DETAILED ACTION
Notice of Pre-AIA or AIA Status
The text of those sections of Title 35, U.S. Code not included in this action can
be found in a prior Office action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to the papers filed on 09/11/2026. Claims 1, 3-7, and 10-12 are currently pending as per claims filed on 09/11/2026. Claim 2, 8, and 9 were cancelled, Claims 1, 5, 11, and 12 have been amended by Applicants’ amendment filed on 09/11/2026.
Therefore, claims 1, 3-7, 10-12 are under examination to which the
following grounds of rejection are applicable. Claims 1 and 11 are independent claims.
Sequence Compliance - 37 CFR 1.821-1.825
Examiner acknowledges the Applicant has corrected the sequence listing to include sequence identifiers for the recited gRNAs for mouse HRH1 and human HRH1, thus the sequence listing is now in compliance. Therefore, the sequence compliance objection has been withdrawn.
Priority
The instant application is a 371 of PCT/US2022/080499 filed on 11/28/2022 which claims benefit of 63/284,424 filed on 11/30/2021. Thus, the earliest possible filing priority for the instant application is 11/30/2021.
Withdrawn objections/rejection in response to Applicants’ arguments or
Amendment
Claim Objections
In view of applicant’s amendment to claim 1, which now spells out HRH1, the claim objection has been withdrawn.
In view of applicant’s amendment to claim 7, which now recites “the subject is a human”, the claim objection has been withdrawn.
In view of applicant’s amendment to claim 11, which now spells out AAV, the claim objection has been withdrawn.
In view of applicant’s amendment to claim 11, which now recites “guide RNA (gRNA)”, the claim objection has been withdrawn.
In view of applicant’s amendment to claim 9 and 12 which now recites “selected from the group consisting of”, the claim objection has been withdrawn.
Claim Rejections - 35 USC § 112(b)
In view of applicant’s amendment of claim 5 to specify glaucoma, optic neuritis or ON traumatic injury, the 112 (b) rejection has been withdrawn.
In view of applicant’s amendment of claim 12 correcting the sequence identifiers, the 112 (b) rejection has been withdrawn.
Maintained and/or modified rejections in response to Applicants’ arguments or
Amendment
35 U.S.C. 112(a) - Scope of Enablement
Claims 1, 3-7, 10-12 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 treating an optic nerve (ON) neuropathy by reducing or ameliorating degeneration of axons and/or soma of retinal ganglion cells using the HRH1 antagonists amoxapine, desloratadine, and maprotiline by administering them intravitreally (para 0144-0145) or intraperitoneally (para 0145) and
an AAV2-vector based HRH1 antagonist with a pair of specific guide RNAs (gRNAs) identified by SEQ ID NOs 35-38 (human gRNA1 and gRNA2 and mouse gRNA1 and gRNA2; para 0158) targeting HRH1 to knockdown (KD) HRH1 expression also administered intravitreally (para 00148),
does not reasonably provide enablement for using any administration route for amoxapine, desloratadine, and maprotiline as a treatment of an ON neuropathy or any AAV vector comprising a genus of unidentified gRNAs that target histamine receptor H1 so as to have a knockdown (KD) effect by CRISPR. Moreover, claim 11 has been amended to recite an optic nerve (ON) neuropathy in a mammalian subject in need thereof including a human subject by using expression of the Cas9 under the control of a murine promoter, i.e., y-synuclein promoter.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification is not enabling for amoxapine, desloratadine, and maprotiline to be administered in any route to the optic nerve of a subject and is not enabling for any AAV using any gRNA such that it can target HRH1 and lead to reduced or ameliorated degeneration of axons and/or soma of the retinal ganglion cells (RGCs), thereby treating the ON neuropathy. This is a modified rejection necessitated by amendments field 09/11/2026.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
the breadth of the claims; the nature of the invention:
Claim 1 is directed to a method of treating optic nerve neuropathies in a mammalian subject a with amoxapine, desloratadine, and maprotiline which can be administered any way to the optic nerve. Claim 3 and 4 further limits claim 1 to systemic and intravitreally administered. Claim 5 and 6 limit claim 1 to optic neuritis, ON traumatic injury, or glaucoma as the ON neuropathy. Claim 10 further limits claim 1 to the tricyclic compound maprotiline. Claim 11 recites administering an effective dose of any AAV vector that targets HRH1 comprising a murine γ-synuclein promoter linked to Cas9 and U6 promoter linked to at least one gRNA which precedes an -NGG protospacer and the promoter is selected from a group of SEQ ID NOs.
