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
Claims 1-3, 6-7, 15-16, 18, 21, 25, 33, 42, 44-50 are pending.
Applicant’s election without traverse in the reply filed on June 4, 2026 of Group I, encompassing claims 1, 6-7, 15-16, 18, 21, 25 and 45-47, directed to methods of reducing nucleic-acid vector-induced toxicity in the inner ear is acknowledged. Applicant also elected an inhibitor of cell-mediated immunity, specifically an inhibitory nucleic acid comprising a gRNA targeting TNFRSF1A/B or TNFRSF13A/B. Applicant’s species election is made with traverse. Applicant argues that no undue examination burden exists by selecting “this species” (Reply, page 1). It is not clear what “this species” is referring to. It is noted that Applicant actually elected four different target genes TNFRSF1A, TNFRSF1B, TNFRSF13A, and TNFRSF13B. In any event, the requirement for a species election was based on lack of unity, which does not require a search and/or examination burden. Examiner will choose one of the 4 target genes recited above for the initial search and examination.
Claims 2-3, 33, 42, 44 and 48-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 18 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 6-7, 15-16, 21, 25 and 45-47 are under examination.
Specification
The use of the term CORALL, RNease, RiboCop, BioAnalyzer, Luna-FL, Gemcode and Cell Ranger, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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 16 and 21 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 16 recites “(c) the cellular de-targeting is an inhibitory nucleic acid… to a transduction-permissive gene”. The metes and bounds of “a transduction-permissive gene” are not clear. The Specification defines “transduction-permissive gene” as “an mammalian gene that is required for or that facilitates effective transduction of a viral vector into a mammalian cell” (page 13). However, this is not a clear-cut definition because it is not clear how far upstream of the transduction pathway the “facilitation” can go. For instance, viral uptake can be mediated by receptor-mediated endocytosis which is an ATP-dependent mechanism. So, in essence, even the glycolytic and aerobic respiration machinery that is required for ATP production can be interpreted as “facilitating” transduction. However, any inhibitory agent to glycolysis or aerobic respiration would surely be detrimental to the gene therapy that the vector is intended to deliver. As such it is not clear whether Applicant intended to include virtually any gene in the genus of “transduction-permissive gene”.
To overcome this rejection, it is suggested to recite a closed set of genes such as those recited on page 25 of the Specification.
Claim 21 is rejected for depending from claim 16 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6-7, 15, 25 and 45-47 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.
MPEP 2163.II.A3.(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.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “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.”
Claim 1 recites “an inhibitor of inflammatory or immune signaling”. “Inhibitor” represents a genus of molecules that are defined by their function of inhibiting the function and/or expression of a gene/protein/lipid that is involved in inflammation or immune signaling. Some such classes of inhibitors are listed in the specification: small molecule, peptide, antibody, or antigen-biding fragment, or nucleic acid (page 10). Regarding nucleic acid-based and CRISPR-based inhibitors, there is a known correlation between the structure of antisense molecules and/or guide RNAs and their inhibitory function, one skilled in the art could have predicted the structure of antisense and CRISPR guide molecules that have the claimed inhibitor function for a specifically recited gene. However, for the reasons described below, Applicants have not sufficiently described the genus of small molecules, peptides or antibodies that have the claimed inflammation and immune signaling inhibitory function such that one skilled in the art could have reasonably concluded applicants had possession of the genus as claimed.
Regarding antibodies and peptides, no peptide or antibody structures that inhibit any protein involved in inflammation and immune signaling are described in the Specification. A definition by function does not suffice to define the genus because it is only an indication of what the peptide or antibody does, rather than what it is. To provide adequate written description and evidence of possession of the claimed peptide and antibody inhibitor genera, the instant specification in view of the art must structurally describe representative peptides and antibodies that function as an inhibitor of inflammation or immune signaling, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
However, in this case the disclosure speaks to the function of the antibody and peptides and not to its structure, and do not disclose any structure or previously developed antibody or peptide by name.
