DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on 05/26/2023. Claims 1-14 are currently pending.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
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, publication No. EP-4008788-A1, fails 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, because the only supporting descriptions of the claimed “method for treating sensorineural hearing loss in a subject in need thereof…” in claim 15 of the prior application are descriptions of in vivo delivery of the claimed compositions to mouse models of sensorineural hearing loss in ¶[0098], ¶[0105], and figure descriptions for FIG. 14 in [0086] of the prior application publication EP-4008788-A1. FIG. 14 demonstrates that lentiviral MYO7A treatment in the inner ear rescues hearing loss in homozygous Shaker-1-/- mice, however it is not included in, or withdrawn from, the instant application. Furthermore, a different working example using heterozygous Shaker-1+/- mice as therapeutic candidates is included in the instant application and there is no support for this working example in the specification of the prior application.
Finally, the inventors later published a negative functional recovery data that directly contradicts the findings shown in FIG. 14 of EP-4008788-A1, and their research article by Schott et al. in 2023 teaches that the lentiviral vector-based MYO7A gene therapy failed to rescue hearing loss in homozygous Shaker-1-/- mice based on auditory brain stem response (ABR) data (FIG. 7A, page 3513; Schott et al. Third-generation lentiviral gene therapy rescues function in a mouse model of Usher 1B. Mol Ther. 2023 Dec 6;31(12):3502-3519. doi: 10.1016/j.ymthe.2023.10.018. Epub 2023 Oct 31.). This indicates that the method claim 15 in the prior application, EP-4008788-A1, was not enabled and was acknowledged by the inventors by not including the related working example in the instant application at the time of filing.
Evidence for vestibular functional improvements as a result of the lentiviral MYO7A gene therapy, which is consistently presented as working examples in both the prior and the instant applications, is irrelevant as the claims direct to a method to treat “sensorineural hearing loss”, which is a distinct disease from vestibular balance disorders despite their close anatomical proximity in the inner ear.
Accordingly, claims 1-14 of the instant applications, which direct to "a method for treating sensorineural hearing loss in a subject in need thereof…” are not entitled to the benefit of the filing date of the prior application.
Specification
Brief Description of the Drawings for FIG. 12 on page 42, line 21 and 23, showing references to colors “(red)” and “(blue)” is objected to because the drawings are in black and white. Appropriate correction is required.
Drawings
The FIGs. 1-19 are objected to.
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for FIGs. 1-19 are preceded by the word "Fig." instead of the abbreviation "FIG.".
37 CFR 1.84(p)(1) states “Reference characters (numerals are preferred), sheet numbers, and view numbers must be plain and legible, and must not be used in association with brackets or inverted commas, or enclosed within outlines, e.g., encircled. They must be oriented in the same direction as the view so as to avoid having to rotate the sheet.”
In the current case, FIG. 1. Has reference characters (e.g. A, B.) oriented sideways while the sheet numbers (1/16) and view numbers (FIG. 1.) oriented upright without rotating the page.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-9, 13 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 2 is rejected for using “the” instead of “a” with “LDL-receptor”, “SLC1A5-receptor”, “Pit1/2-receptor” and “PIRYV-G-receptor” due to lack of antecedent basis because these receptors are mentioned for the first time in claim 2.
Claim 6 is rejected over the phrase "such as", which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 8 is rejected for reciting “The method of claim 1, wherein the cargo sequence…” due to lack of antecedent basis because “cargo sequence” is not recited in claim 1, instead it is recited in claim 7. The broadest reasonable interpretation of claim 1 in its current form includes empty viral particles with no RNA genome and/or a cargo sequence.
Claims 3, 7-9, 13 are also rejected for reciting “selected from the group comprising…” instead of “consisting”. The phrase “comprising” renders the claim an open-ended Markush Language which suggests that the group as claimed is not limited only to the members recited in the group. Therefore, it is unclear what the other members of the group are from this the selection may be made. Accordingly, the metes and bounds of the Markush grouping are unclear.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 7 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), the first paragraph, for failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USP USPQ2d at 1406.
