DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s arguments filed 05/11/2026 have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
Status of the claims
In the reply filed on 05/11/2026, Applicant (1) cancelled claim 14, and (2) amended claim 13.
Claim(s) 13 and 15-23 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claim(s) 13-19), drawn a method for treating age-related macular degeneration, in the reply filed on 11/03/2025 is acknowledged.
Claim(s) 20-23 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
Claim(s) 13 and 15-19 are under consideration.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The certified copy has been filed for Application No. KR10-2022-0094997 (filing date of 07/29/2022) on 09/12/2023 and KR10-2023-0095074 (filing date of 07/21/2023) on 09/12/2023.
All claims have the priority date of 07/29/2022.
Response to Arguments – Specification
The previous objection to the specification for containing color expressions (para 0141, 0142, and 0149) and trademarks/tradenames (para 0088, 0089, 0093, 0094, 0133, 0138, 0140, 0150, and 0152) have been withdrawn in view of Applicant’s amendments to the specification filed 05/11/2026.
Claim Objections
Claim 13 is objected to because of the following informalities: the claim recites, “micoRNA (miRNA), antisense oligonucleotides (ASOs)” in the last line of the claim. It would be remedial to add an “and” between “(miRNA),” and “antisense”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – 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(s) 13 and 15-19 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. This rejection was made in the Office action mailed 02/10/2026 and has been rewritten to address the amendment to the claims in the reply filed on 05/11/2026.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim 13 is drawn to genus of “nucleic acid” that reduces expression of cathepsin S (CTSS), wherein the nucleic acid has sequence complementarity to CTSS mRNA or inhibits expression of CTSS mRNA. Claim 13 also comprises subgenera of “nucleic acid” consisting of siRNA, shRNA, miRNA, and ASOs. The rejected claims thus comprise subgenera of “nucleic acid” and are defined as belonging to the broad class of nucleic acids that must be capable of (i) reducing the expression of Cathepsin S (CTSS) by – (ii) having sequence complementarity to CTSS mRNA or (iii) inhibiting expression of CTSS mRNA – and (iv) treating age-related macular degeneration.
Claim 15 is limits the age-related macular degeneration to age-related macular degeneration under oxidative stress conditions. The rejected claim thus comprises all of claim 13, and must be capable of (i) reducing the expression of Cathepsin S (CTSS) by – (ii) having sequence complementarity to CTSS mRNA or (iii) inhibiting expression of CTSS mRNA – and (iv) treating age-related macular degeneration under oxidative stress conditions.
Claim 16 is limits the age-related macular degeneration to dry or wet age-related macular degeneration. The rejected claim thus comprises all of claim 13, and must be capable of (i) reducing the expression of Cathepsin S (CTSS) by – (ii) having sequence complementarity to CTSS mRNA or (iii) inhibiting expression of CTSS mRNA – and (iv) treating dry or wet age-related macular degeneration.
Claim(s) 17-19 are further drawn to inhibiting inflammatory cytokines, and complement activity in the retina, inhibiting intravascular endothelial production, and/or inhibiting angiogenesis (of claim 17). Wherein the inflammatory cytokine is any one or more selected from the group consisting of TNF-a, IL-1p, and MCP-1 (claim 18 dependent on claim 17), and wherein the complement is any one or more selected from the group consisting of C3, C5, C3a, C5a, and C5b-9 (claim 19 dependent on claim 17). The rejected claims thus comprise all of claim 13, and must be capable of (i) reducing the expression of Cathepsin S (CTSS) by – (ii) having sequence complementarity to CTSS mRNA or (iii) inhibiting expression of CTSS mRNA – (iv) treating age-related macular degeneration under oxidative stress conditions, (v) inhibiting inflammatory cytokines (any one or more inflammatory cytokines selected TNF-a, IL-1p, and MCP-1), (vi) inhibiting complement activity in the retina (any one or more selected from the group consisting of C3, C5, C3a, C5a, and C5b-9), (vii) inhibiting intravascular endothelial production, and/or (viii) inhibiting angiogenesis.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species 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 functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The instant specification envisions at [0072] that “For example, the material may be delivered by a vector, but are not limited thereto.” Despite using “material” as claim terminology, the specification refers to the genus of a “substance”, as recited in paragraph [0008], “One object of the present invention is to provide a pharmaceutical composition for preventing or treating age-related macular degeneration, comprising, as an active ingredient, a substance that reduces the expression or activity of cathepsin S (CTSS).” Substance is also recited in paragraphs [0009], [0010], [0011], and [0013]. Paragraph [0014] recites, “According to an exemplary embodiment of the present invention, the substance may be any one or more selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs), Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas), natural products, proteins, peptidomimetics, antibodies, exosomes, and compounds, but is not limited thereto.”
The specification describes:
[0045]: … “reduction of expression” means any action that reduces the expression of a gene, specifically gene knock-out (knock-down), RNA interference; RNAi, gene DNA sequence deletion, duplication, inversion, or it may be achieved by introducing a mutation such as replacement, but is not limited thereto.
[0046]: … “reduced activity” means that one or more functions generated by cathepsin S are inhibited, and the functions cause age-related macular degeneration, progress or worsen symptoms of age-related macular degeneration, or progress rate of age-related macular degeneration. It may be a function related to the occurrence/deterioration of symptoms of age-related macular degeneration, such as increasing, but is not limited thereto.