A few therapeutic peptides and antibodies are known in the art that target immune signaling and inflammation, such as pembrolizumab and ipilimumba that targets PD-1 and CTLA-4 immune checkpoint proteins, but those are typically used in oncology settings. Rituximab targets CD20, but that is only to deplete B-cells in lymphomas. Adalimumab which targets TNF-a has been tested for treatment of autoimmune inner ear disease (Balouch et al., American Journal of Otolaryngology, (2022), 43(5), 103576). However, the few commercially available biologics that are known antibody inhibitors of inflammatory or immune signaling do not represent the scope of the genus as claimed, which can be interpreted as encompassing therapeutic peptides and antibodies to any gene/protein involved in inflammation and immune cell function.
Regarding small molecule inhibitors, similar to peptide and antibodies, the Specification fails to described the structure or list by name any small molecules that could potentially inhibit inflammatory or immune signaling in the inner ear triggered by nucleic acid delivery. Although there are known small molecule inhibitors, such as MCC950 that inhibits NLRP3 activation of the inflammasome can be used in the inner ear, they have been used specifically to treat autoimmune-linked hearing loss. Additionally, the few commercially available small molecules that are known antibody inhibitors of inflammatory or immune signaling do not represent the scope of the genus as claimed, which can be interpreted as encompassing small molecules that can target any gene/protein involved in inflammation and immune cell function. Around the time of the filing date, skilled artisans understood that discovering inhibitors of proteins generally was unpredictable. Wu observes that although computer-aided protein-inhibitor discovery technology was available, there is insufficient data to predict inhibitors of many proteins (Wu et al., Molecules (2019), 24: 4428, pages 1-14). Wu writes: [U]nder many circumstances, it is hard to find a [compound] library with functionally and structurally diverse molecules with quantitative activity data for a given protein. More importantly, the lack of publications with negative results hinders the identification of inactive molecules, resulting often in the development of qualitative common feature pharmacophores only from active compounds. Finally, as LBVS applications are generally based on the properties of the known ligands, the diversity of the hits discovered are generally limited. (Page 3 of 14, second paragraph.) Wu supports a finding that skilled artisans expected genera of inhibitors of a given protein to be diverse and that as of the effective filing date, they would not have concluded that applicants possessed a representative number of species of small molecule inhibitors of inflammation and immune signaling in particular.
Although Applicants may argue that it is possible to screen for peptides and antibodies that function as claimed in the inner ear, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future peptides or antibodies yet to be discovered that may function in inhibiting inflammation and immune signaling in the inner ear or inflammation associated with nucleic acid vector delivery as claimed.
Given the lack of representative examples to support the full scope of the inflammatory and immune signaling inhibitors encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of peptides, antibodies and small molecules that provide can inhibit inflammatory and immune signaling, the specification in view of the prior art does not provide an adequate written description of molecules that inhibit inflammatory and immune signaling in the inner ear that is required to practice the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 6, 15, 25 and 45-46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brough (US 20040166091 A1).
Regarding claims 1, 6, 15 and 25, Brough teaches administering an adenoviral vector comprising Math1 cDNA (i.e., a polynucleotide encoding a therapeutic agent) operably linked to the CMV promoter (i.e., a ubiquitous promoter) to a guinea pig by injecting into the endolymphatic fluid of the third cochlear turn (i.e., administering locally to the inner ear) ([0088]). Brough teaches including factors that reduce inflammation such as ibuprofen or steroids (i.e., an anti-inflammatory agent) as part of the composition to reduce swelling and inflammation associated with in vivo administration of the viral vector ([0070]).
Regarding claims 45-46, Brough teaches the viral vector in a composition with the anti-inflammatory steroid, wherein the composition is administered (i.e., the viral vector and the anti-inflammatory are administered simultaneously to the inner ear) ([0070).
Claim Rejections - 35 USC § 103
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.
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.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Brough (US 20040166091 A1) as applied to claims 1, 6, 15, 25 and 45-46 above, and further in view of Rauch (Rauch et al., JAMA (2011), 305: 2071-2080).
The teachings of Brough are recited above as for claims 1, 6, 15, 25 and 45-46 and are incorporated here. Briefly, Brough teaches administering the claimed nucleic acid vector to the inner ear and combining it in a composition for delivery with an anti-inflammatory steroid.
Brough does not teach local administration to the inner ear combined with systemic administration with the anti-inflammatory steroid.