Claim 7 directs to a lentiviral vector (LV)-based gene therapy for sensorineural hearing loss (SNHL). The claimed LV comprises a cargo sequence that encodes a broad genus of therapeutics that encompass diverse structures, such as proteins, microRNAs (miRNA), shRNAs, long non-coding RNAs (lncRNAs), and single guiding RNAs (sgRNAs). Some of these cargo sequences are intended to encode normal functional proteins that support mechanotransduction (TMC1), cell adhesion and structure (PCDH15), ion homeostasis (KCNQ1), mitochondrial health/mitophagy (GIPC3, TIMM8A), gap junction formation (GJB2/Connexin 26), and general auditory sensory signaling, affecting hair cells, spiral ganglion neurons, and supporting structures, leading to hearing impairment through various processes from impaired sound conversion to cell death. Others are intended for mediating RNA interference and CRISPR-based genome editing. The diversity in structure and therapeutic mechanisms require sufficient representation in the selection of working models. Using human MYO7A, a structural protein coding gene, as the sole working model or a preferred embodiment is insufficient to represent the extremely diverse structures that underly diverse pathogenesis progression timelines, distribution patterns within the inner ear cell types, and functional deficit mechanisms, which would impact the dosing, target cell types, timing, and therapeutic window.
Moreover, diverse molecular types are proposed to include in the extremely broad genus of nucleic acid-based therapeutics including vastly different molecules from those protein-coding genes represented by MYO7A, such as shRNA or miRNA-directed RNAi, lncRNA-guided regulation, or sgRNA-directed genome editing. These diverse structures and distinct therapeutic actions clearly point to complex species that not any single molecule type, e.g. an siRNA, an shRNA, a miRNA, or an sgRNA could satisfactorily represent because each distinct chemical structure begets unique biological function through unique mechanisms, with distinct dosing, timing, vehicle, and delivery requirements. The involvement of human immunity against the different therapeutic compositions poses another layer of diverse challenges for distinct therapeutic compositions that further highlight the extreme broad nature and high levels of unpredictability of the claimed genus and species of therapeutics.
Furthermore, a high degree of variation is observed with respect to the diverse theoretical embodiments. A recent review article by Das & Manor teaches that despite varied levels of success, viral vector-based gene therapy, RNAi, and CRISPR gene editing, each strategy has unique advantages and disadvantages with high levels of unpredictability in durability/longevity of therapeutic benefits, limited therapeutic window, off-targeting, and the overall challenges interpreting data from mouse models which differ drastically from human conditions (Das S, Manor U. Gene therapy for hearing loss: challenges and the promise of cellular plasticity and epigenetic modulation. Front Neurol. 2024 Dec 11;15:1511938).
Lastly, new genetic mutations underlying SNHL have been continuously discovered over the years, and diverse mutation types with specific loci on affected genes have been recently identified. Walls et al. compiled comprehensive hereditary hearing loss genetic profiles in an online database (accessed Dec 2025; Walls WD, Azaiez H, Smith RJH. Hereditary Hearing Loss Homepage.
hereditaryhearingloss.org; screen shots in pdf provided), which teaches that distinct types of mutations that led to non-syndromic or syndromic hereditary hearing loss could exist in the same gene, e.g. mutations in the DFNB2 lotus of MYO7A leads to Autosomal Recessive Nonsyndromic Hearing Loss, but mutations in the DFNA11 lotus of MYO7A leads to Autosomal Dominant Nonsyndromic Hearing Loss. Although the gene replacement approach of delivering normal MYO7A gene products to the affected inner ear cells is potentially beneficial for hearing loss caused by Autosomal Recessive Nonsyndromic mutations in MYO7A, where biallelic (two copies) mutation leads to SNHL symptoms, it's unclear how it would help alleviate the symptoms of Autosomal Dominant Nonsyndromic Hearing Loss, where a single copy of mutated MYO7A gene would lead to symptoms. The presence of the normal MYO7A gene doesn’t alleviate the symptoms unless the mutated gene products are removed. Gene therapy approaches that target only the mutated gene for removal without impacting the normal gene product, i.e. gene suppression, are not discussed in the instant application. Hence, the specification fails to provide support for the claimed functions with structure. Simply reciting technical features such as miRNA, shRNA, lncRNA, or gRNA by molecule type name as a cargo sequence does not equate to providing sufficiently detailed and credible written descriptions that guide persons of ordinary skill in the art to execute complex custom therapeutic strategies with reasonable expectation in success for each unique mutation underlying Sensorineural Hearing Loss.