[0049]: As used herein, "siRNA" refers to RNA molecules, generally 17 to 24 bp in length, which can interfere with and inhibit the expression of a gene comprising a nucleic acid sequence complementary to the sequence of siRNA.
[0051]: In the present invention, "shRNA" is a short hairpin RNA having a loop structure that induces the NAi phenomenon and refers to a substance that induces mRNA degradation by complementarily binding to target mRNA.
[0052]: In the present invention, "miRNA" is generally a single-stranded RNA molecule with a length of about 22 nucleotides (nt), and refers to a microregulator that binds to the 3'UTR of target mRNA to suppress the expression of the corresponding gene by forming a complex with an Argonaute protein (AGO).
[0053]: In the present invention, "antisense oligonucleotide" is a drug with the potential to realize personalized medicine together with an RNAi therapeutic agent and a single-stranded nucleic acid polymer synthesized with 12 to 25 nucleotides on average, and may regulate protein expression through various mechanisms with specific sequence complementarity to a target RNA.
While the specification envisions the use of any of the above materials, the specification only exemplifies the use of a commercially available siRNA targeting CTSS (Santa Cruz sc-29940) in FIG. 3A-B, FIG. 4A-D, FIG. 5A-D, FIG. 6A-B, FIG. 7A-B, and commercially available Mouse Ctss (Santa Cruz) in Fig. 8. However, the specification fails to provide the siRNA sequence utilized to target CTSS in the RPE cells of FIGs 3 through 7, and fails to provide the siRNA sequence utilized to target mCTSS in the in vivo study in FIG 8.
Nonetheless, the disclosure does not describe a complete or partial structure of any of the following molecules having the claimed function of reducing CTSS expression by either having sequence complementarity to CTSS mRNA or inhibits expression of CTSS mRNA: (a) short hairpin RNA (shRNA), micro RNA (miRNA), and antisense oligonucleotides (ASOs) targeting CTSS mRNA with complementarity; (b) siRNA, shRNA, miRNA and ASOs that target mRNA upstream or downstream of CTSS that indirectly regulate and inhibit CTSS expression; or (c) isoform specific CTSS mRNA complementarity regarding siRNA, shRNA, miRNA, and ASO structure.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only
representative of a two commercially available siRNA of undisclosed sequence and structural modifications. The results are not necessarily predictive of all “nucleic acids” or even siRNA capable of reducing CTSS expression, by either having sequence complementarity to CTSS mRNA or inhibiting expression of CTSS mRNA, and treating age-related macular degeneration.
Thus, it is impossible for one to extrapolate from the two examples described herein that those “nucleic acids” selected from a group consisting of “siRNA, shRNA, miRNA, and ASOs” would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not seem to offset the deficiencies of the instant application in that it does not describe a set of siRNA, shRNA, miRNA, or ASOs capable of reducing CTSS expression, by either having sequence complementarity to CTSS mRNA or inhibiting expression of CTSS mRNA, and treating age-related macular degeneration.
First, looking to the art for nucleic acids to treat age-related macular degeneration, Hassan et al (Targeting the Eye: RNA-Based Therapies, Interferences, and Delivery Strategies, Pharmaceutics, Vol 17, Issue 1326, pages 1-29, October 13, 2025; see PTO 892 from 02/10/2026) teaches posterior segment eye diseases (including age-related macular degeneration), ocular drug delivery strategies, and RNA-based technologies with an emphasis placed on the application of RNA modalities-siRNA, miRNA, shRNA, RNA aptamers, and ASO (page 2, paragraph 3).
Regarding the current state of the art for which nucleic acids target posterior segment eye diseases, Hassan et al teaches, “There are only a few RNA-based therapies approved for diseases in the posterior segment of the eye. FDA-approved RNA-based therapies for posterior eye diseases include Vitravene (fomivirsen), an antisense oligonucleotide for cytomegalovirus retinitis (CMV) in 1998; Macugen (pegaptanib), an aptamer targeting vascular endothelial growth factor (VEGF) protein for wet age-related macular degeneration (AMD) in 2004; and Izervay (avacincaptad pegol), an aptamer targeting complement protein C5 for geographic atrophy (GA) secondary to AMD in 2023. Both Vitravene and Macugen are discontinued and no longer available in the United States. Vitravene was withdrawn due to low demand and Macugen was discontinued after more effective anti-VEGF therapies (e.g., anti-VEGF antibody, antibody fragment, and fusion protein) became available. To our knowledge, there is no approved RNA-based therapy with gene delivery or RNA interference (RNAi) that silences gene expression for posterior eye diseases.”, (page 2, paragraph 2).
Table 5 from Hassan et al teaches the various siRNA as therapeutics in studies their related-eye disease. Bevasiranib and AGN211745 target VEGF in wet AMD; PF-04523655 targets REDD1 gene in AMD; and ISTH0036 targets TGF-beta mRNA in AMD. “Bevasiranib has shown promise in early-phase clinical trials (see Section 5), but the development was halted after a Phase 3 trial due to the lack of sufficient efficacy compared to existing anti-VEGF treatments like ranibizumab (Lucentis) and aflibercept (Eylea).”, (page 14, paragraph 6). Regarding AGN211745, “Although early results showed good tolerability, efficacy was insufficient compared to current anti-VEGF therapies, and its development was discontinued.”, (page 14, paragraph 7). Regarding PF-04523655, the phase 2 was completed in 2013, however, it was only evaluating diabetic macular edema alone (see table 9). Regarding ISTH0036, by phase 1, it was used for targeting TGB-beta2 in glaucoma undergoing trabeculectomy (see table 9).