the amount of direction provided by the inventor; the existence of working
examples:
As recited above, claim 1 is broadly but reasonably interpreted as comprising administration by any route an effective dose of an HRH1 antagonist selected from the group consisting of amoxapine, desloratadine, and maprotiline to treat a neuropathy. Claim 11 is broadly but reasonably interpreted as administering in any route any AAV which comprises a murine y-synuclein promoter in operable linkage with a nucleic acid encoding a Cas9 nuclease; and a U6 promoter in operable linkage with at least one guide RNA (gRNA) 20-21 nucleotides in length, wherein each gRNA precedes an -NGG protospacer, and wherein each gRNA targets histamine receptor H1 (HRH1) to the optic nerve of any subject, including a human, to reduce or ameliorate degeneration of axons and/or soma of retinal ganglion cells (RGCs), thereby treating the ON neuropathy. The specification does not provide support for any AAV administered in any manner, besides intravitreally, or that the disclosed AAV from working examples in a mouse could be effectively used on human subjects.
The specification describes treatment of a crushed optic nerve and glaucoma using three compounds (amoxapine, desloratadine, or maprotiline) in a mouse (para 00144) wherein the compounds are administered intravitreally or intraperitoneally. Importantly, maprotiline was the only compound to show significantly higher survival of retinal ganglion cell (RGC) coma and axons in the ON crushed mouse model (para 00146; Fig 12a, Fig 5D,E). In regard to the AAV vector as an HRH1 antagonist for the treatment of ON neuropathy, the specification discloses the in vivo use of gRNAs targeting mouse HRH1 and injected the mixture of AAV2-mSncg-Cas9 + AAV-mouse HRH1-gRNAs (FIG. 15a) intravitreally into mouse eyes (FIG. 15b) for traumatic ON injury and glaucoma mouse model (para 00149-0150). The specification discloses the mouse HRH1 gRNA sequences are: gRNA1 (5' -GCTCCACAACCCTT CCGAGTA-3') and gRNA2 (5'-GTCCGTCTTCTCCACAACCCT-3') (para 00158)). In the human capacity, the specification only discloses using a HEK293T human cell line to demonstrate knockdown of human HRH1 with a single pair of gRNAs (para 00150), but not using an AAV-vector system.
Therefore, the specification only provides details of the compounds amoxapine, desloratadine, and maprotiline injected intravitreally and intraperitoneally in a mammalian subject, a single pair of gRNAs targeting human HRH1 knockdown in a human cell line, an AAV2-vector with a single pair of mouse gRNAs targeting HRH1 using CRISPR injected intravitreally which treats an ON neuropathy in a mouse described above.
