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 .
Claim Status
Claims 1-4, 12-14, 16-17, 20, 29-30, 33-35, 37-38, 58, 62, and 66 were previously pending.
A non-final Office Action was mailed 22 August 2025.
In response to that Office Action, Applicant filed an Amendment/Request for Reconsideration on 21 January 2026.
As a result of that Amendment/Request for Reconsideration, claim 2 was cancelled and claims 1, 4, 12, 30, 58, and 66 were amended. No claims were added. Therefore, claims 1, 3-4, 12-14, 16-17, 20, 29-30, 33-35, 37-38, 58, 62, and 66 are now pending and under examination.
Priority
This Application claims the following priority:
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Information Disclosure Statement (IDS)
The IDS’s (3) filed 13 January 2026, 12 March 2026, and 17 April 2026 have been considered by the examiner. Signed copies are enclosed.
Withdrawn Claim Rejections
Applicant has amended independent claims 1 and 58 to now require, in part, an immunostimulatory oligonucleotide duplex comprising:
A first RNA strand comprising SEQ ID NO: 1 at a 5’ end;
A second RNA strand comprising SEQ ID NO: 2 at a 3’ end;
Wherein the hybridization of the first RNA strand and second RNA strand results in a 3’ GG overhang; and
Wherein the oligonucleotide is at least 20 nucleobases in length.
Additionally, Applicant has cancelled claim 2 and amended claims 1, 4, 12, 30, 58, and 66. Therefore, the following previous claim rejections are withdrawn:
Claim 30 was previously rejected under 35 U.S.C. 112(b). Applicants’ amendment to claim 30 was sufficient to overcome this rejection and therefore, the rejection is withdrawn.
Claim 13 was previously rejected under 35 U.S.C. 112(d). Applicants’ amendment to claim 13 was sufficient to overcome this rejection and therefore, the rejection is withdrawn.
Claims 1-4 were previously rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Brown (previously cited as: US Patent No. 9,701,966 B2; date of patent: 11 July 2017). Applicants’ amendment to claim 1 and cancellation of claim 2 was sufficient to overcome this rejection and therefore, the rejection is withdrawn.
Claims 12-14, 20, 33-35, 37-38, 58, 62, and 66 were previously rejected under 35 U.S.C. 103 as being unpatentable over Brown (previously cited as: US Patent No. 9,701,966 B2; date of patent: 11 July 2017). Applicants’ amendment to claims 1 and 58 was sufficient to overcome this rejection and therefore, the rejection is withdrawn.
Maintained Claim Rejection
The following previously held rejection is maintained and has only been modified to reflect the cancellation of claim 2 and amendments to the claims.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1, 3-4, 12-14, 16-17, 20, 29-30, 33-35, 37-38, 58, 62, and 66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
An oligonucleotide duplex comprising:
A first RNA strand comprising SEQ ID NO: 1 at a 5’ end;
A second RNA strand comprising SEQ ID NO: 2 at a 3’ end;
Wherein the hybridization of the first RNA strand and second RNA strand results in a 3’ GG overhang; and
Wherein the oligonucleotide is at least 20 nucleobases in length.
does not reasonably provide enablement for an immunostimulatory oligonucleotide duplex thereof used in a method of preventing a viral infection in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)).
These include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based
on the content of the disclosure
All of the Wands factors have been considered with regard to the instant claims as
discussed below:
(A)/(B) The breadth of the claims/The nature of the invention:
These factors weigh strongly against enablement for the following reasons:
The currently claimed invention is drawn to an immunostimulatory oligonucleotide duplex, at least 20 nucleobases in length, comprising SEQ ID NO: 1 at a 5’ end and SEQ ID NO: 2 at a 3’ end, wherein hybridization of SEQ ID NOs: 1 and 2 results in a 3’ GG overhang. The immunostimulatory oligonucleotide duplex broadly claims to confer at least one of the following immune responses:
Induce IFN production in a cell contacted with the duplex;
Activate the RIG-I-IRF3 pathway in a cell contacted with the duplex;
Reduce viral titer or viral load in a cell or population of cells contacted with the duplex;
Increase STAT1 and STAT2 in a cell contacted by the duplex.
