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
Applicant’s amendments and remarks filed on October 14, 2025 are acknowledged. Claims 2-5 and 13-36 have been canceled. Claims 1, 6-8, and 10-12 were amended. Claims 1, 6-12, and 37-49 are pending and are examined on the merits herein.
This action is NON-FINAL due to new grounds of rejection not necessitated by amendment.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(a) written description, 35 U.S.C 102, and 35 U.S.C 103 rejections are withdrawn.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See claim 38. The sequence is present in the sequence listing and should be identified in the claim as SEQ ID NO: 8.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informality:
Paragraph [0049] of the specification filed on 02/16/2024 reads in part “by adminsitration” and should read “by administration”.
Appropriate correction is required.
Claim Objections
Claims 44 and 46 are objected to because of the following informalities:
There are two (2) instances of “a stem cell growth factor” in claim 44.
Claim 46 recites “NexavirNitazoxanide” and should have a comma in between “Nexavir” and “Nitazoxanide”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 46 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 46 contains the trademark/trade name Nexavir, Tamiflu, Valtrex, and Relenza. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an anti-viral drug and, accordingly, the identification/description is indefinite.
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, 6-12, and 37-49 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 a composition comprising oligonucleotide molecules wherein a plurality of the oligonucleotide molecules comprise a nucleotide base sequence defined by SEQ ID NO: 9 wherein the oligonucleotide molecules are single stranded DNA molecules, does not reasonably provide enablement for a composition comprising oligonucleotide molecules wherein a plurality of the oligonucleotide molecules comprise a nucleotide base sequence defined by SEQ ID NO: 9 wherein the oligonucleotide molecules are double stranded DNA molecules. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include, but are not limited to: (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, with the most relevant factors discussed below.
Breadth of claims and nature of the invention:
Claim 1 recites a composition comprising oligonucleotide molecules wherein a plurality of the oligonucleotide molecules comprise a nucleotide base sequence defined by SEQ ID NO: 9. The broadest reasonable interpretation of claim 1 is that the oligonucleotide molecules encompass not only single stranded DNA molecules but also double stranded DNA molecules.
Amount of direction provided by the inventor and existence of working examples:
The instant specification discloses that the invention generally relates to compositions and methods for activating the RNase L enzyme in vivo (e.g., in a cell, in a subject) [0005] (emphasis added). The specification further discloses the following
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The specification envisions that the oligonucleotide molecules in the composition are DNA oligonucleotide molecules. In some embodiments, the DNA oligonucleotide molecules are single stranded and in other embodiments the DNA oligonucleotide molecules are double stranded [0022].
Working example 1 discloses that antisense oligonucleotides were used to test whether knock down of Dicer activates RNase L as a stress response. Figures 1 through 3 demonstrate that oligonucleotides with phosphorothioate modifications can activate RNase L independent of their sequence and independent of Dicer protein levels. Further, adding 2’-O-methyl RNA bases to the ends of the oligonucleotide sequence was shown to enhance RNase L activation [0066]. The oligonucleotides used for transfection into cells comprised of antisense oligonucleotides directed against Dicer as described in Table 1 (reproduced below).
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Working example 2 demonstrates that the modified oligonucleotide (phosphorothioate oligonucleotide) induces a dsRNA response by active transcription and Actinomycin D treatment relieves the stress by inhibiting the transcriptional response. Further, the working example demonstrates that the modified oligonucleotide induces dsRNA longer than 50bp.
As evidenced by the sequences in Table 1 above, all of the sequences all single stranded DNA sequences. Therefore, the instant specification only provides working examples of single stranded DNA. Although the specification envisions using double stranded DNA, there are no working examples of the claimed invention for the double stranded DNA embodiment.
State of the prior art, level of predictability in the art, and level of one of ordinary skill:
Toonen et al. (Nucleic Acid Therapeutics 2018; reference cited by Applicant) discloses that 2’-5’-oligoadenylate synthase-like protein 2 (Oasl2) is a dsRNA-activated antiviral enzyme involved in the innate antiviral response. Further, Toonen et al. discloses that Oasl2 requires double-stranded RNA as a cofactor [page 67, first full paragraph].