Rauch teaches hearing loss has been treated with oral corticosteroid for more than 30 years (Context).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have delivered the anti-inflammatory steroid systemically in the method of Brough. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that the steroid taught in Brough to reduce inflammation associated with the Ad vector could be provided orally, and been motivated to have done so, because Rauch teaches using oral corticosteroids for the treatment of hearing loss – the same overall purpose as Brough’s Ad-vector gene therapy – is routine in the art.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Brough (US 20040166091 A1) as applied to claims 1, 6, 15, 25 and 45-46 above, and further in view of Isgrig (Isgrig et al., Nature Communications (2019), 10: 427).
The teachings of Brough are recited above as for claims 1, 6, 15, 25 and 45-46 and are incorporated here. Briefly, Brough teaches administering the claimed nucleic acid vector to the inner ear and combining it in a composition for delivery with an anti-inflammatory steroid. Brough also teaches the viral vector can be an AAV vectors ([0023]). Brough teaches advantages of using AAV vectors for administration of therapeutic nucleic acids is the absence of toxic side effects due to the absence of viral genes and that AAV vectors are not known to cause disease ([0023]).
Brough does not teach in a single embodiment the therapeutic gene under the control of the CMV ubiquitous promoter in an AAV vector and delivered in a composition with an anti-inflammatory.
Isgrig teaches delivering transgenes to the inner and outer hair cells of the cochlea in AAV vectors (Abstract). Isgrig teaches the AAV8BP2 engineered AAV vector resulted in moderate-to-high transgene expression in inner and outer hair cells (page 2, ¶5). Isgrig also teaches the AAVBP2 vector triggered an inflammatory response when delivered to the inner ear (page 4, ¶1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have substituted the Ad vector of Brough with the AAV8BP2 vector of Isgrig and co-administered an anti-inflammatory as suggested by Brough based on the results of Isgrig. It would have amounted to the simple combination of elements by known means to yield predicted results. The skilled artisan would have predicted that the AAV8BP2 vector could be used for Mach1 delivery to the inner ear cells because Isgrig teaches the delivery of a different transgene using the vector and Brough suggests using AAV vectors. The skilled artisan would have been motivated to use AAV8BP2 because Isgrig teaches high transgene expression in the target cells of Brough. Additionally, the skilled artisan would have been motivated to maintain anti-inflammatory treatment with AAV9BP2 since Isgrig teaches that the AAV vector that enhances transgene expression also induces an inflammatory response.
Claims 16 and 21 is rejected under 35 U.S.C. 103 as being unpatentable over Brough (US 20040166091 A1) and Isgrig (Isgrig et al., Nature Communications (2019), 10: 427) as applied to claims 1, 6-7, 15, 25 and 45-46 above, and further in view of Muhuri (Muhuri et al., J Clin Invest (2021), 131(1):e143780) and Moon (Moon et al., Annals of Otology, Rhinology & Laryngology (2019), 128: 8S-15S).
The teachings of Brough and Isgrig are recited above and applied as for claims 1, 6-7, 15, 25 and 45-46. Although Brough teaches administering an anti-inflammatory with viral vectors for gene therapy to reduce an immune response caused by the viral vectors, Brough and Isgrig do not teach the anti-inflammatory is an inhibitory nucleic acid.
Muhuri teaches overcoming innate immune barriers that impede AAV gene therapy vectors (Title). Muhuri teaches AAV vectors are sensed by TLR9 receptors that induce proinflammatory cytokines like TNF-a (Figure 1, legend).
Moon teaches cochlear inflammation is frequently associated with hearing loss and excessive inflammation can lead to immune-mediated damage of sensory cochlear cells (page 8S, ¶1). Moon teaches cochlear cells can be damaged by high levels of TNF-a (page 8S, ¶2). Moon teaches that TNF-a acts via TNFR1 (page 10S, ¶4). Moon teaches that TNFR1 mediates activation of Caspase-1, a pro-apoptotic protein, upon TNF-a binding (¶ spanning pages 11S and 12S). Moon teaches silencing TNFR1, also known as TNFRSF1A, by administering an siRNA targeted to TNFR1 (i.e., an inhibitory nucleic acid
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered a TNFRSF1A siRNA together with the AAV8BP2 gene delivery vector rendered obvious above for claim 7. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that the TNFR1 siRNA could be administered with the AAV vector since both can be administered to the inner ear. The skilled artisan would have been motivated to include the TNF1R siRNA because 1) Brough teaches providing anti-inflammatories with viral vectors, 2) Muhuri teaches AAV vectors can trigger TNF-a signaling, and 3) Moon teaches TNF-a signaling can damage hair cells, which is the opposite effect the viral vector of Brough and Isgrig is supposed to promote. It would have been entirely predictable that the skilled artisan looking for a means to reduce AAV-induced TNF-a signaling would have used Moon’s TNFR1 siRNA administered to the inner ear since TNF-a signals through the TNFR1 receptor to induce pro-inflammatory responses.