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 7 is overly broad with insufficient evidence of possession at the time of filing to one with ordinary skill in the art. Therefore, claim 7 does not meet the written description requirement.
Claim Rejections - 35 USC § 112 Scope of Enablement
Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of using a 3rd generation lentiviral vector encoding human MYO7A to treat SNHL caused by mutations in Myo7a/MYO7A, the working example using Shaker-1 transgenic mouse model does not reasonably provide enablement for treating SNHL simply by using a 3rd gen lentiviral vector alone without any therapeutic molecule, or for targeting any gene other than MYO7A. The specification does not enable any person ordinarily skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
The claimed invention directs to similar in vivo methods of 3rd generation lentiviral vector-mediated gene therapy treating SNHL in a subject in need thereof. Thus, the methods require a reliable implementation of: i) providing sufficient titer of said 3rd generation lentiviral vector to the inner ear of a subject suffering from mutations that render the subject susceptible or lead to SNHL; ii) evaluating the efficacy of required amount of the reagent; iii) in any subject in need thereof with an affected inner ear.
The Breadth of the Claims
The scope of the independent claim 1 limits the method to delivering a broad group of compositions comprising a 3rd generation lentiviral vector without limiting the genetic contents of the lentiviral vector. Based on the broadest reasonable interpretation, these vectors could comprise empty lentiviral vectors without either a viral RNA genome, or a cargo sequence, or both. The specification further describes that “the composition of the invention may furthermore comprise growth factors, e.g. a neurotrophic factor such as BDNF, GDNF, NT3 or IGF” on page 14 line 28-30, suggesting that the scope of claim 1 is extremely broad as the composition may even include additional components such as proteins in addition to lentiviral vectors as claimed. There is no limitation as to what else may comprise the composition aside from the 3rd generation lentiviral vectors with a pseudotyped viral envelope glycoprotein capable of binding to a receptor expressed on a cell in the inner ear of a subject.
The scope of dependent claim 8 encompasses distinct types of genes. Walls et al. teaches that some of these genes are associated with mutations that contribute to the symptoms of either syndromic or non-syndromic hearing loss, and involve mutations that are dominant or recessive, autosomal, sex-linked, mitochondrial, or non-cochlear related (i.e. auditory neuropathy spectrum disorder, ANSD; Walls WD, Azaiez H, Smith RJH. Hereditary Hearing Loss Homepage. hereditaryhearingloss.org; screen shots in pdf provided). In addition, the specification indicates that cell phenotype reprogramming target genes include transcription factors or neurotrophic factors without any limitation on the number and variety of combinations (specification, page 14 lines 21-30), i.e. the composition could comprise any number and variety of all of the above genes. Furthermore, the specification contemplates the options to incorporate protein degraders or destabilization domains to serve as safety measures against cytotoxicity in page 14 lines 31 & 32, page 15 lines 1-14. Lastly, the specification indicates the cargo sequence is an “intact copy” of mutated genes in page 14 line 9 and “preferably is a complimentary DNA (cDNA)” on page 15 line 15. This further indicates the extreme breadth of claim 8 in that alternative splicing of some intact gene sequences could further diversify the claimed composition. Despite the references to these options in the specification, no working example was offered to support the breadth of the claims. Accordingly, claims 1 and 8 are unduly broad.