Shu et al. (Cytokine & Growth Factor Reviews 2014) discloses that cyclic GMP-AMP synthase (cGAS) is a cytosolic dsDNA sensor mediating the innate immunity to microbial DNA. cGAS is activated by dsDNA and catalyze the synthesis of a cyclic dinucleotide cGAMP with 2’,5’ and 3’,5’ phosphodiester linkages [abstract]. Further, Shu et al. discloses that the cGAS-STING pathway is also critical for the restriction of RNA viruses in addition to DNA viruses [page 647, left column, last paragraph].
Andreeva (2018) discloses that cGAS is a central sensor of cytosolic DNA expressed in almost all cell types. cGAS recognizes cytosolic dsDNA in a broad sequence-indiscriminatory manner and synthesizes the second messenger cyclic GMP-AMP (pG(2’-5’)pA(3’-5’), 2’3’-cGAMP) from ATP and GTP [page 1, second paragraph].
However, the prior art is silent with regard to the use of dsDNA for activating the RNase L enzyme.
Quantity of experimentation:
In view of the breadth of the claims which embrace a composition comprising oligonucleotide molecules wherein a plurality of the oligonucleotide molecules comprise a nucleotide base sequence defined by SEQ ID NO: 9 wherein the oligonucleotide molecules encompass not only single stranded DNA molecules but also double stranded DNA molecules, the state and level of predictability in the art, the lack of working examples to show a composition comprising double stranded DNA molecules wherein a plurality of the oligonucleotide molecules comprise a nucleotide base sequence defined by SEQ ID NO: 9, and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 37 recites the composition of claim 1 wherein the plurality of oligonucleotide molecules comprises randomers. Claim 1 recites in part a composition comprising oligonucleotide molecules wherein a plurality of the oligonucleotide molecules comprise a nucleotide base sequence defined by SEQ ID NO: 9. SEQ ID NO: 9 is a randomer sequence; therefore, claim 37 does not further limit the claim which it depends on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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, 6, 8-12, 37, 39, and 47-49 are rejected under 35 U.S.C. 103 as being unpatentable over Swayze (WO 2008/049085).
Regarding claims 1, 6, 8, and 37, Swayze teaches gapmer oligomeric
compounds for reduction of target RNA in vivo comprising different nucleotide modifications within one or both wing regions [abstract]. Swayze teaches compositions containing two or more antisense compounds targeted to different regions of the same nucleic acid target [page 38, lines 5-6]. Swayze also teaches gap-widened antisense oligonucleotides that are 18 to 24 nucleotides in length with various wing-gap-wing motifs such as 5-13-5 [page 11, fourth paragraph bridging to page 12]. Further, in certain embodiments, the nucleotides in the gap are unmodified and the nucleotides in the wings are modified. In addition, in certain embodiments, the modification(s) within each wing are the same [page 11, second paragraph] Swayze also teaches that each internucleoside linkage of a gapmer antisense oligonucleotide is a phosphorothioate modified internucleoside linkage [page 3, line 36]. Further, in certain embodiments, oligomeric compounds comprise one or more nucleosides having a modified sugar moiety (e.g., 2’-OCH3) to increase the affinity of the antisense compound for its target and/or increase nuclease resistance [page 19, last paragraph bridging to page 20]. Although Swayze does not explicitly teach the claimed modification pattern of the oligonucleotide as recited in claim 1, it would have been obvious to try because Swayze taught gap-widened antisense oligonucleotides with a 5-13-5 wing-gap-wing motif wherein the nucleotides in the wings comprise the same modification. One of ordinary skill in the art would have had a reasonable expectation of success because Swayze taught that oligomeric compounds comprising one or more nucleosides having a modified sugar moiety such as 2’-OCH3 increases the affinity of the antisense compound for its target and/or increases nuclease resistance.
Regarding claim 9, Swayze teaches that the antisense compounds
can be utilized in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier [page 39, lines 7-8].
