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 .
DETAILED ACTION
This Office Action is a reply to Applicant’s Amendment and Remarks filed June 22, 2026.
Claims 16-24 have been canceled. Claim 1 has been amended.
Claims 1 and 25-29 are pending in the instant application.
Claims 1 and 25-29 have been examined on the merits as detailed below:
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Information Disclosure Statement
Applicant’s information disclosure statement (IDS) filed July 20, 2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith.
Applicant’s IDS filed June 5, 2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith.
Applicant’s IDS filed May 28, 2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith.
Nucleotide Sequence Disclosures
In the previous Office Action mailed February 25, 2026, it was noted that the present application failed to comply with the requirements of 37 C.F.R. §1.821-1.825. This notice is maintained because the sequence listing contains ERRORS for the reason(s) set forth on the attached Notice To Comply with Requirements for Patent Applications Containing Nucleotide Sequence Disclosures.
Applicant must fully comply with the sequence rules for any response to this action to be considered fully responsive.
Claim Rejections - 35 USC § 112
In the previous Office Action mailed February 25, 2026, claim 23 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. This rejection is moot in view of Applicant’s Amendment filed June 22, 2026 to cancel this claim.
Claim Rejections - 35 USC § 103
In the previous Office Action mailed February 25, 2026, claims 1 and 16-29 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/201301 A1 (NYU) (2014-12-18) in view of WO 2010/122538 A1 (HILDEBRANDT-ERIKSEN) and EP2194129 A2 (ELMEN). This rejection is moot against claims 16-24 in view of Applicant’s Amendment filed June 22, 2026 to cancel these claims. This rejection is maintained against claims 1 and 25-29 for the reasons set forth in the previous Office Action mailed February 25, 2026.
Response to Arguments
In response to this rejection Applicants traverse and argue that none of NYU, Hildebrandt-Eriksen, nor Elmen, alone or in combination, teach or suggest the present claims. Applicants submit that the present claims define a specific and constrained oligonucleotide architecture that is absent from NYU and neither Hildebrandt-Eriksen nor Elmen remedies these deficiencies.
Regarding Hildebrandt-Eriksen, Applicants argue that this reference describes antisense oligonucleotides in general terms and provides broad guidance regarding modification patterns, such as incorporating a nucleotide analogue at every second or third position in a repeating pattern. Applicants submit that the claimed antisense oligonucleotides do not follow such a repeating pattern, but are instead specific, non-repeating arrangements of modified and unmodified nucleotides. Applicants contend that Hildebrandt-Eriksen provides no teaching or guidance that would lead a person of ordinary skill in the art to the presently claimed structures with a reasonable expectation of success.
Concerning Elmen, Applicants submit that this reference discloses only general design considerations and the inclusion of LNAs at terminal positions, however, these generalized teachings also do not disclose or suggest the specific sequences and structural constraints recited in the present claims.
Applicants argue that when NYU is combined with Hildebrandt-Eriksen and Elmen, the cited references fail to teach or suggest the claimed antisense oligonucleotides. Further, Applicants submit that a person of ordinary skill in the art starting from NYU, whether alone or in view of Hildebrandt-Eriksen and Elmen, would have faced an enormous design space in attempting to develop antisense oligonucleotides with the arrangement of modified and unmodified nucleotides and particular modification patterns as presently claimed.
Applicants also argue that the evidence of unexpected results in the present application further supports a finding of non-obviousness. Applicants point the Examiner to Examples disclosed in the present Specification and Figures 1-4 of the instant application, which supposedly report higher potency; increased miR-27b inhibition; and significant upregulation of target gene derepression. Applicants submit that these unexpected results are directly linked to the claimed structural features and further confirm that the claimed antisense oligonucleotides are not a predictable variation of the prior art.
For these reasons, Applicant respectfully requests withdrawal of the rejection.
Applicant’s arguments have been fully considered, however they are not found persuasive. As detailed in the previous Office Action filed February 25, 2026, the combination of references teach and suggest an antisense oligonucleotide that is a mixmer having from seven to fourteen affinity-enhancing nucleotide analogues and does not contain a stretch of more than three contiguous DNA nucleotides. For example, NYU was relied upon to teach DNA/LNA mixmer antisense oligonucleotides with fully phosphorothioate modified backbones targeted to mir-27b. One particular sequence of NYU, AGAACTTAGCCACTGTGA, comprises the base sequence of the present claims.
HILDEBRANDT-ERIKSEN and Elmen were relied upon to teach patterned nucleotide modifications of antisense DNA-LNA mixmer oligonucleotides. That is, specific, non-repeating arrangements of modified and unmodified nucleotides.
