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 .
Election/Restrictions
Claims 3, 7, and 9 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/26/2025.
Amendments and Arguments
This action is in response to papers filed 24th August 2026 in which claim 1 was amended with limitations from canceled claims. All of the amendments have been thoroughly reviewed and entered, some claims were cancelled and new claims were added. New claims are added to examined group.
Applicant's arguments are directed to the previous rejections of the previous claims.
The amendments made to the claims have overcome these previous rejections; the §112(a) rejection of claims 1, 4, 6, 8, and 10-14 for lack of written description, the §102 rejection of claims 1-2, 4, and 14 over ALARCON-MARTINEZ, and the §103 rejection of claims 1-2, 4-6, 8, and 10-14 over Chen in view of others is withdrawn. However, new rejections applicable to the current claims are presented in this office action. Applicant's remarks have been fully considered but are moot because they do not specifically address the current rejections of the current claims. Any rejection or objection not reiterated herein has been overcome by amendment.
Status of Claims
Claims 1, 4-6, 8, 10-14, and 19-26 are under consideration.
Drawings
The drawings are objected to because:
The text in FIGs. 2, 4, 5, 6, 7, 8, 9, 10, 12, and 13 are not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”; in other words, the text in the figures stated is too small.
Similarly, the light text on the light shading in Fig. 14 is hard to.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
Claim 1:
retinal or choroidal disease
The spec on pg. 16. 2nd to the last para defines retinal or choroidal disease as a vascular permeability-related retinal or choroidal disease, but is not limited thereto. Therefore, retinal or choroidal diseases are being interpreted to mean disorder of ocular vascularization that could be retinal or choroidal. See abstract, Campochiaro, Progress in Retinal and Eye Research, Volume 49, November 2015, Pages 67-81 (previously cited).
a retinal or choroidal disease accompanied by at least one selected from the group consisting of pericyte loss, pericyte degeneration, abnormal neovascularization, vascular leakage, microaneurysm, drusen formation, and inflammation is being interpreted as the treatment of retinal or choroidal diseases wherein the retinal or choroidal disease arises from or shows at least one of: a reduction in numbers of pericytes, unwanted neovascularisation, vascular leakage, microaneurysm, drusen formation, and inflammation.
Claim 8: the method above results in improvement in choroidal vasculature in any of the diseases recited.
Claim 14: the result of the inhibition is any one effect as recited.
Withdrawn Claim Rejections - 35 USC § 102
ALARCON-MARTINEZ taught capillary constriction caused by retinal ischemia can be inhibited by suppressing the expression of a-SMA (ACTA2), taught the correlation of diabetic retinopathy, retinal artery occlusion, microvascular pericyte contraction and a-SMA (corresponding to ACTA2) expression inhibition, and indicate that capillary contraction caused by retinal ischemia is inhibited by inhibiting the expression of a-SMA. ALARCON-MARTINEZ also taught inhibition of Acta2 has various effects on vascularization, for e.g., SMA inhibition results in inhibition of vascular leakage (because pericyte dysfunction promotes blood-retina barrier leakiness as well as disruption of the blood-brain and cochlear blood-intrastrial fluid barrier).
However, nothing in ALARCON-MARTINEZ taught that the subject to be treated can be a retinal or choroidal disease accompanied by at least one selected from the group consisting of pericyte loss, pericyte degeneration, abnormal neovascularization, vascular leakage, microaneurysm, drusen formation, and inflammation (see claim interpretation).
Therefore, the arguments of Applicant regarding, ALARCON-MARTINEZ are persuasive. The §102 rejection is withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-6, 8, 14 and 19-26 are rejected under 35 U.S.C. 103 as being unpatentable over Ueno (WO 2020009248 A1), as taught by its Machine-English translation in view of
GenBank (NM_007392.3, Mus musculus actin, alpha 2, smooth muscle, aorta (Acta2), mRNA NCBI Reference Sequence, retrieved from <https://www.ncbi.nlm.nih.gov/nuccore/440309867?sat=48&satkey=124635688>, revision October 10 2020, retrieved Mar 3 2026, 5 pgs., previously cited) and Fakhr (Fakhr, E., Zare, F. & Teimoori-Toolabi, L. Cancer Gene Ther 23, 73–82 (2016), previously cited).