Lastly, Table 9 of Hassan et al teaches RBM-007, SYL1801, OLX10212, and HG202 for targeting wet AMD. RBM-007 is an anti-FGF2 aptamer. SYL1801 an siRNA with an unknown target. OLX10212 is a cell penetrating asymmetric small interference RNA targeting inflammation pathways in the development of AMD (page 21 and paragraph 1). HG202 is phase 1 CRISPR/Cas13 system for partially knocking down the expression of VEGFA for wet AMD.
Thus, when looking to the state of the art for treating age-related macular degeneration, it is silent on siRNA, shRNA, miRNA, and ASOs reducing expression of CTSS by either having sequence complementarity to CTSS mRNA or inhibiting expression of CTSS mRNA, and treating age-related macular degeneration. The art does teach current clinical trials with the potential of siRNA or CRISPR/Cas13 being a viable AMD therapy, however, these materials/nucleic acids involve targeting VEGF, therefore, the art does not make up for the lack of description provided by the specification.
Secondly, looking to the art for how CTSS inhibitors are used in therapeutics, Gao et al (Cathepsin S: molecular mechanisms in inflammatory and immunological processes, Front Immunol, Vol 16, Issue 1600206, pages 1-11, July 2025; see PTO 892 from 02/10/2026) lists seven drugs in various stages of clinical trials for their use in Sjogren’s syndrome, celiac disease, nerve pain, psoriasis, aortic aneurysm, rheumatoid arthritis, and neuropathic pain (Table 1 – A list of CTSS inhibitors at different stages of clinical trials). Gao et al suggests, “While foundational insights into CTSS-disease associations have been established, there remain critical gaps in systematically mapping its molecular mechanisms across immune-inflammatory pathways…The current clinical development of CTSS inhibitors shows promise in attenuating inflammatory lesions while preserving homeostatic functions, although further refinement is needed to optimize therapeutic efficacy.”, (see page 9, column 1, paragraph 2).
Gao et al further mentions, “[W]e propose a strategy targeting CTSS through isoform-specific inhibition . . .”, (see page 9, column 1, paragraph 2).
Other than the current clinical trial inhibitors targeting CTSS, Gao et al does not mention any other “nucleic acids” used for targeting CTSS expression and activity, particularly in the treatment of age-related macular degeneration.
Thus, the art (state of the art and prior art) does not appear to offset the deficiencies of the specification. Merely describing “nucleic acids” from the group consisting of siRNA, shRNA, miRNA, and ASOs capable of reducing CTSS expression, by either having sequence complementarity to CTSS mRNA or inhibiting expression of CTSS mRNA, and treating age-related macular degeneration without sufficient detail relating to the “ nucleic acids” such i.e., siRNA, shRNA, miRNA, and ASOs, in treating age-related macular degeneration does not allow a skilled artesian to reasonably conclude that the Applicant was in possession of the claimed invention for claim(s) 13 and 15-19.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Written Description
The previous rejection of claim 14 under 35 U.S.C 112(a) for written description is moot in view of Applicant’s cancellation of the claim filed 05/11/2026.
With respect to the rejection of claims 13 and 15-19 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, Applicant's arguments from page 12-13 of the reply filed 05/11/2026 have been fully considered but they are not persuasive.
Applicant’s remarks received on 05/11/2026 have been fully considered but they are not persuasive for at least the following reasons.
Applicant contends (1) that claims have been amended so that the claims are no longer directed to a broadly defined functional concept (i.e., “material”), and have been amended to limit the claims to “a specific and clearly defined technical category” through the limitation of “nucleic acids that suppress CTSS expression based on sequence complementarity to CTSS mRNA”. Applicant contends (2) that “While the specific modes of action may differ, siRNA and shRNA primarily induce degradation of target mRNA, miRNA generally acts by translational repression and/or mRNA degradation, and antisense oligonucleotides inhibit expression through sequence-specific binding to target RNA.”, and Applicant contends that all of these nucleic acids share a common “technical principle” of reducing gene expression based on sequence complementarity to a target mRNA. Applicant contends (3) that one of ordinary skill in the art would directly and unambiguously recognize this unified concept from the original disclosure and would understand that the inventor was in possession of the claimed invention at the time that the application was filed.
Regarding (1), claim 13 is limited to the recitation of “wherein the nucleic acid has sequence complementarity to CTSS mRNA. . .”, however, it also includes an alternative embodiment of “wherein the nucleic acid inhibits expression of CTSS mRNA” as per the “or” in line 6 of claim 13. That alternative or optional embodiment broadly encompasses siRNA, shRNA, miRNA, and ASOs that do not require complementarity to CTSS mRNA and could broadly encompass binding the mRNA of proteins that are upstream or downstream of CTSS and regulate CTSS expression in a way that when those mRNAs of said upstream or downstream proteins are dysregulated, they inhibit the expression of CTSS. Thus, while the Applicant states that the limitation of “nucleic acids that suppress CTSS expression based on sequence complementarity to CTSS mRNA” contain “a specific and clearly defined technical category”, the addition of the phrase “. . . or wherein the nucleic acid inhibits expression of CTSS mRNA” renders the claim to broadly encompass any mRNA that could inhibit CTSS and those are not adequately described in the instant specification or made up for by the prior art.
