DETAILED ACTION
Applicant’s response filed November 21, 2025 has been received and entered into the application file. All arguments have been fully considered. Claims 23 and 56-70 are currently pending. Claims 1-22 and 24-55 are cancelled. Claim 23 is currently amended.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 21, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
REJECTION(S) WITHDRAWN
Claim Rejections - 35 USC § 103
RE: Rejection of Claim(s) 23, 56-58, 60-67 and 69 under 35 U.S.C. 103 as being unpatentable over Apte, in view of Rayner and Naar, as evidenced by Najafi-Shoushtari and Britannica:
Applicant’s amendment submitted 11/21/2025 has amended claim 23 to now require treatment of dry age-related macular degeneration in a subject in need thereof.
As noted in Applicant’s Remarks, the cited reference to Apte teaches methods that are focused on treating diseases of the eye that are related to age-related macular degeneration (AMD), such as choroidal neovascularization (CNV), which is considered “wet” macular degeneration.
Therefore, due to the claim amendments the rejection under 35 U.S.C. 103 has been withdrawn, however the amendment has necessitated a new ground of rejection, as set forth below.
RE: Rejection of Claim(s) 59 under 35 U.S.C. 103 as being unpatentable over Apte, in view of Rayner and Naar, as evidenced by Najafi-Shoushtari and Britannica, and further in view of Monoharen;
Rejection of Claim(s) 68 under 35 U.S.C. 103 as being unpatentable over Apte, in view of Rayner and Naar, as evidenced by Najafi-Shoushtari and Britannica, and further in view of Vargeese; and
Rejection of Claim(s) 70 under 35 U.S.C. 103 as being unpatentable over Apte, in view of Rayner and Naar, as evidenced by Najafi-Shoushtari and Britannica, and further in view of Rayner 2011:
For the reasons discussed above, the rejection claim(s) 23, 56-58, 60-67 and 69 under 35 U.S.C. 103 as being unpatentable over Apte, in view of Rayner and Naar, as evidenced by Najafi-Shoushtari and Britannica is withdrawn, and thus the rejection of claims 59, 68 and 70 that is based on the same basis is likewise withdrawn. However, the amendment submitted 11/21/2025 has necessitated new grounds of rejection, as set forth below.
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
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.
Claim(s) 23, 56-58, and 60-70 are rejected under 35 U.S.C. 103 as being unpatentable over Rudolf et al., (US 2018/0207233; see PTO-892) (“Rudolf”), in view of Rayner et al., (NATURE, VOL 478, 2011; see IDS 4/29/2025, previously cited) (“Rayner 2011”) and Naar et al., (WO 2010/120508; previously cited) (“Naar”), as evidenced by Encyclopaedia Britannica -Nucleic acid (see PTO-892) (“Britannica”).
Regarding claims 23, 56-57 and 69-70, it is noted that Rudolf is directed to methods for treating age-related macular degeneration (AMD), by administering apolipoprotein (apo) mimetics (e.g., , L-4F or D-4F) in conjunction with another therapeutic agent, wherein the treatment is administered to subjects in different stages of AMD, including different phenotypes of AMS including geographic atrophy, i.e., dry AMD, (see specification at page 2, line 3, page 15, line 37, page 23, line 10 and page 28, lines 14-15) ([0002], [0142], claims 136-139). Rudolf teaches the other therapeutic agents include without limitation anti-dyslipidemic agents ([0003]-[0004]), such as anti-sense polynucleotides that target miRNA-33a and miRNA-33b, as recited in claims 69-70 (i.e., nucleotides complementary to an miR-33 target nucleic acid), which results in increase expression of ABCA1 which is responsible for mediating the efflux of cholesterol. Rudolf teaches use of the anti-sense polynucleotides that are complementary to miRNA-33a and/or miRNA-33b increases reverse cholesterol transport and HDL production and decreases VLDL-TG and fatty acid production ([0162] and [0168].
Rudolf (at paragraph [0367]) exemplifies treating macaque’s (non-human primates) having naturally occurring age-related maculopathy (exhibiting age related drusenoid macular changes resembling early AMD in humans, i.e., considered dry macular degeneration) (see Specification at page 2, lines 1-2 and page 15, lines 35-36). Rudolf’s treatment method intravitreally injected the subjects with a sterile balanced salt solution (BSS) of the apoA-I mimetic L-4F, Ac-DWFKAFYDKVAEKFKEAF-NH2 acetate salt (SEQ. ID. NO. 13) (n=7), or a placebo (a sterile BSS of scrambled L-4F [sL-4F] having the same amino acids but in a non-functional order) (n=2). One eye per animal received 6 monthly injections of the same escalating dosages of L-4F or scrambled L-4F (total of 625 pg) in a 50 μL volume. The second eye per animal was not injected and was just observed. The injected eye exhibited worse drusenoid changes than the uninjected eye per animal at baseline. Table 1 shows the dosing regimen used in the macaque study.