the state of the prior art; the level of predictability in the art:
Regarding the use of AAV vector for treating an ON neuropathy in any mammalian subject, Agrawal et al (American J. of Ophthalmology, November 2025, pages 555-570) teaches that because the blood-retinal barrier generally precludes AAV serotypes from reaching the eye from systemic circulation, localized delivery including intravitreal routes of administration and subretinal injection is typically used (page 557, methods of delivery). Moreover, Agrawal teaches “of the natural AAV serotypes, only AAV2 has demonstrated any ability to penetrate the ILM and transduce cells in the inner retina, including some retinal ganglion cells” (page 558, capsids used for intravitreal gene therapy for retinal vascular diseases). On a similar token, when using AAVs as a treatment across species, it was shown that the ability of AAVs to achieve equivalent patterns between mouse and primate models is not necessarily guaranteed as, for example, AAV- 7m8 mediated a punctate expression pattern in the inner and outer retina including some photoreceptors but not RPE, likely due to a thicker ILM in primate than in mouse (page 558, capsids used for intravitreal gene therapy for retinal vascular diseases). Similarly, the use of a mouse promoter, as recited in claim 11, further impedes successful translation of the AAV in a non-murine species. Additionally, it is well established in the gene therapy art that translation from ex vivo experiments, such as cell culture, does not necessarily ensure gene therapy’s effectiveness in an in vivo clinical setting. For instance, the packaging of CRISPR components, which includes the gRNA and Cas9 nuclease, remains a challenge and the high editing efficiency when transferred to human in vivo application is not necessarily guaranteed, which may not lead to the desired outcome of treating an optic near neuropathy, for example (Mout et al, 2017, pages 1-12; see page 4 – Challenges).
Regarding the use of gRNA to target genes of interest such as HRH1, it is well understood that while designing gRNAs can be routinely accomplished by using computer algorithms and prediction software, gRNAs must be tested and validated due to the unpredictable influence of biological parameters which can impact the effectiveness of the gRNA in combination with a nuclease such as Cas9. Konstantakos et al (Nucleic acids research, 2022, pages 3616–3637) teaches that “The efficiency of DNA cleavage, both on-target and off target, depends not only on the intrinsic nuclease activity, but also on target site accessibility and the affinity of DNA binding domain(s) (e.g. gRNA) to the target sequence. However, there is a lack of understanding on the exact behavior of the engineered Cas9 nuclease in living cells, especially regarding the dynamics of its interaction with DNA, and the cell cycle-dependent cleavage activity. Due to the limited biological knowledge, prediction of nuclease target accessibility and cleavage rates in living cells remain difficult. Therefore, experimental validation of target-site selection is necessary” (page 3618, Predicting On-Target Activity).
the quantity of experimentation needed to make or use the invention based on the
content of the disclosure:
The skilled artisan would be required to perform under levels of experimentation
in order to practice the claimed invention. The instant specification does not reduce to
practice the claimed invention; the instant specification does not provide guidance on what AAV, besides AAV2, and what method of administration, besides intravitreal injection for the AAV and intravitreal or intraperitoneal for the recited compounds, would permit the treatment of an ON neuropathy in mammalian species when using the compounds or in any species besides a mouse for the AAV vector. Furthermore, the specification does not provide guidance permitting a person of ordinary skill to predict without empirical testing, which of the numerous possible guide RNAs target the HRH1. The specification only describes methods for administering AAV2 into the peripheral retina to achieve 3 X 109 vg/retina (page 46, para 00159), with no indication of timing interval of administration and using 2 disclosed gRNAs pairs for human (however, only used in vitro in HEK293T cells) and in vivo in a mouse (human and mouse each have gRNA1 and gRNA2). Thus, the skilled artisan would be forced to 1) which route of administration of the compound or AAV is appropriate for the mammalian subject, 2) what AAV serotype to use, 3) which dose for both the AAV and compound would be necessary for proper treatment in a mammalian subject such that it is an effective dose, 4) designing and testing the guide RNAs that sufficiently target the HRH1 and 5) determine what result is sufficient to deem the method being capable of adequately treating the ON neuropathy in the mammalian subject.
the level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion:
When all of the Wands factors are considered together, they establish a prima
facie case that the specification is not enabling for the claims. The Specification only provides details for a method of treating an ON neuropathy in a mouse using the HRH1 antagonists 1) compounds amoxapine, desloratadine, and maprotiline by administering them intravitreally (para 00144-00145) or intraperitoneally at 2 mM concentration, 2) an AAV2-vector based HRH1 antagonist with a pair of gRNAs wherein the gRNA sequences are: mouse gRNA1 SEQ ID NO: 35 (5' -GCTCCACAACCCTT CCGAGTA-3') and mouse gRNA2 SEQ ID NO: 36 (5'-GTCCGTCTTCTCCACAACCCT-3'), a murine γ-synuclein promoter, and the vector is also administered intravitreally (para 00148) and at a concentration of 3 X 109 vg/retina in a mouse, and 3) gRNAs targeting human HRH1 gRNA1 SEQ ID NO:37 (5'-GTCTCCGTCCTCCTTAACCCC-3') and gRNA2 SEQ ID NO:38 (5'- GATTCTCCGTCCTCCTTAAC-3') using human in vitro cell lines.