Regarding (2), siRNA, shRNA, miRNA, and ASOs may all share a “common technical principle” for reducing expression based on sequence complementarity, however, these sequences must be capable of treating macular degeneration. As taught by Gao et al, there remain critical gaps in systematically mapping its molecular mechanisms across immune-inflammatory pathways, and the current clinical development of CTSS inhibitors shows promise in attenuating inflammatory lesions while preserving homeostatic functions, although further refinement is needed to optimize therapeutic efficacy
Regarding (3), in combination with the response to arguments in (1) and (2), one of ordinary skill in the art would not have been able to look to the specification to understand possession of the invention at the time of the application being filed with a lack of disclosing of any/all other mRNAs that may be of target to nucleic acids that could inhibit the expression of CTSS, or any/all chemical modifications of said nucleic acids that must be capable of reducing CTSS expression, by either having sequence complementarity to CTSS mRNA or inhibiting expression of CTSS mRNA, and treating age-related macular degeneration without sufficient detail relating to the “ nucleic acids” such i.e., siRNA, shRNA, miRNA, and ASOs, in treating age-related macular degeneration.
Accordingly, the rejection on 35 U.S.C. 112(a) for lack of written description is maintained for claim(s) 13 and 16-19.
Claim Rejections - 35 USC § 112(a) – Enablement
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(s) 13 and 15-19 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 enablement requirement. The claim(s) contain 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 use the invention. Claimed subject matter is a method of treating age-related macular degeneration, the method comprising administering a pharmaceutical composition comprising an effective amount of a material that reduces the expression or activity of cathepsin S (CTSS) to a subject in need thereof. This rejection was made in the Office action mailed 02/10/2026 and has been rewritten to address the amendment to the claims in the reply filed on 05/11/2026.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: (1) the nature of the invention, (2) the breadth of the claims, (3) the guidance or amount of direction provided by the Inventor, (4) the existence of working examples, (5) the predictability and state of the art, and (6) the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the claims, with the most relevant factors discussed below.
(1) Nature of the invention and (2) Breadth of the claims:
Claim 13 is drawn to A method of treating age-related macular degeneration, the method comprising administering a pharmaceutical composition comprising an effective amount of a material to a subject in need thereof, wherein the material is a nucleic acid that reduces expression of cathepsin S (CTSS), wherein the nucleic acid has sequence complementarity to CTSS mRNA or inhibits expression of CTSS mRNA, and wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs). The nature of the invention is complex in that the reducing of CTSS expression with a nucleic acid that has sequence complementarity to CTSS mRNA or a nucleic acid that inhibits expression of CTSS mRNA, wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs) must result in treating age-related macular degeneration.
Claim(s) 15-16 are drawn to the method of claim 13, wherein the age-related macular degeneration is age-related macular degeneration under oxidative stress conditions (claim 15) and wherein the age-related macular degeneration is dry age-related macular degeneration or wet age-related macular degeneration (claim 16). The nature of the invention is complex in that the reducing of CTSS expression with a nucleic acid that has sequence complementarity to CTSS mRNA or a nucleic acid that inhibits expression of CTSS mRNA, wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs) must result in also treating age-related macular degeneration under oxidative stress conditions and/or dry and/or wet.
Claim(s) 17-19 are drawn to the method of claim 13, further comprising inhibiting inflammatory cytokines and complement activity in the retina, inhibiting intravascular endothelial production, and/or inhibiting angiogenesis (claim 17). Claim 18 further limits claim 17, wherein the inflammatory cytokine is any one or more selected from the group consisting of TNF-a, IL-1p, and MCP-1. Claim 19 further limits claim 17, wherein the complement is any one or more selected from the group consisting of C3, C5, C3a, C5a, and C5b-9. The nature of the invention is complex in that the reducing of CTSS expression with a nucleic acid that has sequence complementarity to CTSS mRNA or a nucleic acid that inhibits expression of CTSS mRNA, wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs) must result in also treating age-related macular degeneration and inhibit inflammatory cytokines and complement activity in the retina, inhibit intravascular endothelial production, and/or inhibit angiogenesis.
The broadest reasonable interpretation of claims 13 and 15-19 is that the invention is drawn to a method for treating age-related macular degeneration (wet or dry or under oxidative conditions) comprising administering a pharmaceutical composition comprising an effective amount of a material to a subject in need thereof (“subject” refers to a subject in need of treatment of a disease, and more specifically, refers to a mammal such as a human or a non-human primate, a mouse, a rat, a dog, a cat, a horse, and a cow [0101]), wherein the material is siRNA, shRNA, miRNA and/or an ASO that reduces expression of CTSS, wherein the any/all siRNA, shRNA, miRNA and/or ASO have sequence complementarity to CTSS mRNA or the any/all siRNA, shRNA, miRNA and/or ASO inhibit expression of CTSS mRNA.