Rudolf’s teaching at [0367] does not further exemplify the inclusion of the anti-dyslipidemic anti-sense nucleic acids targeting miRNA-33a and miRNA-33b. However, it is noted that Rudolf further teaches combining the apolipoprotein (apo) mimetic with other therapeutic agents including without limitation anti-dyslipidemic agents ([0003]-[0004]), wherein the anti-dyslipidemic agents are anti-sense polynucleotides that target miRNA-33a and miRNA-33b (as recited in claims 69-70) (i.e., nucleotides complementary to an miR-33 target nucleic acid) ([0168]), which results in increasing the expression of ABCA1 which is responsible for mediating the efflux of cholesterol.
Thus, Rudolf does render obvious treating dry macular degeneration comprising administering to the subject a composition comprising the combination of an apolipoprotein (apo) mimetic with other therapeutic agents including without limitation anti-sense polynucleotides that target miRNA-33a and miRNA-33b, that is, Rudolf teaches the limitations required by the current claims and as all limitations are found in one reference it is held that the inclusion of anti-sense oligonucleotides is within the scope of the teachings of Rudolf, and thus renders the invention of claim 23 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to combine the anti-sense polynucleotides that target miRNA-33a and miRNA-33b with the apolipoprotein (apo) mimetic for treating dry macular degeneration. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Rudolf.
Further regarding claim 23 and the limitations that the oligonucleotide comprises 7 to 50 nucleotides and at least 6 contiguous nucleotides complementary to an miR-33 target nucleic acid, it is noted that Rudolf does not further comment on the length of the anti-sense oligonucleotides or the number of contiguous nucleotides that are complementary to an miR-33 target. However, Rayner 2011 is directed to methods for inhibiting miR-33a/b in non-human primates in order to raise plasma HDL, lower VLDL-associated triglycerides, and increase expression of ABCA1 (Abstract). Rayner 2011 teaches treating African green monkeys with antisense miR33 (anti-miR33). Rayner 2011 teaches the anti-miR33 oligonucleotide was equally effective at targeting/inhibiting both miR-33a and miR-33b (page 404, right col. second paragraph). Rayner 2011 specifically discloses the anti-miR-33 oligonucleotide is single-stranded and comprises 21 contiguous nucleotides having the following sequence:
5’-TGCAATGCAACTACAATGCAC-3’ (see Figure 1a).
Thus, Rayner 2011 has established it was known in the art before the effective filing date of the claimed invention, that single-stranded anti-sense oligonucleotides targeting both miR-33a and miR-33b, and comprising 21 contiguous nucleotides having the following sequence: 5’-TGCAATGCAACTACAATGCAC-3’, successfully inhibit both miR-33a and miR-33b, thus resulting in raising plasma HDL, lowering VLDL-associated triglycerides, and increasing expression of ABCA1.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute the anti-miR-33 oligonucleotide of Rayner 2011 for the anti-miR-33 oligonucleotide of Rudolf since both Rayner 2011 and Rudolf teach the anti-sense oligonucleotides are known to target/inhibit miR-33a and miR-33b thus resulting in mediating efflux of cholesterol and increasing HDL, decreasing VLDL-associated triglycerides and increase expression of ABCA1. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of miR-33 anti-sense oligonucleotide for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12). Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Further regarding claims 23, 58, 60 and 64 and the limitations that the oligonucleotide comprises at least one bridged nucleotide (claim 23), the bridged nucleotide is a locked nucleic acid (claim 58), the oligonucleotide further comprises at least one internucleoside linkage comprising a phosphorothioate diester (claim 60) and the oligonucleotide comprises at least one modified sugar residue (claim 64), it is noted that Rudolf does not further comment on said limitations.
However, Naar is directed to compositions comprising nucleic acid sequences that target miR-33 microRNAs, thus resulting in increasing the expression of ABCA1, said nucleic acid sequences that target miR-33 microRNAs include antisense oligonucleotides comprising SEQ ID Nos: 3-8 (Abstract; page 2, lines 1-4 and lines 17-33). Naar teaches the nucleic acids that target miR-33 can be stabilized against nucleolytic degradation by modifications such as a phosphorothioate at the first, second or third internucleotide linkage, a 2’-modified nucleotide (e.g. 2’-fluoro), and the nucleic acids are "locked," i.e., comprise nucleic acid analogues in which the ribose ring is "locked" by a methylene bridge connecting the 2'-0 atom and the 4'-C atom (i.e., modified sugar residue) (page 16, lines 14-27).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the oligonucleotide targeting miR-33 to include stabilization against nucleolytic degradation by including a phosphorothioate at the first, second or third internucleotide linkage, a 2’-modified nucleotide (e.g. 2’-fluoro), and the nucleic acids are "locked," i.e., comprise nucleic acid analogues in which the ribose ring is "locked" by a methylene bridge connecting the 2'-0 atom and the 4'-C atom (i.e., modified sugar residue).