In addition, the claims are directed at using the immunostimulatory oligonucleotide duplex in a method to treat or prevent a viral infection in a subject whereby the viral infection is caused by an extremely broad spectrum of viruses. The following shows the representative nature of the vastly different viruses claimed:
Virus Family
Claimed Virus
Genome
Host
Primary Target
Orthomyxoviridae
Influenza Type A
Influenza Type B
Linear ss RNA
Negative sense
Birds
Various mammals Humans
Epithelial cells
Lentivirus
HIV
Linear ss RNA
Positive sense
Humans
CD4+ T cells
Coronaviruses
Coronavirus
SARS-CoV
SARS-CoV-2
Linear ss RNA
Positive sense
Birds
Various Mammals
Humans
Cells expressing ACE2
Poxviridae
Molluscum contagiosum
Linear ds DNA
Humans
Keratinocytes
Herpesviridae
Herpes
Herpes Simplex I and II
Epstein-Barr
Linear ds DNA
Various mammals
Epithelial cells
Rhabdoviridae
Rabies
Linear ss RNA
Negative sense
Various mammals
Neurons
Astrocytes
The breadth of the claims and nature of the invention weigh strongly against enablement because the claimed subject matter requires specific properties such as being immunostimulatory and having the capability of preventing such a wide spectrum of viruses, each with vastly different hosts, cellular targets, genomes, and mechanisms of infection.
However, the claims themselves provide very little guidance, apart from a hybridized RNA motif comprising four nucleobases, the complementary nucleobases, and a GG overhang. The remainder of the 16+-long oligonucleotide is not specifically claimed. Therefore, the nature of the invention is unpredictable across the full scope of the claims.
(C)/(E) State of the prior art/Level of predictability in the art:
These factors weigh against enablement for the following reasons:
Regarding the structure of the alleged immunostimulatory motif, the prior office action discussed Brown (previously cited as US Pat. No. 9,701,966 B2) as disclosing a dsRNA comprising a CUGA motif (Brown’s SEQ ID NO: 128, length: 25 nucleotides), complementary pairing and hybridization (col. 4, lines 10-19), and 3’ overhang regions up to 6 nucleotides long (col. 3, lines 20-32). As previously discussed, Brown’s oligonucleotides serve to evade detection by and prevent response of the immune system (col. 145, lines 30-36), which directly contradicts applicants’ claimed invention. This implies there is a high level of unpredictability in the art.
As it pertains to the state of prior vaccine art, examiner acknowledges use of poly(I:C) or RIG-I Agonists to induce antiviral response. However, as shown by Chiang, the RIG-I-mediated protective antiviral response is sequence specific (p. 8011-8012).1
While prior art recognizes some immunostimulatory motifs and dsRNA analogs, this in itself does not enable a POSITA to predict which species of the broadly claimed oligonucleotide duplex genus could be used to prevent viral infection. Known immunostimulatory examples in the art, such as poly(I:C) and RIG-I agonists, have vastly different structures and mechanisms. The existence of general dsRNA duplex/analog technology does not mean that a POSITA could make and use the claimed genus of the invention without undue experimentation. The claims are not limited to a specific oligonucleotide or narrow class of oligonucleotides. Rather, the scope of the claims covers an astronomical number of potential sequence configurations only defined by the motif requirement of a 4-nucleobase sequence, its complement, and a GG overhang. Thus, while the prior art may reduce the amount of routine experimentation needed for a narrowly elected species, it does not cure the lack of commensurate guidance for the fully
claimed scope.
(D) Level of one of ordinary skill:
The level of ordinary skill in the art weighs somewhat in favor of enablement, but does
not overcome the breadth and unpredictability of the claims. One having ordinary skill in the art
would have an advanced degree in immunology such as a PhD and/or a medical doctor degree. Therefore, the level of skill is high.
However, even a skilled immunologist or doctor would need to conduct substantial
experimentation to determine whether a given oligonucleotide duplex 1) has immunostimulatory properties and 2) is capable of use to prevent a wide variety of viral infections.