The claims broadly encompass the administration of a nucleic acid to reduce Cathepsin S expression, where the nucleic acid (i.e., siRNA, shRNA, miRNA, and ASO) is/are defined solely or primarily by function. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
(3) Guidance of the specification and (4) existence of working examples:
(3) The specification envisions treating age-related macular degeneration. The method envisioned comprises of a material to a subject in need thereof, wherein the material is a nucleic acid that reduces expression of cathepsin S (CTSS), wherein the nucleic acid has sequence complementarity to CTSS mRNA or inhibits expression of CTSS mRNA, and wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs). More specifically, the specification envisions guidance on (a) treating, (b) administering, (c) pharmaceutical composition, (d) effective amount, (e) nucleic acids, (f) reducing expression, and (g) subject through disclosing the following (bold added for emphasis):
(a) “…"treatment" refers to all actions that ameliorate or beneficially change a target disease and the resulting metabolic abnormalities by administration of the pharmaceutical composition according to the present invention, and the "amelioration" refers to all actions that reduce a target disease and associated parameters, for example, the severity of symptoms, by administration of the composition according to the present invention.”, (see paragraph [0103]).
(b/c) “The "administration" as used herein refers to the provision of a predetermined composition of the present invention to a subject in need thereof by any suitable method.”, (see paragraph [0102]). “The pharmaceutical composition of the present invention may be administered to a subject in need via various routes. All methods of administration may be expected, but the pharmaceutical composition may be administered by, for example, oral administration, subcutaneous injection, peritoneal administration, intravenous injection, intramuscular injection, paraspinal space (intradural) injection, sublingual administration, buccal administration, intrarectal insertion, intravaginal injection, ocular administration, ear administration, nasal administration, inhalation, spraying via the mouth or nose, skin administration, transdermal administration, and the like.”, (see paragraph [0099]).
(c/d) -“The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat diseases at a reasonable benefit/risk ratio applicable to medical treatment, and an effective dosage level may be determined according to factors comprising the type of disease of a patient, the severity of the disease, the activity of drugs, sensitivity to drugs, administration time, administration route, excretion rate, treatment period, and simultaneously used drugs, and other factors well known in the medical field.” (see paragraph [0097]).
(e) “According to an exemplary embodiment of the present invention, the substance may be any one or more selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA), antisense oligonucleotides (ASOs), Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas), natural products, proteins, peptidomimetics, antibodies, exosomes, and compounds, but is not limited thereto.”, (see paragraph [0014]).
“As used herein, "polynucleotide" or "nucleic acid" refers to deoxyribonucleic
acid (DNA) or ribonucleic acid (RNA) in either a single- or double-stranded form. Unless otherwise limited, the term also encompasses known analogs of natural nucleotides which are hybridized to a nucleic acid in a manner similar to naturally occurring nucleotides.”, (see paragraph [0048]).
The specification envisions siRNAs as generally 17-24bp in length [0049], shRNAs as a short hairpin RNA having a loop structure that induces the Nai phenomenon [0051], miRNAs as a single-stranded RNA molecule with a length of about 22 nucleotides [0052], and ASOs as a single-stranded nucleic acid polymer synthesize with 12 to 25 nucleotides on average [0053]. The specification envisions ASO modifications such that an ASO may be used being modified with a phosphorothioate, a phosphorodiamidate morpolino oligonucleotide, a peptide nucleic acid, a locked nucleic acid, ribose modifications, and the like [0054].
(f) “As used herein, "expression suppression" refers to all actions that reduce the expression of a gene, and may be achieved by gene knock-out, knock-down, or introducing mutations such as deletion, duplication, inversion, or translocation into gene DNA sequences, but is not limited thereto.”, (see paragraph [0127]).
(g) “As used herein, the “subject” refers to a subject in need of treatment of a disease, and more specifically, refers to a mammal such as a human or a non-human primate, a mouse, a rat, a dog, a cat, a horse, and a cow.”, (see paragraph [0101]).
The specification provides working examples for the following (each number below in this section corresponds to the working example provided in the specification):
(1) In vitro: Confirming the decrease in cultured RPE cells viability according to peroxide (H2O2) treatment. ARPE-19 cells were treated with increasing concentration of peroxide for 48 hours, MTT solution was added to the medium for 4 hours, cells were lysed, and optical density readings at 540 nm were taken. FIG. 1A shows a decrease in cell viability with the group treated with peroxide, demonstrating peroxide acts as a stress that can affect RPE cell survival. iNOS mRNA levels were measured in RPE cells and showed an increase with peroxide treatment in FIG. 1B, demonstrating that peroxide acts as an oxidative stress on RPE cells (summation of paragraphs [0130] to [0134] and FIG. 1A-C).
(2) In vitro: Confirming an increase in expression of CTSS in RPE cells under the previously determined oxidative stress of peroxide. mRNA and protein levels of CTSS were measured in RPE cells after treatment with peroxide (summation of paragraphs [0135] to [0136] and FIG. 2A-B).