Response to Applicant’s arguments as they apply to rejection of claims 1, 3-7, 10-12 under 35 USC § 112(a)
Applicant’s arguments filed 09/11/2026 have been fully considered but not persuasive.
Applicant asserts that 1) the compounds amoxapine, desloratadine, and maprotiline inhibit RGC ER stress and significantly protects RGCs and ONs after traumatic ON injury and the mouse glaucoma model confirm maprotilines effect on glaucoma and 2) knockdown of HRH1 expression by CRISPR inhibition, which uses guide RNAs, is shown to provide neuroprotection in ON injury model and glaucoma models according to their disclosure and that selecting and substituting guide RNAs is a fast and straightforward technique using online design algorithms.
Regarding argument 1, Examiner has modified the 112(a) rejection in light of Applicant’s clarification of all three compounds demonstrating ability to protect RGCs and ONs after traumatic ON injury, rendering Applicant’s argument moot.
Regarding argument 2, Although applicants' disclosure may establish that a POSA could design candidate guide RNAs complimentary to various sequences within the gene for HRH1, the ability to generate candidate guide RNAs does not establish that the full scope of guide RNAs encompassed by the claim can be used to achieve the contemplated function of the HRH1 knockdown (KD) effect of CRISPR in the optic nerve of a mammalian subject without undue experimentation. As recited in the 112(a) rejection above, gRNAs must be tested and validated due to the unpredictable influence of biological parameters which can impact the effectiveness of the gRNA in combination with a nuclease such as Cas9. Konstantakos et al (Nucleic acids research, 2022, pages 3616–3637) teaches that “The efficiency of DNA cleavage, both on-target and off target, depends not only on the intrinsic nuclease activity, but also on target site accessibility and the affinity of DNA binding domain(s) (e.g. gRNA) to the target sequence. However, there is a lack of understanding on the exact behavior of the engineered Cas9 nuclease in living cells, especially regarding the dynamics of its interaction with DNA, and the cell cycle-dependent cleavage activity. Due to the limited biological knowledge, prediction of nuclease target accessibility and cleavage rates in living cells remain difficult. Therefore, experimental validation of target-site selection is necessary” (page 3618, Predicting On-Target Activity). Guide RNAs directed to different regions of the same gene may exhibit context dependent activity and the specification does not provide sufficient guidance permitting a POSA to predict without empirical testing, which of the numerous possible guide RNAs targeting HRH1 will possess the activity required by the claim. Thus, practicing the full scope of the claim would require the POSA to design produce and screen candidate guide RNAs to identify operative species
In view of the breadth of the claimed genus, the limited working examples and guidance provided by the specification, the unpredictability regarding the activity of individual guide RNAs, such experimentation would be undue.
Claim Rejections - 35 USC § 103
Please, note the rejection of claim 10 below under 35 USC § 112 (b) and interpretation of claim 10 as dependent on claim 1.
Claim(s) 1, 3, 4, 7 and 10 remain rejected under 35 U.S.C. 103 as being unpatentable over He et al (WO 2021222507 A1; as cited in IDS) and further in view of Firkusny et al (Br J clin Pharmac ,1994; pages 383-388; as cited in office action filed 05/26/2026) as evidenced by Biotechne (R&D systems by biotechne, pages 1-8, downloaded 10/01/2026) This is a modified rejection necessitated by amendments field 09/11/2026.