(F)/(G) The amount of direction provided by the inventor/The existence of working
examples:
These factors weigh against enablement for the following reasons:
The currently claimed invention pertains to short motifs as outlined in the specification (see below).
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([00118]).
These motifs represented by SEQ ID NOs: 1 and 2 are further attached to nucleobases whereby the claims only require the entire length of the oligonucleotide duplex is at least 20 nucleobases not including the GG overhang ([0066]). Furthermore, the duplex can tolerate a degree of mismatches ([00119]). Finally, Applicants disclose the sequence makeup of the duplex 3’ of the 5’-monophosphate-CUGA-3’ (SEQ ID NO: 1) sequence is not critical to the interferon induction ([00119]). Therefore, it is implied the sense strand 5’-CUGA-3’ (SEQ ID NO: 1) and antisense strand 3’-GGGACU-5’ are required to confer immunostimulatory activity.
Applicants’ arguments reflect this:
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(see Applicant Remarks, p. 6-8).
These aforementioned remarks have been considered, but are not persuasive for the following reasons:
Applicant transfected A549-dual cells with duplexed RNAs of the invention for 48 hours ([0096]). Figure 16 ([0096]) shows a comparison of the immunostimulatory activities of the different RNA duplexes measured by activation of the IFN pathway:
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As evidence in the above figure, RNA-N (SEQ ID NOs: 37 and 38) and RNA-O (SEQ ID NOs: 39 and 40) were insufficient to induce the desired immunostimulatory activity despite containing the claimed motifs of SEQ ID NOs: 1 and 2:
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(Fig. 14).
While examiner acknowledges RNA-N and RNA-O contain 16 and 17 duplexed nucleobases2, respectively, instead of the at least 20 nucleobases as claimed, it is important to note that RNA-L, also containing the claimed motifs of SEQ ID NOs: 1 and 2, is only 19 duplexed nucleobases in length, yet confers an immune response:
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(Fig. 14).
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Similarly, RNA-6 and RNA-7 both comprise the claimed motifs. RNA-7 contains 19 nucleobases while RNA-6 contains 25 nucleobases, yet both produce immune responses:
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(Fig. 7).
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These results show immune response is not entirely dependent upon: 1) the presence of the motif represented by SEQ ID NOs: 1 and 2; and/or 2) the length of RNA duplex. A conclusion can be drawn that the oligonucleotide sequence outside of the motif of SEQ ID NOs: 1 and 2 plays at least a partial role in inducing an immune response not dependent upon its length alone.
In total, Applicant has provided evidence of the following oligonucleotide duplexes meeting the limitations of instant claim 1 in terms of motifs (SEQ ID NOs: 1 and 2), GG overhang, and length (duplex is at least 20 nucleobases long) which confer immunity:
Duplex Identifier
SEQ ID NOs
Length
A and 6
13, 14
25
B and 2
5, 6
25
C
19, 20
25
D and 4
9, 10
25
1
3, 4
25
Applicants claim a broad genus of oligonucleotide duplexes comprising the conserved motifs of SEQ ID NOs: 1 and 2, a GG overhang, and any remaining combination of nucleobases at any length from 20-300 (see Specification, [00120]). Applicants further claim species of this genus are capable of treating or preventing any viral infection in a subject (claim 12); increasing the efficacy of any anti-viral therapeutic (claim 29); inducing IFN production (claim 37); and increasing the efficacy of any vaccine (claim 66). Yet, Applicants only provide five representative species of this broad genus, each 25 nucleobases long, with very little variation between disclosed sequences.