(3) In vitro: Confirming CTSS mRNA expression in cultured RPE cells treated with both peroxide and CTSS siRNA. Relative expression of CTSS in CTSS knockdown RPE cells was about 1/100th of that of the control despite peroxide treatment. This example also confirmed immunofluorescence of CTSS in RPE cells treated with both peroxide and CTSS siRNA. CTSS was significantly decreased in CTSS siRNA + peroxide compared to control siRNA + peroxide (Summation of paragraphs [0138] to [0142] and FIG. 3A-B).
(4) In vitro: Confirming inflammatory cytokine reduction in cultured RPE cells when CTSS is knockdown. RPE cells (control siRNA versus CTSS siRNA) were treated with peroxide. Inventor measured p-NFkB (the active form of NfkB) expression and the mRNA/proteins levels of TNF-alpha, IL-1beta, and MCP-1. The results indicate that the RPE cells treated with control siRNA and peroxide demonstrated increased mRNA expression levels of TNF-alpha, IL-1beta, and MCP-1 versus the CTSS siRNA with and without peroxide (Fig. 4A-C). As well as reduced protein levels of pNF-kB, TNF-alpha, IL-1beta, and MCP-1 when RPE cells were treated with CTSS siRNA and peroxide compared to the control (FIG. 4D) (summation of paragraphs [0143] to [0144] and FIG. 4A-D).
(5) In vitro: Confirming complement factor expression is reduced in cultured RPE cells subjected to CTSS siRNA. C3aR and C5aR mRNA levels were induced by peroxide treatment but reduced in conditions of CTSS siRNA. C3, C5, C3aR, C5aR, and C5b-9 proteins were induced by peroxide treatment but reduced in conditions of CTSS siRNA (summation of paragraphs [0145] to [0147] and FIG.5A-D).
(6) In vitro: Confirming inhibitory effect of complement activity in cultured RPE cells by treating RPE cells with control and CTSS siRNA or DMSO and an NF-kB inhibitor (Bay 1170-82), and then a mixture of both CTSS siRNA and NF-kB inhibitor. Immunofluorescence was performed for C3a and C5a. Data points to CTSS siRNA suppressing complement expression more readily than Bay 1170-82 (FIG. 6A-B). A combination of CTSS siRNA and Bay 1170-82 demonstrated a synergistic effect greater than either composition alone (summation of paragraph [0148] to [0149] and FIG. 6A-B).
(7) In vitro: Confirming angiogenesis reduction in cultured RPE and HUVEC cells with CTSS siRNA. RPE cells treated with peroxide showed an increase in PPAR and VEGFA/AKT, whereas treatment with CTSS siRNA shows a significant decrease (Fig. 7A). HUVECs demonstrated an increase in tube formation when treated with peroxide however that was inhibited when treated with CTSS siRNA (summation of paragraphs [0150] to [0151] and FIG. 7A-B).
(8) In vivo: Confirming angiogenesis is reduced with CTSS siRNA in a choroidal neovascularization (CNV) model. CNV in the mouse was induced by laser. Three retinal burn lesions were induced in the right eye of each mouse. Formation of a bubble was considered a valid burn and a sign of Bruch’s membrane rupture. Control and CTSS siRNA were diluted in water and injected into both eyes. Immunohistochemistry was performed. Results indicate that the amount of CNV was significantly reduced after injection with CTSS siRNA versus control (summation of paragraphs [0152] to [0153] and FIG. 8).
The following is in regard to whether or not the specification demonstrates enablement:
A subject, as defined by the specification refers to a subject in need of treatment of a disease, and more specifically, refers to a mammal such as a human or a non-human primate, a mouse, a rat, a dog, a cat, a horse, and a cow. Working examples (1) through (7) are performed in vitro in either RPE or HUVEC cells to demonstrate reduction of expression and/or activity of CTSS, however, example (8) utilizes a mouse, which is encompassed in the definition of a subject.
Even if one accepts the single working example (8) as a display of enablement, claim 13 broadly encompasses nucleic as: small interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA), and antisense oligonucleotides (ASOs); all of which necessitate various routes of administration, various modifications, as well as varying effective amounts to reduce expression of CTSS. Working example (8) utilizes only one material, a commercially available mCTSS siRNA, that of which is different than the CTSS siRNA utilized in RPE/HUVEC cells. Working example (8) does not demonstrate a clear reduction in CTSS expression or activity, only a correlative observation that choroidal neovascularization was reduced with the commercially available mCTSS. All working examples, lack utilization of materials other than two commercially available siRNA.
Thus, there are no working examples of the use of the claimed method of treating age-related macular degeneration, the method comprising administering a pharmaceutical composition comprising an effective amount of a material to a subject in need thereof, wherein the material is a nucleic acid that reduces expression of cathepsin S (CTSS), wherein the nucleic acid has sequence complementarity to CTSS mRNA or inhibits expression of CTSS mRNA, and wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs).
(5) Predictability and state of the art:
(5) Looking to the state of the art on reducing CTSS expression for the treatment of age-related macular degeneration in two research articles and a review:
Lai et al (The Use of Adenovirus-Mediated Gene Transfer to Develop a Rat Model for Photoreceptor Degeneration, Invest Ophthalmol Vis Sci, Vol 41, pages 580-584, 2000; see PTO 892 filed on 02/10/2026) discloses investigating the effects of the downregulation of cathepsin S on retinal pigment epithelium and/or neural retina in vivo (“purpose” section, page 580). Lai et al previously constructed a recombinant adenovirus carrying the cathepsin S (CatS) gene in antisense orientation (Ad.CatSAS). Ad.CatSAS transduces cultured RPE cells with high efficiency and downregulates endogenous CatS production in the transduced cells (page 580, column 2, paragraph 1).