Regarding claims 1, 3, 4, 7, and 10, He teaches a method of treating a human subject (page 9, line 7) having a disease associated with Myelination failure (e.g. an optic nerve injury/neuropathy) by administering to the subject an agent which can be clemastine fumarate (page 19, para 3 line 4-8), which is a histamine H1 receptor antagonist (HRH1) as evidenced by Biotechne (page 2, Product description). Biotechne provides support for histamine H1 antagonist also being a histamine H1 receptor antagonist. He teaches that the agent, when contacted with a oligodendrocyte progenitor cell (OPC) in the presence of an axon increase myelination of the axon regenerates an axon (i.e. reduces degeneration of an axon) (page 5, lines 16-24). He teaches that an agent can be intravitreally injected (Fig 4J; page 40, line 30-31) or administered systemically (page 23, line 9), rendering obvious method of treating an optic nerve (ON) neuropathy in a mammalian subject in need thereof, the method comprising: administering an effective dose of an histamine receptor H1 (HRH1) antagonist to the optic nerve of the subject to reduce or ameliorate degeneration of axons and/or soma of retinal qanqlion cells (RGCs), thereby treating the ON neuropathy (claim 1), wherein the composition is administered intravitreally (claim 3), wherein the composition administered systemically (claim 4), and wherein the subject is a human (claim 7).
He does not teach that a small molecule having histamine H1 antagonistic properties is selected from the group consisting of maprotiline, amoxapine, and desloratadine (claim 1).
However, one of ordinary skill in the art would have considered the teachings of Firkusny as this reference is analogous prior art pertaining to maprotiline as an antagonist of histamine receptors.
Firkusny teaches maprotiline shows direct antagonism at pulmonary histamine receptors (page 386, Discussion, para 1) and histamine-induced bronchoconstriction was abolished after a single dose of maprotiline and this effect persisted throughout multiple dose treatment (abstract), suggesting a histamine H1 receptor antagonistic property of maprotiline.
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a method to treat an ON neuropathy wherein the treatment increases myelination of an axon of the retinal ganglion cells by substituting clemastine fumarate of He having histamine H1 receptor antagonistic properties for the maprotiline of Firkusny having histamine H1 receptor antagonistic properties. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
One would be motivated to do so since it was known that maprotiline also has histamine antagonistic properties, so intravitreal administration of maprotiline should be reasonably expected to increase myelination of an axon by contacting an oligodendrocyte progenitor cell (OPC) in the presence of an axon, thus reducing or ameliorating degeneration of axons and/or soma of retinal ganglion cells, thereby treating the ON neuropathy. A skilled artisan would have had a reasonable expectation of success as treatment of ON neuropathies using HRH1 antagonists for regenerating axons was known in the art before the effective filing date of the claimed invention.
Regarding claim 10, the teachings of He and Firkusny render obvious claim 1.
In regard to the recitation “wherein the tricyclic agent is maprotiline formulated for ocular delivery” as required in claim 10, It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of using maprotiline for as a clinical treatment from Firkusny to be formulated for ocular delivery as reformulation of pharmaceuticals for alternative regions of interest of the body is known technique in the art. One would be motivated to do so to ensure effective usage of maprotiline to treat an eye disease and have a reasonable expectation of success.
*****
Claim(s) 1, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over He and Firkusny as applied to claim 1 above, and further in view of Sgambellone et al (biomolecules, 11 Aug 2021, pages 1-10 as cited in office action filed 05/26/2026),
Regarding claim 1, the teachings of He and Firkusny render obvious claim 1.
The combined teachings do not teach wherein the ON neuropathy is glaucoma, optic neuritis, or ON traumatic injury (claim 5), and wherein the ON neuropathy is glaucoma (claim 6).
However, one of ordinary skill in the art would have considered the teachings of Sgambellone as this reference is analogous prior art pertaining to histamine’s role in glaucoma and presence of HRH1 in the retinal ganglion cells.