Guidance of the Specification
The specification is silent as to: what treatment outcomes should be reasonably expected by persons of ordinary skill in the art (POSITAs) for empty lentiviral vectors claimed by claim 1; what adjustments are necessary to optimize the lentiviral vector packaging efficiency for any of the 106 genes, aside from MYO7A, listed in claim 8 in order to achieve appropriate expression profiles in the relevant cell types in the inner ear of a subject in need thereof; what design adjustments are needed for multiple cargo sequences to be expressed by the same lentiviral vector as the suggested alternatives; what levels of success should POSITAs reasonably expect to achieve following the disclosure when it comes to incorporating shRNA, miRNA, sgRNA, lncRNA, and degradation/destabilization domains in the cargo sequence; how to ensure the performance of incorporating intact genes with alternative splicing gene expression profiles; or how to achieve inner ear cell phenotype reprogramming or gene editing without off targeting and side effects inherent with respective technology platforms.
In the only example described in Specification on page 44 line 25 – page 52 line 12, several envelope glycoproteins (tables on page 46 & 47) and target genes (Table 1 on pages 48 & 49) were shown to generate lentiviral particles with sufficient titer concentrations. However, only MYO7A-based lentiviral vectors were produced and validated for in vivo delivery that resulted in transgene expression in the intended inner ear cell types and prevention of SNHL progression in heterozygous Shaker-1+/- mice based on functional hearing assay, i.e. ABR threshold measurements (FIG. 19). Given the diversity in how the 107 candidate target genes (including MYO7A) listed in claim 8 may contribute to normal hearing function, this example is not seen as working example for target genes, other than MYO7A, with distinct sequence, epigenomic context, structure, and functions.
Regarding the challenges of interpreting mouse models for human SNHL, a review article by Das and Manor (2024) teaches that: 1). The normal gene expression initiation time, the normal gene mature expression time, and the phenotypic manifestation time determines the critical time window for attempting gene therapy targeting (Das S, Manor U. Gene therapy for hearing loss: challenges and the promise of cellular plasticity and epigenetic modulation. Front Neurol. 2024 Dec 11;15:1511938). This critical window of timing differs from gene to gene; 2). “The heterochrony between mouse and human auditory system development. While human cochlear maturation is well-advanced at mid-gestation and complete at birth, mice are born deaf and their cochlea reach maturation around postnatal day 20 (P20). Most successful interventions in mouse models have been performed during the early neonatal period (P0–P2), which corresponds to embryonic stages in humans. This timing disparity means that many proof-of-concept studies in mice are assessing prevention rather than restoration of hearing impairment, as interventions performed shortly before hearing onset (P8–P11) have been ineffective” (Das & Manor, 2024; On page 04, left column, second ¶). The example of the instant application used P04 as the time point for providing lentiviral vectors encoding normal MYO7A in order to achieve prevention of the progression of hearing loss in Shaker-1+/- mice. The same guidance may not apply to a different target gene in a distinct transgenic mouse model or in human subjects.
Das & Manor further teaches: “However, given the different developmental timelines, these interventions in mice would correspond to embryonic stages in humans. This discrepancy highlights the need for developing strategies that can address fully matured cochlea, which in mice would require interventions from approximately P30 onwards. To date, genuine restoration of hearing impairment in mature systems have been achieved in only two mouse mutants: Vglut3−/− and Otof−/−, both of which involve defects in inner hair cell synaptic vesicle proteins. Notably, human clinical trials with dual AAV-mediated delivery of Otoferlin have also shown success, but raise yet another critical window of therapeutic success that cochlear implant research has already anticipated: If hearing is not restored by the age of 5 or 6, it is unlikely that auditory language processing will be possible.” (Das & Manor, 2024; Page 04, left column, 3rd ¶).
To one with ordinary skill in the art, the example in the instant application is not seen as working examples of treating SNHL that involve diverse genetic mutations other than MYO7A autosomal recessive mutations. Conversely, it is only enabling for treating hearing loss in heterozygous Shaker-1 mouse models or potentially humans with SNHL as a result of non-syndromic autosomal recessive mutations in MYO7A.