The Examiner maintains that starting with the AGAACTTAGCCACTGTGA sequence and DNA/LNA mixmer disclosure of NYU, a person of ordinary skill in the art would have been motivated to use the patterned nucleotide modifications of HILDEBRANDT-ERIKSEN and Elmen to arrive at the mixmers having from seven to fourteen nucleotide analogues and lacking stretches of more than three contiguous DNA nucleotides of the present invention. This is particularly true due to the explicit teachings and suggestions of Elmen who disclose in their Examples and Tables 1, and 2, non- repeating arrangements of modified and unmodified nucleotides represented as: “new design”; “new enhanced design”; and “XxxX design”. In fact, Elmen are explicit in disclosing, “New and enhanced new design as preferred design for blocking microRNA function”. Elmen are also explicit that the new design and new enhanced design were the best functional inhibitors for tested microRNA targets.
Applicant is reminded that KSR forecloses an obvious to try rationale may be proper when the possible options for solving a problem are known, finite, and predictable, with a reasonable expectation of success. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. Also, see MPEP § 2143 and 2144.05. Furthermore, the modification amounts to the combination of prior art elements according to known methods to yield predictable results. See KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 416-417 (2007).
Regarding Applicant’s arguments concerning unexpected results, this is not found persuasive because it should be noted that the claims do not recite functional language. Instead, the claims are drawn to an antisense oligonucleotide comprising a sequence of 18-19 nucleotides in length complementary to miR-27b, wherein the antisense oligonucleotide is a mixmer having from seven to fourteen affinity-enhancing nucleotide analogues and does not contain a stretch of more than three contiguous DNA nucleotides, wherein said antisense oligonucleotide comprises one to 18 phosphorothioate internucleoside linkages, and wherein the antisense oligonucleotide is anyone of SEQ ID NOs: 22, 20, 19, 16, 12 and 8, wherein capital letters are LNA, small letters are DNA, capital C denotes LNA 5-methylcytosine, LNA is beta-D-oxy LNA, "i" is inosine and all internucleoside bonds are phosphorothioate bonds. The claims are also drawn to a method for the treatment, alleviation, amelioration, pre-emptive treatment or prophylaxis treatment of a miR-27b related disease of the CNS or PNS, said method comprising administrating to a subject in the need thereof an antisense oligonucleotide comprising a sequence of 18-19 nucleotides in length complementary to miR-27b, wherein the antisense oligonucleotide is a mixmer having from seven to 14 affinity-enhancing nucleotide analogues and does not contain a stretch of more than three contiguous DNA nucleotides, and wherein said antisense oligonucleotide comprises one to 18 phosphorothioate internucleoside linkages.
The present application discloses:
“Antisense oligonucleotide” means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.
The claims do not recite any functional language. Therefore, Applicant’s arguments regarding unexpected results reporting higher potency; increased miR-27b inhibition; and significant upregulation of target gene derepression of the antisense oligonucleotides of the present invention appear to be misplaced. It appears that Applicant is arguing against limitations not found in the instant claims. Nowhere do the claims recite or require any degree of potency; miR-27b inhibition; or derepression of microRNA-27b target genes. Applicant is reminded that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Assuming arguendo that the claims recited functional language, such as miR-27b inhibition, Elmen are explicit in disclosing, “Surprisingly, new design and new enhanced design were the best functional inhibitors for…microRNA targets”. The Examiner maintains that given the KSR obvious to try rationale and provided that the chemical modifications amounts to the combination of prior art elements according to known methods to yield predictable results (KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 416-417 (2007)), the “unexpected results” reported and argued by Applicant are not in fact unexpected.
In conclusion, both HILDEBRANDT-ERIKSEN and Elmen teach that positioning modifications along the antisense oligonucleotide is how the skilled artisan tunes properties and functionalities associated with inhibitory nucleic acids. The art broadly recognizes LNA content and placement as variables that control binding affinity, nuclease stability, and RNase H recruitment. The art also recognized LNA design rules, mixmer distinctions and screening methods and techniques to predict and identify patterned modified oligonucleotide functionality.
Using routine experimentation and optimization, a person of ordinary skill in the art would have been motivated to make the antisense oligonucleotide with specific and constrained oligonucleotide architecture of the claimed invention for the purpose of conferring a desired property or optimization for a specific utility.
Using nothing more than routine experimentation and optimization along with KSR, the skilled artisan would have expected reasonable success to arrive at the antisense oligonucleotide with specific and constrained oligonucleotide architecture of the claimed invention. Also, see MPEP 2143 and 2144.05.
Turning to the facts, the presumption of obviousness applies here, and none of the means for rebutting it has been shown. In view of the foregoing, when all the evidence is considered, the totality of the rebuttal evidence of non-obviousness fails to outweigh the evidence of obviousness made of record. Thus, it is maintained that the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/ Primary Examiner, Art Unit 1635
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