Sgambellone teaches that glaucoma is characterized by the progressive degeneration of retinal ganglion cells (abstract), glaucoma can be cause by optic nerve damage (page 1, para 3), and the histamine H1 receptor has been localized to the inner later of ganglion cells and that circuits involved with vision may be altered by histamine release (page 4, para 1). Sgambellone also teaches that the dysregulation of histamine secretion may contribute to the pathophysiology of Glaucoma (page 2, para 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to select glaucoma as the type of ON neuropathy, particularly because Sgambellone teaches that glaucoma can be caused by optic nerve damage and histamine dysregulation and the combined teachings of He and Firkusny disclose treatment of ON neuropathy by administering the HRH1 antagonist maprotiline to the optic nerve for treating an optic nerve (ON) neuropathy.
As use of maprotiline for histamine-related disorders and treatment of ON neuropathies such as glaucoma with HRH1 antagonists for regenerating axons has been shown, one would be motivated to combine the teachings to have an alternative treatment option for glaucoma and would have a reasonable expectation of success.
*****
Claim(s) 11 and 12 remains rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (The Journal of Neuroscience, 2020, pages 3896–3914 as cited in office action filed 05/26/2026) and further in view of Sgambellone et al (biomolecules, 11 Aug 2021, pages 1-10 as cited in office action filed 05/26/2026), and Wu et al (Quantitative Biology, 2014, page 59-70 as cited in office action filed 05/26/2026) and as evidenced by NCBI (Human HRH1 DNA sequence GenBank: AB041380.1, published first on April 18 2000 as cited in office action filed 05/26/2026). This is a modified rejection necessitated by amendments field 09/11/2026.
Wang teaches a neuroprotective treatment for optic neuropathy in a mouse comprising in vivo administration of an AAV2 comprising a mouse γ -synuclein (mSncg) promoter to knockdown endogenous DNA-damage inducible transcript 3 (Ddit3; gene name for the transcription factor CHOP) and Sarm1, thus preserving the acutely injured RGC somata and axons (page 3897, left col, para 3). Wang teaches gRNAs targeting knockdown of Ddit3 and Sarm1 were used to in an AAV vector and the vector carried the gRNA scaffold with a U6 promoter (page 3901, right col, para 1; page 3908, right col, para 1). Wang teaches the gRNAs to mouse Ddit3 and Sarm1 genes are 20-nucleotides and preceded by a 5’-NGG protospacer-adjacent motif (page 3902, right col, para 1).
Wang does not teach that each gRNA targets HRH1 to the optic nerve of the subject to reduce or ameliorate degeneration of axons and/or soma of retinal ganglion cells (RGCs), thereby treating the ON neuropathy.
However, one of ordinary skill in the art would have considered the teachings of Sgambellone, Wu, and NCBI as these references are analogous prior art pertaining to the role of histamine receptors in retinal neuroprotection and methods to design gRNAs targeting HRH1.
Sgambellone teaches that glaucoma is characterized by the progressive degeneration of retinal ganglion cells (abstract), glaucoma can be cause by optic nerve damage (page 1, para 3), and the histamine H1 receptor has been localized to the inner later of ganglion cells and that circuits involved with vision may be altered by histamine release (page 4, para 1). Sgambellone also teaches that the dysregulation of histamine secretion may contribute to the pathophysiology of Glaucoma (page 2, para 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of AAV vectors for targeting downregulation of Ddit3 and Sarm1 using guide RNAs against Ddit3 and Sarm1 as taught by Sgambellone to instead use a guide RNAs that target HRH1 since Sgambellone taught that HRH1 is expressed in ganglion neurons and that dysregulation of histamine secretion may contribute to pathophysiology of glaucoma, thus knocking down HRH1 using AAV technology with guide RNAs which target HRH1 could be used to treat an optic nerve neuropathy such as glaucoma.