The person of ordinary skill in the art would have been motivated to modify the anti-miR33 oligonucleotide of the combined prior art to include stabilization against nucleolytic degradation by including a phosphorothioate at the first, second or third internucleotide linkage, a 2’-modified nucleotide (e.g. 2’-fluoro), and the nucleic acids are "locked," i.e., comprise nucleic acid analogues in which the ribose ring is "locked" by a methylene bridge connecting the 2'-0 atom and the 4'-C atom (i.e., modified sugar residue), as taught by Naar, for the predictable result of successfully improving the efficacy of the therapeutic oligonucleotide, thus meeting the limitations of claims 23, 58, 60 and 64.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Naar with Rudolf and Rayer 2011 because each of these teachings are directed at therapeutic uses of miR-33 inhibitors.
Regarding Claims 61-62, Rayner 2011 teaches the anti-miR33 comprises the following sequence:
5'- TGCAATGCAACTACAATGCAC-3' (Figure 1a), thus meeting the limitation of claims 61-62.
Regarding claim 63, Rudolf teaches the therapeutic agents can be formulated for delivery into the eye using excipients and carriers, including phosphate-buffered saline, i.e., a buffer ([0326]) and Rudolf’s Example 1 ([0367]) exemplifies intravitreally injecting with a sterile balanced salt solution (BSS), i.e., a buffer, thus meeting the limitation of claim 63.
Regarding claim 65, Naar teaches the nucleic acids are “locked” in which the ribose (sugar) ring is "locked" by a methylene bridge connecting the 2'-0 atom and the 4'-C atom (page 16, lines 14-27), which is considered to read on 100% of the nucleotides are locked. Thus, the claimed range lies within the prior art range. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Regarding claim 66, Rayner 2011 teaches the anti-miR33 oligonucleotide comprises nucleic acid sequence and Britannica evidences that nucleic acids (RNA and DNA) comprise sugar residues, thus it is considered that Rayner 2011’s disclosed anti-sense oligonucleotide comprises 100% sugar residues.
Therefore, Rayner 2011’s teaching meets the limitation of claim 66.
Regarding claims 67-68, Rudolf ([0367]) teaches intravitreal injection administration, thus meeting the limitations of claims 67-68.
Claim(s) 59 is rejected under 35 U.S.C. 103 as being unpatentable over Rudolf, in view of Rayner 2011 and Naar, as evidenced by Britannica, as applied to claims 23, 56-58, and 60-70 above, and further in view of Monoharen et al., (U.S. Patent No. 7,582,744; previously cited) (“US ‘744”).
The teaching of Rudolf, in view of Rayner 2011 and Naar, as evidenced by Britannica, is set forth above.
Regarding claim 59 and the limitation the at least one bridged nucleotide comprises an ethylene bridge, it is noted as discussed above regarding the rejection of claim 23, the combined prior art teaches bridged nucleotides comprising methylene bridges, but does not further disclose ethylene bridges. However, US ‘744 is directed to chemically modified oligonucleotides, e.g., micro-RNA, for inhibiting gene expression (col 1, lines 12-41) and further teaches modifications for increased nuclease resistance and/or binding affinity to the desired target, wherein the bridged modifications include 2’, 4’ ethylene-bridged nucleic acids (col. 17, lines 15-22).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to substitute ethylene bridge modification as taught by US ‘744, for the predictable result of successfully increasing nuclease resistance and/or binding affinity to the desired target, thus meeting the limitation of claim 59. US ‘744 has shown that ethylene bridge modification is an effective and well-known nucleic acid modification that increases nuclease resistance and/or binding affinity to the desired target; thus, one would have had a reasonable expectation of successfully substituting ethylene bridge modification in the method of the prior art. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Response to Remarks
Rejection under 35 USC 103:
As set forth above, Applicant’s amendment now requires treatment of “dry” age-related macular degeneration, and thus differentiates over the cited reference to Apte.
However, new grounds of rejection are set forth above specifically addressing the newly amended limitation.
Conclusion
No claim is 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633