The State of the Prior Art
With regard to the state of the art, a review article by Omichi et al. (2019) published before the effective filing date of the instant application teaches that diverse viral vectors have been used in early exploratory studies to treat SNHL, including lentiviral vectors (Omichi et al. Gene therapy for hearing loss. Hum Mol Genet. 2019 Oct 1;28(R1):R65-R79). By 2024-2025, review articles by Lu et al. (2024) and Elbagoury (2025) confirm that at the current state of art, only AAV vectors-based experimental gene therapies are under clinical investigation (Lu et al., Say No to deafness: perspective of gene therapy for sensorineural hearing loss. Acta Otolaryngol. 2025 Feb;145(2):150-155; Elbagoury NM. Hearing loss: a global view for gene therapy approaches and challenges. Eur J Pediatr. 2025 Aug 27;184(9):578).
Montini et al. calls for caution and balancing for the use of lentiviral vectors in gene therapies by outlining safer design principles in a recent article (Montini et al., Balancing efficacy and safety in lentiviral vector-mediated hematopoietic stem cell gene therapy.Mol Ther. 2025 Jan 8;33(1):6-8. doi: 10.1016/j.ymthe.2024.12.028. Epub 2024 Dec 26).
The success of some viral vectors in the clinical settings and the recent emerging views of the long-term safety considerations for lentiviral vectors specifically paints a picture of urgent need in caution and care when evaluating the designs and executions of lentiviral vector-based gene therapies.
The Level of Predictability in the Art
As described in the specification of the current application (pages 3-5), the numerous early efforts in using lentiviral vectors to develop gene replacement therapies in the inner ear of animal models have not demonstrated the therapeutic potentials, highlighting the unpredictability of the art.
In the inventors’ own hands, the experimental efforts have yielded unpredictable results. In the prior application, publication No. EP-4008788-A1, ABR threshold improvements were shown for homozygous Shaker-1-/- mouse models. Its removal in view of the article, Schott et al., by the inventors in 2023 confirms that those observations are no longer considered valid by the applicant, hence the exclusion from the instant application (FIG. 7A, page 3513; Schott et al. Third-generation lentiviral gene therapy rescues function in a mouse model of Usher 1B. Mol Ther. 2023 Dec 6;31(12):3502-3519. doi: 10.1016/j.ymthe.2023.10.018. Epub 2023 Oct 31.). This discrepancy between the prior application and the instant application indicates the highly unpredictable nature of investigation in this art.
In the review articles by Lu et al. (2024) and Elbagoury (2025), various gene therapy approaches with diverse gene mutation profiles as therapeutic candidates are compared and only select few were able to advance to the clinical testing stage, and there is no FDA approved gene therapy for SNHL yet. While AAV-based therapies targeting OTOF show great promise, the same cannot be assessed for other viral vector designs or other potential target genes. There is very high level of unpredictability in the art.
The Quantity of Experimentation necessarily Needed
In light of the high level of unpredictability in the art, and the limited amount of direction provided by the inventor for targeting genes other than Myo7a in mouse models, and the noticeable absence of working examples other than gene replacement therapies as a preventive measure against SNHL progression, the quantity of experimentation necessarily needed to make or use the invention as claimed, especially with respect to treating diverse clinical types of SNHL with complex genetic mutation profiles, based on the disclosure is considerably high. For example, it would be necessary for one skilled in the art to identify optimal cargo sequences for select therapeutic targets, dosing timing and schemes, and timepoints to make or use the invention to treat clinical indications of hereditary or ototoxic subtypes of SNHL. There would be an unreasonable amount of experimentation required by a person of ordinary skill in the art.
Conclusion of 35 U.S.C. 112(a) Enablement Analysis
After applying the Wands factors and analysis to claims 1 and 8, taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 1 and 8 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Claims 2-14 are also rejected for depending from claim 1 and failing to remedy the lack of enablement therein.