Regarding claims 1, 14, and, 25-26, Ueno discloses a drug composition (OBP801) that inhibits fibrosis in multiple ocular tissues. The subject population is one that demonstrates at least choroidal neovascularization ([0041], [0081]; retinal pigment epithelium, choroidal neovascularization, or age-related macular degeneration, [0027]). Various other conditions that are treated with Ueno’s composition include inflammation [0081]. Ueno’s composition administered to a model representing the above conditions results in inhibition of collagen and α-SMA production (Front page Fig. and Figs. 12,14-15, 22, 24, 30-31, 34). Ueno is silent on what gene encodes α-SMA. However, Genbank, referred to below in the rejection, provides that α-SMA is encoded by the ACTA2 gene (Summary: the protein encoded by this gene belongs to the actin family of proteins). Therefore Ueno’s composition reduces the expression of ACTA2 and is an α-SMA/ACTA2 inhibitor The pathological relief of such treatment accompanied by α-SMA inhibition is seen in the form of controlling the expression of pathological aggravating factor genes of choroidal neovascularization or choroidal angiogenesis [0041] to eventually result in suppression of fibrosis (title) and / or angiogenesis-inhibiting effect and scar formation in ocular tissue cells in vivo [0024]. Thus, Ueno’s composition is an α-SMA inhibitor.
Regarding claim 8, Ueno teach age-related macular degeneration (AMD) [0083].
Regarding claims 25-26, Ueno teach retinal disease (age-related macular degeneration (AMD) is a disease in which retinal pigment epithelial cells (RPE) in the macula degenerate causing choroidal neovascularization (CNV) [0009].
Ueno does not teach an active ingredient in the treatment of retinal or choroidal disease which is an siRNA or miRNA inhibitor to ACTA2 (claims 1 and 4) nor the specific sequences of siRNA (claims 5-6) or (claims 19-24).
However, before the effective filing date of instant invention, GenBank had taught the ACTA2 sequence, NM_007392. 3 mRNA transcript.
As seen by alignment, Applicant’s SEQ ID NO: 3-8 target the mouse Acta2 gene. For e.g., SEQ ID NO: 3 aligned with NM_007392. 3 Mus musculus ALPHA2 ACTA2 mRNA is shown below:
RESULT 1
US-18-249-036-3
Query Match 0.7%; Score 19; DB 1; Length 19;
Best Local Similarity 84.2%;
Matches 16; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 2076 CGTACACAAGACTCTCACA 2094
||:|||||||||:|:||||
Db 1 CGUACACAAGACUCUCACA 19
Also, before the effective filing date of instant invention, Fakhr had taught applying known cellular pathways of RNA interference for efficient siRNA design using automated tools, software, and algorithms (abstract and Fig 1). Fakhr had taught -efficiency of siRNA molecule design depends on known factors including target availability, secondary structures of mRNA, position of matching and intrinsic characteristics of siRNA and mRNA (pg. 73 para 4). Fakhr had taught detailed basic criteria for designing efficient siRNA for gene expression inhibition which includes target site factors, length of siRNA, specificity checking, and nucleotide content (pg. 73 para 5 and Table 1). Fakhr had taught efficient siRNA length of 19 as well as longer siRNAs ranging from 21 to 29 nucleotides with very good results (pg. 74 para 1). Fakhr had taught asymmetrical nucleotide content in the duplex for increasing targeting, with more G/C content at the 5′-end of the sense strand and more A/U at the 3′-end (pg. 75 para 4). Fakhr had taught other available known and effective siRNA design programs including AsiDesigner, siDesign and RNAi codex, Oligowalk (Table 2 pg. 77). Fakhr further had taught a scoring system for enhanced siRNA design to optimize gene targeting (pg. 79, Fig 3). Therefore, one of skill in the art would try to design siRNA sequences given the Genbank availability of the Acta2 mRNA sequence.
One of skill in the art knows that trial and error procedure is still required to identify potent siRNA candidates, further establishing the need to “try” the designed sequences to find optimal candidates.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try an siRNA sufficiently similar to Applicant’s SEQ ID NO: 3-8 using the siRNA design system of Fakhr and 100% complementarity with the GenBank mRNA sequence in order to target ACTA2 because siRNA designing was an art-recognized methodology. Before the effective filing date of Applicant’s invention, Fakhr had taught a design need for nucleic acid sequences which can influence target gene expression in multiple species. SiRNA targeting systems rely on a finite number of identified parameters such as target length, limited RNA nucleotides, combinations of nucleotides, and nucleotide length less than 30nt but ideally between 19 and 25nt, with a finite number of identified, predictable sequences. The length of Genbank evidenced ACTA2 mRNA is ~2572 nucleotides long and siRNAs vary between 19-25 nucleotides. Thus, there are ~2553 possible 19-mers that can target siRNA with 100% identity. As such, there are finite number of identified solutions evidenced by the GenBank sequences. The large, but finite number of possible solutions becomes much smaller and their function even more predictable once the skilled artisan makes use of the known screening tools taught in Fakhr. It would have been obvious to try siRNA oligonucleotides from SEQ ID NO: 3-8 to target a ACTA2 because Fakhr demonstrates that given a known target, siRNA sequences can be generated within their design system to influence gene expression with a measured and predictable outcome. Thus, one of ordinary skill in the art would have pursued the finite number of options, thereby arriving at the instantly claimed subject matter of pairs of sense and antisense RNA with a reasonable expectation of success. See MPEP 2144 II and 2143 I (E).