Claims 16 and 21 is rejected under 35 U.S.C. 103 as being unpatentable over Brough (US 20040166091 A1) and Isgrig (Isgrig et al., Nature Communications (2019), 10: 427), Muhuri (Muhuri et al., J Clin Invest (2021), 131(1):e143780) and Moon (Moon et al., Annals of Otology, Rhinology & Laryngology (2019), 128: 8S-15S), as applied to claims 1, 6-7, 15-16, 21, 25 and 45-46 above, and further in view of Farhang (Farhang et al., Human Gene Therapy (2019), 30: 1161-1175) and Zuris (Zuris et al., Nature Biotechnology (2015), 13: 73-80). This rejection is directed to Applicant’s elected species, a gRNA having a sequence that targets the TNFRSF1A gene, which is also known as TNFR1, the receptor for TNF-a.
The teachings of Brough, Isgrig, Murhuri and Moon are recited above and applied as for claims 1, 6-7, 15-16, 21, 25 and 45-46. Although Brough teaches administering an anti-inflammatory with viral vectors for gene therapy to reduce an immune response caused by the viral vectors, and Moon teaches inhibiting TNF-a:TNFR1 signaling for reducing inflammation, Brough, Isgrig, Muhuri and Moon do not teach CRISPR/Cas systems comprising guide RNAs (gRNA) for reducing TNFR1 expression.
Farhang teaches reducing TNFR1 expression using CRISPR epigenome editing (Abstract). Farhang teaches that TNF-a promotes proinflammatory signaling when binding TNFR1, but confers antiapoptotic and regenerative effects with binding TNFR2 (page 1162, ¶3). Farhang teaches that by targeting TNFR1 instead of TNF-a, only the proinflammatory signaling will be blocked (page 1162, ¶3). Farhang teaches expressing a dCas9-KRAB and a gRNA complementary to the TNFR1 gene promoter in target cells (1163, ¶4-7), which reduced TNFR1 expression levels (Fig 1), and reduced pro-inflammatory and pro-apoptotic signaling (Figs 2-4).
Zuris teaches delivering liposomes comprising Cas9 and gRNAs into the mouse cochlea (page 78, ¶8). Zuris teaches the Cas9/gRNA complexes were successfully delivered to mouse outer hairs cells, which did not appear to affect the health or structure of the hair cells or cochlear architecture (page 79, ¶1; Fig 6d). Zuris teaches the Cas9/gRNA complexes were successful at editing the targeted gene in 13% of outer hair cells (page 79, ¶1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered a dCas9-KRAB and gRNA targeting the TNFRSF1A gene together with the AAV8BP2 gene delivery vector rendered obvious above for claim 7. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that the TNFR1-targeted dCas9/gRNA could be administered with the AAV vector since both can be administered to the inner ear as shown by Isgrig and Zuris. The skilled artisan would have been motivated to include the TNFR1-targeted dCas9/gRNA because 1) Brough teaches providing anti-inflammatories with viral vectors, 2) Muhuri teaches AAV vectors can trigger TNF-a signaling, 3) Moon teaches TNF-a signaling can damage hair cells, which is the opposite effect the viral vector of Brough and Isgrig is supposed to promote, and 4) Farhang teachings targeting TNFR1 with a dCas9-KRAB/gRNA is an effective way at reducing TNFR1 pro-inflammatory signaling. It would have been entirely predictable that the skilled artisan looking for a means to reduce AAV-induced TNF-a signaling would have used Farhang’s TNFR1-targeted dCas9/KRAB gRNA administered to the inner ear since TNF-a signals through the TNFR1 receptor to induce pro-inflammatory responses.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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