Claim Rejections - 35 USC § 112 Improper Markush Grouping
Claim 8 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of cargo sequence is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The list of genes are diverse in their roles in the etiology of SNHL and only some of these genes may lead to beneficial gene replacement therapy in a cargo sequence delivered by the claimed 3rd generation lentiviral vector. Some of these mutated genes need gene suppression approaches where providing a normal copy of the mutated gene using the 3rd generation lentiviral vectors do not alleviate the symptoms of SNHL. See Walls et al. (accessed Dec 2025; Walls WD, Azaiez H, Smith RJH. Hereditary Hearing Loss Homepage. hereditaryhearingloss.org; screen shots in pdf provided) to understand why the list of 107 genes in claim 8 is an improper Markush Grouping. Walls et al. teaches that distinct types of mutations that led to non-syndromic and syndromic hereditary hearing loss could exist in the same gene, e.g. mutations in the DFNB2 lotus of MYO7A leads to Autosomal Recessive Nonsyndromic Hearing Loss, but mutations in the DFNA11 lotus of MYO7A leads to Autosomal Dominant Nonsyndromic Hearing Loss. Since gene replacement approaches of delivering normal MYO7A gene products to affected inner ear cells is beneficial for Autosomal Recessive Nonsyndromic Hearing Loss, where biallelic (two copies) mutation in MYO7A leads to SNHL symptoms. Symptoms of Autosomal Dominant Nonsyndromic Hearing Loss, where a single copy of mutated MYO7A gene would lead to symptoms. requires gene suppression as a therapeutic strategy, not by providing the normal copy of the gene because it’s already in place and cannot stop the symptoms caused by the mutated copy. In addition, some of these cargo sequences are intended to encode normal functional proteins that support mechanotransduction (e.g. TMC1), cell adhesion and structure (e.g. PCDH15), ion homeostasis (e.g. KCNQ1), mitochondrial health/mitophagy (e.g. GIPC3, TIMM8A), gap junction formation (e.g. GJB2/Connexin 26), and general auditory sensory signaling.
Furthermore, transcription factors responsible for reprogramming other types of cells in the inner ear into hair cells or neurotrophins responsible for nurturing the regeneration of damaged hair cells are not themselves responsible for the development of SNHL. These genes contribute to distinct therapeutic mechanisms from the genes responsible for SNHL etiology. These are not alternatives that share common structure or serve similar functions.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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, 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 for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claims 1-3, 6-11, 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (Neural Regen Res. 2013 Jun 15;8(17):1551-9; Cited on the IDS submitted on 05/26/2023) in view of Hashimoto et al. (2007; Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B. Gene Ther. 2007 Apr;14(7):584-94.; Cited on the IDS submitted on 05/26/2023), and in further view of Akil et al. (2019; Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model, Proc. Natl. Acad. Sci. U.S.A. 116 (10) 4496-4501).
Pan et al. (2013) teaches that a 3rd generation lentiviral vector pseudotyped with VSVG comprising a cargo sequence encoding reporter gene green fluorescent protein and an Atoh1 transgene, commonly associated with sensorineural hearing loss (SNHL) in certain types of genetic mutations, can be successfully delivered to the inner ear of a subject (normal rats with no SNHL) via local microinjections at sufficiently high titers (3x108 TU/ml) and led to reporter and transgene expression in inner ear cells including inner and outer hair cells, which in turn augments Myo7a expression in hair cells, without damage to the hair cells or cause loss of hearing function based on ABR threshold measurement (Pan et al. 2013; page 1552, right column, second¶ and Figure 1).
Pan et al. (2013) does not teach using the method to treat SNHL in an animal model of SNHL, nor does it teach targeting Myo7a in the animal model.
Hashimoto et al. (2007; on IDS submitted 05/26/2023) teaches that gene replacement therapy using a 3rd generation, self-inactivating lentiviral vector without a Woodchuck hepatitis virus posttranscriptional regulatory element, can be used to effectively deliver MYO7A cDNA (6962bp) to shaker-1 mouse models for Usher syndrome, but to the retinal cells (page 591, left column last ¶, right column first ¶).