Thus, Ueno in view of GenBank and Fakhr make obvious instant claims 1, 4-6, 8, 14 and 19-26.
Claims 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Ueno (WO 2020009248 A1), as taught by its Machine-English translation in view of GenBank (NM_007392.3, Mus musculus actin, alpha 2, smooth muscle, aorta (Acta2), mRNA NCBI Reference Sequence, retrieved from <https://www.ncbi.nlm.nih.gov/nuccore/440309867?sat=48&satkey=124635688>, revision October 10 2020, retrieved Mar 3 2026, 5 pgs., previously cited) and Fakhr (Fakhr, E., Zare, F. & Teimoori-Toolabi, L. Cancer Gene Ther 23, 73–82 (2016), previously cited) as applied to claims 1, 4-6, 8, 14 and 19-26 above and further in view of Campochiaro (Progress in Retinal and Eye Research, Volume 49, November 2015, Pages 67-81).
Neither, Ueno nor Genbank nor Fakhr taught the limitations of claims 10-14.
However, before the effective filing date of instant invention, Campochiaro had taught abnormalities of ocular vascularization are key features of retinal or choroidal diseases (Fig. 2).
Regarding the treatment of claim 1, Campochiaro teach various therapies are directed to inhibiting vascularization (Neutralization of VEGF is currently the first line therapy …, but new treatments directed at some of the other molecular targets, …, are likely to provide additional benefit for subretinal/choroidal NV (neovascularization) and macular edema, abstract; Endogenous antiangiogenic proteins are appealing candidates for treatment of ocular NV, pg. 76, para 5.7.2).
Therefore, Campochiaro indicate that a method of treating vascular disorders would be a method of treating retinal or choroidal diseases.
Regarding claims 10 and 11, Campochiaro teach current methods of treating AMD are intravitreal administration (prolonged intravitreous injections in patients with choroidal NV due to AMD, pg. 79, para 9.2).
Regarding claim 12, Campochiaro teach current methods of treating AMD are intravitreal administration of VEGF inhibitors. However, anti-VEGF inhibitors as a single agent is fraught with problems. Therefore, Campochiaro advocate combination therapy. For e.g., Campochiaro teach, selective blockade of PDGF-B causes mild suppression of choroidal NV at Bruch's membrane rupture sites and has an additive suppressive effect when combined with a VEGF antagonist (bridging pgs. 73 and 74). Campochiaro teach that VEGF antagonists alone are unable to eliminate macular edema in some patients and the need for prolonged treatment to control edema is problematic and urge the reader to identify other contributors to macular edema that can be targeted (pg. 79, para 9.2). Therefore, Campochiaro teaches that treatment be carried out with a composition that comprises an anti-VEGF agent and another agent.
Regarding claim 13, it is evident that if two agents are to be delivered, they can be delivered either simultaneously or sequentially, as there are no other ways.
It would have been prima facie obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to have combined an inhibitor of ACTA2 as taught by Ueno into a method of treating ocular vascular disorders such as retinal or choroidal diseases because Campochiaro had indicated that methods of treating ocular vascular disorders work by relieving the pathological effects of abnormal vascularization and Ueno demonstrated that vascular abnormalities are caused by aberrant Acta2 expression. One would be motivated to do so for the advantage of obtaining a treatment that Campochiaro indicate is much needed in the field of ocular treatments. An inhibitor to ACTA2 was disclosed by Ueno, specifically that inhibiting ACTA2 reversed pathological effects, and one skilled in the art could have incorporated these prior art elements in to a method of treating as taught by Campochiaro. The combination would have worked as predicted with a reasonable expectation of success, because the combined elements would be working with no change in the respective functions exhibited before combination. See MPEP 2143 I.(A) and MPEP 2144.
Thus, Ueno, Genbank, and Fakhr in view of Campochiaro make obvious instant claims 10-13.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 24th August, 2026 to anticipation of amended claims under 35 USC § 102 have been fully considered and are persuasive. Indeed, the applied reference of Alarcon-Martinez does not teach limitations as amended.
The 35 USC §102 rejection of claims in view of Alarcon-Martinez is withdrawn.
Applicant's arguments filed 24th August, 2026 to a prima facie case of obviousness of claim rejections under 35 USC §103 have been fully considered and are persuasive. However, the arguments are directed to previous version of claims. The amendment has overcome the rejection. However, a new primary reference of Ueno has been applied in current office action, which reference applies to instant claims as amended.
As discussed in the current rejection above, the same secondary references are relied upon as in the previous office action for dependent claims.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1636
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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