Further, Applicants have provided no evidence of correlation between structure and immunostimulatory function of the broadly claimed genus. Cited in the prior Office Action, Brown (previously cited as US Pat. No. 9,701,966 B2) discloses a dsRNA comprising a CUGA motif (Brown’s SEQ ID NO: 128, length: 25 nucleotides), complementary pairing and hybridization (col. 4, lines 10-19), and 3’ overhang regions up to 6 nucleotides long (col. 3, lines 20-32). However, as previously discussed, Brown’s oligonucleotides serve to evade detection by and prevent response of the immune system (col. 145, lines 30-36). Therefore, Brown makes clear, as does Applicants’ own RNA-O and RNA-N, that the motifs of SEQ ID NOs: 1 and 2 are not alone correlated with immunostimulatory function. Therefore, Applicant has failed to disclose the remainder of the oligonucleotide duplex responsible for conferring an immune response. Furthermore, Brown and Applicants’ RNA-7 show length of the oligonucleotide duplex, in combination with the conserved motifs, is not correlated with immunostimulatory function. Finally, the specification provides little guidance for the remaining nucleobases apart from length between 20-300.
As it pertains to the method of preventing a viral infection, Applicant has provided working examples showing inhibition of the following viruses:
HCoV-NL63 and SARS-CoV-2 ([00278]);
Influenza A/HK/8/68 (H3N2) ([00278]) and influenza A/WSN/33 (H1N1) ([00290]).
These virus variants, especially with regards to the influenza virus, are very specific and constantly mutating as evidenced by the lack of universal vaccine. Additionally, the influenza virus and coronavirus both have linear ss RNA genomes. The claimed method allegedly prevents viral infection across virus genomes that include: dsDNA (herpesviruses, adenoviruses, poxviruses); ssDNA (parvoviruses); dsRNA (rotavirus); negative-sense (influenza, rabies); positive-sense (coronaviruses, DENV, Zika virus); reverse-transcribing (HIV, Hepatitis B); linear segmented (influenza); linear non-segmented (coronavirus); and circular (HPV). The viral genome would impact which viral enzyme or stages are good targets. More importantly, the claimed viruses have vastly different targets/mechanism as shown in the table above. In developing a method to prevent viral infection in a subject, a POSITA would need to consider different surface proteins, cell tropisms, replication strategies, and immune-evasion mechanisms for each genus of virus causing the claimed viral infection.
(H) The quantity of experimentation needed to make or use the invention based on the
content of the disclosure:
In view of the foregoing analysis, the quantity of experimentation needed to practice the full scope of the invention would be undue.
Since very little guidance is provided in the specification or claims, it is unclear what would transform that which is currently claimed as “an immunostimulatory oligonucleotide duplex” into something that would actually have immunostimulatory properties. Even more unclear is what structure would be capable of preventing a viral infection caused by vastly different viruses. Whether an oligonucleotide is immunostimulatory depends on numerous factors including sequence, structure, chemical modifications, length, delivery context, etc. It would be nearly impossible, without extensive undue experimentation, to enable one of ordinary skill in the art to produce an oligonucleotide duplex that is also immunostimulatory and capable of preventing viral infection caused by the broadly claimed viruses based on the disclosures. The quantity of experimentation that amounts to far more than routine optimization and supports a conclusion that the specification does not enable the full scope of the claimed invention.
Considering the Wands factors as a whole, the currently claimed invention lacks scope of
enablement. A significant amount of undue experimentation would be required to make and use the oligonucleotide duplex under the full scope of the claimed invention. While the specification may enable a limited number of extremely specific oligonucleotide duplexes fully defined by sequence used to prevent a viral infection caused by an extremely narrow scope of virus, the specification does not enable what is currently claimed. The specification does not provide sufficient representative examples, predictive guidance, or formulation rules commensurate with the broad scope of the claims.
Conclusion
Claims 1, 3-4, 12-14, 16-17, 20, 29-30, 33-35, 37-38, 58, 62, and 66 are rejected. No claim is allowed.
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.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Julia A. Rossi whose telephone number is (571)272-0138. The examiner can normally be reached M-Th 7:30-5:30 (MST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax can be reached at (571)272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JULIA A ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
1 Chiang et al., Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists. J Virol. 2015 Aug;89(15):8011-25. doi: 10.1128/JVI.00845-15. Published: 27 May 2015.
2 Applicant has disclosed the oligonucleotide duplex length does not include the single-stranded GG overhang ([0066]).
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