However, Hashimoto et al. (2007) does not teach the use for SNHL therapy and only demonstrates the feasibility of lentiviral vector-based MYO7A gene delivery to targeted cell types with no functional assessment (page 584, abstract)
Akil et al. (2019) teaches that viral vectors comprising cargo sequences that encode a full size otoferlin cDNA (~6kb in length) to treat a DFNB (Deafness, Autosomal Recessive) form of SNHL with functional evidence of improvements in hearing in mouse models (page 4497, Fig. 1, bottom of page; page 4500, Fig. 4, top of page).
All three prior arts share the same ultimate purpose, i.e. to identify a gene therapy strategy using commonly used viral vectors to deliver gene replacement therapies to DFNB type of symptoms related to SNHL (Usher syndrome involves both SNHL and retinal disorders).
Since the choice of dual AAV vector by Akil et al. (2019) is based on the need to deliver a large/long cargo sequence beyond the normal cargo capacity of a single AAV vector, like the human MYO7A cDNA in the example of the instant application, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan et al. (2013) or Hashimoto et al. (2007) to deliver large gene replacement cargo sequence of choice as claimed in the instant application, e.g. Otof/OTOF or Myo7a/MYO7A, to an appropriate transgenic mouse model to arrive at the same inventions disclosed in the instant application. Furthermore, the benefits of simplified viral vector designs and production for large cargo sequence delivery, such as OTOF or MYO7A, and the more durable transgene expression profile of lentiviral vectors in non-dividing cells would have been strong motivations for a POSITA to modify the inventions of Akil et al. (2019) by replacing the dual AAV vector system with the 3rd generation lentiviral vector system with refined features to boost efficacy, durability, and safety with a reasonable expectation for success.
Regarding claim 2, 3, and 6, Pan et al. (2013) teaches that a 3rd generation lentiviral vector (cited Dull et al. 1998 in Methods section, on page 1556, left column, last ¶) pseudotyped with a VSV-G envelope glycoprotein (mentioned “pseudotyping envelope vesicular stomatitis virus glycoprotein” in the first ¶ on page 1556, right column), which is capable of binding to a LDL receptor, can be used for local delivery to the inner ear for potentially therapeutic transgene product to be expressed in cell types relevant for SNHL in the inner ear of a subject.
Regarding claim 7, Pan et al. (2013) teaches that a 3rd generation lentiviral vector comprising a cargo sequence that is a protein coding gene by reciting “the Atoh1 cDNA was inserted into the unique Smal and KpnI sites of the pLenti-enhanced green fluorescent protein-Neo plasmid” on page 1556, right column, line 14-16.
Regarding claim 8, Pan et al. (2013) teaches that a 3rd generation lentiviral vector comprising a cargo sequence that encodes Atoh1 (see page and citation above), which is a highly conserved essential transcription factor and an ortholog of ATOH1 in humans, an alternative listed in the Markush group of the claim 8 of the instant application (Pan et al. 2013; Neural Regen Res. 2013 Jun 15;8(17):1551-9; Cited on the IDS submitted on 05/26/2023).
Regarding claim 9, Pan et al. (2013) teaches that a 3rd generation lentiviral vector derived from HIV-1 (by mentioning “human immunodeficiency virus-1 rev’ on page 1556, last ¶), can be used for local delivery to the inner ear for potentially therapeutic transgene product to be expressed in cell types relevant for SNHL in the inner ear of a subject.
Regarding claim 10, claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zufferey et al. (1997; Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol. 1997 Sep;15(9):871-5. doi: 10.1038/nbt0997-871) in view of Zufferey et al. (1998; Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 1998, 72, 9873–9880. Cited on IDS filed on 05/26/2023), and further in view of Dull et al. (A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998 Nov;72(11):8463-71. doi: 10.1128/JVI.72.11.8463-8471), all three of which collectively teach that a 3rd generation self-inactivating lentiviral vector encompasses all elements of limitations of claim 10 based on the specification of the instant application.