More specifically, Lai et al discloses, “In a previous study, the accumulation of auto fluorescent debris in animals injected with cysteine protease inhibitors was reported to be accompanied by some disorganization in the POS layer. Compared with these protease inhibitor studies, the neural retinal changes observed in Ad.CatSAS-injected animals were more pronounced. These changes included the shortening of the POSs and a decrease in the number of layers of photoreceptor cells in the outer nuclear layer, which were not observed in vehicle-, Ad.gfp-, or Ad.CatSS-injected animals. Therefore, it can be concluded that these changes were induced by Ad.CatSAS. Protease inhibitor uptake is not a cell-specific process; thus, protein inhibition studies were unable to determine whether changes in the photoreceptor layer were due to inhibition of neural retinal cysteine protease activity or to the breakdown of RPE function. Because subretinally delivered recombinant adenoviruses specifically transduce RPE cells, and the effect of the antisense RNA is limited to the transduced cells, it is thus suggested that the neural retinal changes observed are secondary effects of the downregulation of CatS activity in the RPE cell layer. From this study, a correlation between Ad.CatSAS delivery and photoreceptor degeneration was established.”, (page 583, column 2, paragraph 1).
Lastly, Lai et al suggests, “CatS may play an important role in the maintenance of normal retinal function.”, (page 584, column 1, paragraph 2).
In a later review, Im and Kazlauskas (The role of cathepsins in ocular physiology and pathology, Experimental Eye Research, Vol 84, pages 383-388, August 7th, 2006; see PTO 892 filed 02/10/2026) teaches the following:
Deregulation of cathepsin activity may be a contributing factor to various degenerative diseases of the neural retina such as age-related macular degeneration (page 85, column 1, paragraph 2);
There was an increase in the level of cathepsin S mRNA and protein in the RPE/choroid, of mice as they aged (page 85, column 1, paragraph 2);
Cystatins are potent, endogenous inhibitors of cysteine proteases, included cathepsins (page 58, column 2, paragraph 1);
Cystatin C in the RPE could be involved in the regulation of photoreceptor degradation, which is mediated by cathepsin D and S (page 58, column 2, paragraph 2);
Expression of mature cystatin C in RPE correlated with an increased risk of developing exudative AMD (page 58, column 2, paragraph 2).
Of note: Cystatin C is an inhibitor of Cathepsin S as evidenced by the abstract of Nagy et al (Elevated Serum Cystatin C and Decreased Cathepsin S/Cystatin C Ratio Are Associated with Severe Peripheral Arterial Disease and Polyvascular Involvement, Dianostics (Basel), Vol 12, Issue 4, pages 1-15, March 28, 2022; see PTO 832 filed 02/10/2026).
To tie Im and Kazlauskas’s teachings to current state of the art, a recent post filing art, Lee and Seo (Potential Casual Effects of Cystatin C on Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study, biomedicines, Vol 13, Issue 2827, pages 1-13, November 20th, 2025; see PTO 892 filed 02/10/2026), teaches the following:
“Studies in cell cultures and animals suggest that cathepsins support retinal photoreceptor and Bruch’s membrane health, including by releasing antiangiogenic endostatins from Bruch’s membrane collagen… The harmful effect of elevated serum cystatin C is thought to arise from its interference with the protective role of cathepsins in releasing anti-angiogenic endostatins from Bruch’s membrane collagen, increasing the risk of exudative AMD…”, (see page 9, paragraph 2). More specifically, Lee and Seo discloses, “In conclusion, our study provides evidence that genetically elevated cystatin C levels are causally associated with increased risk of AMD and its subtypes…”, (page 10, paragraph 2).
Looking to the art for how CTSS inhibitors are used in therapeutics, Gao et al (Cathepsin S: molecular mechanisms in inflammatory and immunological processes, Front Immunol, Vol 16, Issue 1600206, pages 1-11, July 2025; see PTO 892 from 02/10/2026) lists seven drugs in various stages of clinical trials for their use in Sjogren’s syndrome, celiac disease, nerve pain, psoriasis, aortic aneurysm, rheumatoid arthritis, and neuropathic pain (Table 1 – A list of CTSS inhibitors at different stages of clinical trials). Gao et al suggests, “While foundational insights into CTSS-disease associations have been established, there remain critical gaps in systematically mapping its molecular mechanisms across immune-inflammatory pathways…The current clinical development of CTSS inhibitors shows promise in attenuating inflammatory lesions while preserving homeostatic functions, although further refinement is needed to optimize therapeutic efficacy.”, (see page 9, column 1, paragraph 2).