In relation to at least one guide RNA (gRNA) 20-21 nucleotides in length, one of ordinary skill in the art would consider the teachings of NCBI who teaches the gene sequence of HRH1 (i.e. the target sequence) and Wu who teaches that several tools (eleven tools are cited in Wu; page 66, left col, para 2) have been developed for designing guide RNAs such that off-target effects are mitigated. Wu teaches that the tools take into consideration the input sequence, a genomic region, or a gene and predicts guide RNAs with minimal off-target effects. Wu teaches that these tools can also consider the presence of SNPs and secondary structures, the genomic context of the guide, and GC content, all of which can impact the effectiveness of the gRNA (page 66, left col, para 2-3). As the gene sequence of HRH1 was known at the time of filing of the instant application, as evidenced by the gene sequence disclosed by NCBI, one of ordinary skill in the art would be able to design gRNAs using Wu’s teachings for Wang’s method.
Regarding claim 12, the teachings of Wang, Sgambellone, Wu, and NCBI render obvious claim 1. Wang also teaches a murine γ-synuclein promoter (mSncg-1.45kb, in Fig 1-1 extended data) that has 100% sequence alignment to SEQ ID NO: 31 in the instant application claim 12. See alignment below.
Qy = SEQ ID NO 31 from instant application, Db = Wang’s mSncg-1.45kb sequence
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825
657
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864
652
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358
665
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Response to Applicant’s arguments as they apply to rejection of claims 1, 3-7 and 10-12 under 35 USC § 103
Applicant’s arguments filed 09/11/2026 have been fully considered but not persuasive.
Applicant asserts that the present claims are not made obvious by the cited combination of references as 1) He is drawn to the use of a chemically and functionally distinct molecule which does not share structurally similarity to the present claims and therefore one of skill in the art would not have a reason to substitute, 2) Sgambellone suggests a role of histamine, but do not teach or suggest the compounds set forth in the present claims, 3) He does not teach or suggest the use of CRISPR knockout of HRH1 for the treatment of ON neuropathy.
Regarding argument 1 and 2, Applicant asserts that the compounds in instant claim 1 are a tricyclic chemical structure and are capable of significantly inhibiting CHOP-luciferase activity by ER stress (page 8 of Applicant remarks) and since He does not teach these characteristics, it does not render obvious the claimed invention. The Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, He’s teaching of a method to reduce degeneration of axons by increasing myelination of an axon in retinal ganglion cells in an optic injury by intravitreally injecting clemastine fumarate, which has histamine H1 receptor antagonistic properties, Firkusny, teaches maprotiline has histamine HI receptor antagonistic properties, So if intravitreal administration clemastine fumarate increases myelination of an axon in retinal ganglion cells to treat an optic nerve (ON) neuropathy, intravitreal administration of a therapeutically effective amount of maprotiline should be reasonably expected to promote myelination of an axon in retinal ganglion cells for the same reason clemastine fumarate promote remyelination – both compounds has histamine H1 receptor antagonistic properties.
In other words, the characteristic/property of being a histamine H1 receptor antagonistic is shared between clemastine fumarate of He and maprotiline of Firkusny. Indeed, the claim only recites the compounds have an histamine receptor antagonistic property such that when administered to the optic nerve of the subject, can reduce degeneration of axons and retinal ganglion cells. For the reasons above, the combined teachings of He and Firkusny read on claim 1 of the instant application.
Regarding argument 3, the art of He as applied to claims 11 and 12 has been withdrawn, rendering this argument moot.
New rejections in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 112 (b)
Claim 10 is newly 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. This is a new rejection necessitated by amendments field 09/11/2026.
Claim 10 depends from cancelled claim 8, thereby rendering it indefinite and is therefore “incomplete.” See MPEP § 608.01(n)(V). The claim 10 limitation (“wherein the tricyclic agent…” ) lacks antecedent basis from canceled base claim 8. See MPEP § 2173.05(e). It appears claim 10 should depend from 1. For purposes of compact prosecution, for the remainder of examination, claim 10 will be considered as if it depended on claim 1.
Claim 10 recites the limitation "tricyclic agent" in line 18. There is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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