino acids in length, and thus the 2.8kb 5’ half and the 3.2kb 3’ half would roughly correspond to amino acids 1-933, and amino acids 934-1997, respectively.

Simons et al disclosed the first vector encodes:
a 5’ OTOF cDNA, nucleotides 1469-3988 of SEQ ID NO:41 (e.g. pg 138, lines 18 and 30), which corresponds to amino acids 1-841 of instant SEQ ID NO:1, as shown below:
KSYPERRLRGVLEELSCGCHRFLSLSDKDQGRSSRTRLDRERLKSCMRELESMGQQAKSLRAQVKRHTVRDKLRSCQNFLQKLRFLADE//.
Simons et al disclosed the second vector encodes:
a 3’ OTOF cDNA, nucleotides 130-3450 of SEQ ID N:39 or nucleotides 53-3463 of SEQ ID NO:40 (e.g. pg 138, line 6), which corresponds to amino acids 842-1997 of instant SEQ ID NO:1, as shown below:
//PQHSIPDVFIWMMSNNKRIAYARVPSKDLLFSIVEEELGKDCAKVKTLFLKLPGKRGFGSAGWTVQAKLELYLWLGLSKQRK……
EAEKNPVGLARNEPDPLEKPNRPDTAFVWFLNPLKSIKYLICTRYKWLIIKIVLALLGLLMLALFLYSLPGYMVKKLLGA*.

Boye et al disclosed the first vector encodes:
a 5’ OTOF cDNA, nucleotides 1153-3600 of SEQ ID NO:1 (e.g. Figure 3A), which corresponds to amino acids 1-802 of instant SEQ ID NO:1, as shown below:
NDVQEMIKTEKSYPERRLRGVLEELSCGCHRFLSLSDKDQGRSSRTRLDRERLKSCMREL//.
Boye et al disclosed the second vector encodes:
a 3’ OTOF cDNA, 565-4095 of SEQ ID NO: 2 (e.g. Figure 3B), which corresponds to amino acids 803-1997 of instant SEQ ID NO:1, as shown below:
//ESMGQQAKSLRAQVKRHTVRDKLRSCQNFLQKLRFLADEPQHSIPDVFIWMM...
LEKPNRPDTAFVWFLNPLKSIKYLICTRYKWLIIKIVLALLGLLMLALFLYSLPGYMVKKLLGA*.

Boye et al disclosed the first vector encodes:
a 5’ OTOF cDNA, nucleotides 1153-3558 of SEQ ID NO:14 (e.g. Figure 13), which corresponds to amino acids 1-802 of instant SEQ ID NO:1, as shown below:
NDIQEMIKTEKSYPERRLRGVLEELSCGCCRFLSLADKDQGHSSRTRLDRERLKSCMREL//
Boye et al disclosed the second vector encodes:
a 3’ OTOF cDNA, nucleotides 565-4152 of SEQ ID NO:15 (Figure 14). which corresponds to amino acids 803-1997 of instant SEQ ID NO:1, as shown below:
//ENMGQQARMLRAQVKRHTVRDKLRLCQNFLQKLRFLADEPQHSIPDIFIWMM…
EKPNRPDTSFIWFLNPLKSARYFLWHTYRWLLLKLLLLLLLLLLLALFLYSVPGYLVKKILGA*

1-802//803-1997 (Boye et al)
1-841//841-1997 (Simons et al)
1-933//934-1997 (Alemi)
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Instant specification fails to disclose an element of criticality for the N-terminal OTOF-5 being amino acids 1-802 of SEQ ID NO:1 and the C-terminal OTOF-5 being amino acids 803-1997 of SEQ ID NO:1, as disclosed by Boye et al, as opposed to the 1-841//841-1997 (Simons et al) and/or 1-933//934-1997 (Alemi) pairings.
With respect to Claim 34, Aurrichio et al disclosed wherein the dual vector pharmaceutical composition may be administered intravenously, intramuscularly, subcutaneously, or parenterally (e.g. [0086]), and thus would increase expression of the vector-encoded therapeutic protein in one or more cells in the subject.
Simons et al disclosed wherein the dual vector pharmaceutical composition may be administered intravenously, intramuscularly, subcutaneously, or parenterally (e.g. pg 31, lines 2-4), and thus would increase expression of the vector-encoded OTOF-5 protein in one or more cells in the subject.
Boye et al disclosed wherein the dual vector pharmaceutical composition may be administered intravenously, intramuscularly, subcutaneously, or parenterally (e.g. pg 19, lines 7-9), and thus would increase expression of the vector-encoded OTOF-5 protein in one or more cells in the subject.
See discussion above per 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as it regards the subject “in need thereof”.
With respect to Claim 35, Simons et al disclosed a working example (Examples 8-9), wherein the dual rAAV-OTOF vector pharmaceutical composition is administered to a hearing loss mouse subject directly into the scala tympani at a dose of about 3x10^8 to 3x10^9 vector genomes/ear.
Boye et al disclosed a working example (pgs 34-35, joining para), wherein the dual rAAV-OTOF vector pharmaceutical composition is administered to a hearing loss mouse subject directly into subject’s ear via round window membrane injection at a dose of about 6x10^9 vector genomes/ear.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.

Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.

8. Claims 1-8, 11, 13-14, 17-18, 21-22, and 34-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. U.S. Patent 11,660,353 in view of Alemi (2012; of record in IDS) in view of Simons et al (WO 18/039375; of record in IDS), Boye et al (WO 18/204734; of record in IDS), and Petit et al (U.S. 2018/0055908).
‘353 claims a dual rAAV vector system comprising a Myo15 promoter (SEQ ID NO:36) operably linked to a nucleic acid sequence encoding an Otoferlin (OTOF) protein.
SEQ ID NO:36 naturally comprises instant SEQ ID NO:7, SEQ ID NO:9, and SEQ ID NO:10, SEQ ID N:14, SEQ ID NO:15, and nucleotides 291-965 of instant SIN:21(search results available in SLIC).
‘353 does not claim the specific OTOF-5 embodiments of the instant claims.
However, as discussed above, Alemi, Simons et al, and Boye et al fulfill such limitations.
Thus, the instant claims are considered obvious variants of the ‘353 patented claims.

9. Claims 1-8, 11, 13-14, 17-18, 21-22, and 34-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. U.S. Patent 12,233,136 in view of Alemi (2012; of record in IDS) in view of Auricchio et al (U.S. 2016/0076054), Simons et al (WO 18/039375; of record in IDS), Boye et al (WO 18/204734; of record in IDS), and Petit et al (U.S. 2018/0055908).
‘136 claims a nucleic acid vector comprising a Myo15 promoter (SEQ ID NO:13) operably linked to a nucleic acid encoding OTOF.
SEQ ID NO:13 naturally comprises instant SEQ ID NO:7, SEQ ID NO:9, and SEQ ID NO:10, SEQ ID N:14, SEQ ID NO:15, and nucleotides 291-965 of instant SIN:21(search results available in SLIC).
‘136 does not claim the specific OTOF-5 embodiments of the instant claims.
However, as discussed above, Alemi, Simons et al, and Boye et al fulfill such limitations.
Thus, the instant claims are considered obvious variants of the ‘136 patented claims.

10. Claims 1-8, 11, 13-14, 17-18, 21-22, and 34-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. U.S. Patent 12,252,520 in view of Alemi (2012; of record in IDS) in view of Auricchio et al (U.S. 2016/0076054), Simons et al (WO 18/039375; of record in IDS), Boye et al (WO 18/204734; of record in IDS), and Petit et al (U.S. 2018/0055908).
‘520 claims an rAAV vector comprising a Myo15 promoter (SEQ ID NO:15) operably linked to a nucleic acid encoding OTOF.
SEQ ID NO:15 naturally comprises instant SEQ ID NO:7, SEQ ID NO:9, and SEQ ID NO:10, SEQ ID N:14, SEQ ID NO:15, and SIN:21(search results available in SLIC).
‘520 does not claim the specific OTOF-5 embodiments of the instant claims.
However, as discussed above, Alemi, Simons et al, and Boye et al fulfill such limitations.
Thus, the instant claims are considered obvious variants of the ‘520 patented claims.

Conclusion
11. Claims 1-8, 11, 13-14, 17-18, 21-22, and 34-35 are rejected.
Claims 28 and 30-31 are objected to for reciting allowable subject matter, but being dependent upon rejected claims.
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KEVIN K. HILL
Examiner
Art Unit 1638

/KEVIN K HILL/ Primary Examiner, Art Unit 1638