Thus, one of skill in the art would appreciate the unpredictability of a method of treating age-related macular degeneration, the method comprising administering a pharmaceutical composition comprising an effective amount of a material to a subject in need thereof, wherein the material is a nucleic acid that reduces expression of cathepsin S (CTSS), wherein the nucleic acid has sequence complementarity to CTSS mRNA or inhibits expression of CTSS mRNA, and wherein the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antisense oligonucleotides (ASOs). The art teaches that CTSS reduction, either by an antisense CTSS (Lai et al) or through elevated cystatin C (Lee and Seo) (an endogenous inhibitor of CTSS) leads to an increased risk of age-related macular degeneration. Lai et al teaches that protease inhibitor uptake is not a cell-specific process, limiting the possibilities for various routes of administration. Gao et al teaches, that there remain critical gaps in systematically mapping its molecular mechanisms across immune-inflammatory pathways and that the current clinical development of CTSS inhibitors shows promise in attenuating inflammatory lesions while preserving homeostatic functions, although further refinement is needed to optimize therapeutic efficacy.
Therefore, with siRNA to commercially available mouse CTSS being the only nucleic acid used throughout the application, claims 13, and 15-19 are not enabled.
(6) Amount of experimentation necessary:
(6) The quantity of experimentation required to carry out the scope of the invention is large. First, one would be required to randomly screen different nucleic for the ability to reduce expression of CTSS through being complementary to CTSS mRNA and mRNA of other proteins that regulate the expression of CTSS mRNA. Next, one would need to test each identified nucleic acid in an art-accepted model of each type of age-related macular degeneration (wet and dry and under oxidative stress) for the ability to treat. Success with any one nucleic acid (e.g., miRNA) would not guarantee success with any other nucleic acid (e.g., siRNA). This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering that any positive results (e.g., successfully treating age-related macular degeneration in a subject through reducing expression of CTSS) with any nucleic acid through any route of administration, wet or dry and/or under oxidative stress, would amount to a significant advancement in the state of the art, additional experimentation required is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to use the claimed invention. Therefore, claims 13 and 15-19 are not considered to be enabled by the instant disclosure.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Enablement
The previous rejection of claim 14 under 35 U.S.C 112(a) for Enablement is moot in view of Applicant’s cancellation of the claim filed 05/11/2026.
With respect to the rejection of claims 13 and 15-19 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 Enablement requirement, Applicant's arguments on pages 13-14 of the reply filed 05/11/2026 have been fully considered but they are not persuasive.
Applicant’s remarks received on 05/11/2026 have been fully considered but they are not persuasive for at least the following reasons.
Applicant contends (1) that the specification establishes that suppression of CTSS expression leads to improvement of disease-related pathological conditions by demonstrating siRNA-based experiments, that suppression of CTSS expression under oxidative stress conditions in RPE cells results in consistent reduction of inflammatory cytokines, complement activation, and angiogenesis-related markers, and that the in vivo experiments using a CNV model show a significant reduction in neovascularization. Applicant contends (2) that the amended claim(s) no longer are directed to a heterogenous group of unrelated materials and are now limited to nucleic acids that share the same mechanism of action. Applicant contends that (3) it is routine for a person of skill in the art to design complementary nucleic acids capable of suppressing expression using standard design and optimization methods.
Regarding (1), the Examiner agrees that the specification demonstrates use of commercially available siRNA to CTSS and mCTSS, however, the specification fails to demonstrate use of shRNA, miRNA, or an ASO for treatment of age-related dry or wet macular degeneration.
Regarding (2), Applicant stated that the recited nucleic acids are now limited to nucleic acids that share the same mechanism of action, however, on page 12 of the response filed 05/11/2026 Applicant also states that “While the specific modes of action may differ, siRNA and shRNA primarily induce degradation of target mRNA, miRNA generally acts by translational repression and/or mRNA degradation, and antisense oligonucleotides inhibit expression through sequence-specific binding to target RNA.”, thus providing the fact that each nucleic acid molecule varies by the mode of action. Further, claim 13 is limited to the recitation of “wherein the nucleic acid has sequence complementarity to CTSS mRNA. . .”, however, it also includes an alternative embodiment of “wherein the nucleic acid inhibits expression of CTSS mRNA” as per the “or” in line 6 of claim 13. That alternative or optional embodiment broadly encompasses siRNA, shRNA, miRNA, and ASOs that do not require complementarity to CTSS mRNA and could broadly encompass binding the mRNA of proteins that are upstream or downstream of CTSS and regulate CTSS expression in a way that when those mRNAs of said upstream or downstream proteins are dysregulated, they inhibit the expression of CTSS. Thus, while the Applicant states the amended claims are now limited to nucleic acids that share the same mechanism of action, the addition of the phrase “. . . or wherein the nucleic acid inhibits expression of CTSS mRNA” renders the claim to broadly encompass any mRNA that could inhibit CTSS and those are not enabled by the instant specification.
Regarding (3), in combination with the response to arguments in (1) and (2), Examiner agrees that is it routine to design complementary nucleic acids capable of suppressing expression using standard design and optimization methods. However, when it comes to nucleic acid design for therapy, Gao et al teaches that there remain critical gaps in systematically mapping its molecular mechanisms across immune-inflammatory pathways and that the current clinical development of CTSS inhibitors shows promise in attenuating inflammatory lesions while preserving homeostatic functions, although further refinement is needed to optimize therapeutic efficacy. Thus, one would not look to the instant specification and be enabled to make or use said nucleic acids for the treatment of age-related macular degeneration without undue experimentation.
Accordingly, the rejection on 35 U.S.C. 112(a) for Enablement is maintained for claim(s) 13 and 15-19.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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