Zufferey et al. (1997), Zufferey et al. (1998), and Dull et al. (1998) collectively teach an improved conditional packaging system for lentiviral particles based on 4 plasmid constructs, incorporating a self-inactivating (SIN) safety feature, that became widely used by persons of ordinary skill in the art. All of the schematic features of a 3rd generation lentiviral vector provirus architecture in FIG. 1A of the instant application, have been featured in Zufferey et al. (1997, page 873, Figure 3), Zufferey et al. (1998, page 9875 FIG. 1 & page 9876 FIG. 3) and Dull et al. (1998, page 8469 FIG. 4). A recent review article by Poletti & Mavilio. (Poletti V, Mavilio F. Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases. Viruses. 2021 Aug 2;13(8):1526. doi: 10.3390/v13081526) visually summarized the collective designs (Poletti & Mavilio, 2021, page 4 of 14, Figure 1A, see below).
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Regarding claim 11, Pan et al. (2013) teaches that a 3rd generation lentiviral vector is able to transduce hair cells in the inner ear of a subject.
Regarding claim 13, Pan et al. (2013) teaches that round window microinjection can be a chosen route for administering a 3rd generation lentiviral vector-based composition to the inner ear of a subject.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (2013) in view of Hashimoto et al. (2007) and Akil et al., (2019) as applied to claim 1 above, and further in view of Bauche et al. (US20150182617A1, published in 2015).
Pan et al. (2013), Hashimoto et al. (2007), and Akil et al. (2019) do not teach pseudotyping lentiviral vectors using MARAV-G or COCV-G. However, Bauche et al. (US20150182617A1, published in 2015) teaches that MARAV-G and COCV-G are known in the art as alternative envelope glycoprotein for targeted transgene product delivery using lentiviral vectors Page 10, ¶[0083], Page 15, ¶[0155]).
Since different envelope glycoproteins bind to different cognate receptors on distinct cell types in the inner ear, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan et al. (2013) and Hashimoto et al. (2007) following the disclosure of Bauche et al. (2015) to improve on cell type-specific targeted transgene delivery and apply the therapeutic approach in Akil et al. (2019).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (2013) in view of Hashimoto et al. (2007) and Akil et al. (2019) as applied to claim 1 above, and further in view of Benskey & Manfredsson. (Benskey, M.J., Manfredsson, F.P. 2016 Lentivirus Production and Purification. In: Manfredsson, F. (eds) Gene Therapy for Neurological Disorders. Methods in Molecular Biology, vol 1382. Humana Press, New York, NY.).
Pan et al. (2013), Hashimoto et al. (2007) and Akil et al. (2019) do not teach the purification and concentration methods of the viral vectors used respectively. However, Benskey & Manfredsson (2016; pages 107-114) teaches that 3rd generation lentiviral vectors can be concentrated and purified using a variety of methods including ultracentrifugation, precipitation, etc., which are well known in the art. It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan et al. (2013) and Hashimoto et al. (2007), following the protocols of concentration and purification of lentiviral vectors described by Benskey & Manfredsson (2015) to achieve greater transduction efficiency using sufficiently high titers of lentiviral particles and apply the materials for therapeutic purpose following Akil et al. (2019)‘s directions to treat SNHL to arrive at the same inventions claimed by the instant application.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (2013) in view of Hashimoto et al. (2007) and Akil et al. (2019) as applied to claim 1 above, and further in view of Shaw & Cornetta (Design and Potential of Non-Integrating Lentiviral Vectors. Biomedicines. 2014 Jan 27;2(1):14-35; listed in IDS submitted on 05/26/2023).
Pan et al. (2013), Hashimoto et al. (2007), and Akil et al. (2019) do not teach the use of non-integrating lentiviral vectors.
However, Shaw & Cornetta (2014) discloses the strategy of constructing a non-integrating 3rd generation lentiviral vector (page 19, Figure 3).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan et al. (2013) and Hashimoto et al. (2007) using the methods described by Shaw & Cornetta (2014) to reduce the concern of insertional mutagenesis and oncogenesis associated with integrative lentiviral vectors, following the therapeutic applications directed by Akil et al. (2019) and arrive at the same claimed invention by the instant application.
Conclusion
No claims are allowed.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636