Regarding claims 10 and 11, Swayze teaches that 50 nM to 300 nM of
antisense oligonucleotide is used when the antisense oligonucleotide is transfected using a liposome reagent [page 41, second full paragraph].
Regarding claim 12, Swayze teaches that the concentration of oligonucleotide used varies from cell line to cell line. To determine the optimal oligonucleotide concentration for a particular cell line, the cells are treated with a positive control oligonucleotide at a range of concentrations. Although Swayze teaches that 50 nM to 300 nM of antisense oligonucleotide is used when the antisense oligonucleotide is transfected using a liposome reagent [page 41, second full paragraph], Swayze does not explicitly teach that the oligonucleotide concentration is at least 300 nM. However, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the claimed concentration in the process of optimizing the antisense oligonucleotide concentration.
Regarding claim 39, Swayze teaches that the compositions can also be
combined with other non-antisense compound therapeutic agents [page 38, line 7].
Regarding claim 47, Swayze teaches that the pharmaceutical
compositions may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. In a preferred embodiment, administration is topical to the surface of the respiratory tract (e.g., by inhalation) [page 37, third full paragraph].
Regarding claims 48 and 49, with regard to the functional language recited
in the claims, the structure in the prior art is indistinguishable from the structure that is claimed, and absent evidence to the contrary the recited function is inherent in the structure. See MPEP 2112.
Claims 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Swayze (WO 2008/049085) as applied to claims 1, 6, 8-12, 37, 39, and 47-49 above, and further in view of Zhang et al. (US 2021/0228615).
Regarding claims 40-42, the teachings of Swayze are discussed above.
However, Swayze does not teach that the additional therapeutic agent comprises at least one chemotherapeutic drug such as a HDAC inhibitor.
Zhang et al. teaches SMN2 oligonucleotides and compositions capable of treating SMN2-related conditions, disorders, and diseases such as SMA (spinal muscular atrophy) and ALS (amyotrophic lateral sclerosis) [abstract]. Zhang et al. also teaches that a provided chirally controlled oligonucleotide composition is a gapmer [0765]. Further, one or more additional therapeutic agents may be administered together with provided oligonucleotides wherein the additional therapeutic agent is a histone deacetylase (HDAC) inhibitor [1226].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a chemotherapeutic drug as taught by Zhang et al. in the composition of Swayze with a reasonable expectation of success. One would have been motivated to do so because Zhang et al. taught that compositions comprising oligonucleotides and a histone deacetylase (HDAC) inhibitor are capable of treating spinal muscular atrophy and amyotrophic lateral sclerosis.
Claims 43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Swayze (WO 2008/049085) as applied to claims 1, 6, 8-12, 37, 39, and 47-49 above, and further in view of Iversen (US 2011/0118334) and Shaw et al. (US 2013/0090367).
Regarding claims 43 and 44, the teachings of Swayze are discussed above.
However, Swayze does not teach that the additional therapeutic agent comprises at least one immunomodulatory agent such as an interferon.
Iversen teaches antisense oligonucleotides for use in treating an influenza virus infection and antiviral treatment methods employing the oligonucleotides [0003]. Iversen also teaches that modulating agents utilized according to the methods may comprise RNAi oligonucleotides such as chimeric oligonucleotides, or "chimeras," which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound [0217].
Shaw et al. teaches that therapeutic or prophylactic agents can be used in combination with the compounds described for the prevention, treatment and/or management of influenza virus infection wherein the agents include immunomodulatory agents such as interferon [0358].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an immunomodulatory agent as taught by Shaw et al. in the composition of Swayze with a reasonable expectation of success. One would have been motivated to do so because Iversen taught antisense oligonucleotides for use in treating an influenza virus infection and Shaw et al. taught that compositions comprising an immunomodulatory agent such as interferon are capable of treating an influenza virus infection.
Claims 45 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Swayze (WO 2008/049085) as applied to claims 1, 6, 8-12, 37, 39, and 47-49 above, and further in view of Swayze et al. (WO 2012/145697) and Bhat et al. (US 2008/0261904).
Regarding claims 45 and 46, the teachings of Swayze are discussed above.
However, Swayze does not teach that the additional therapeutic agent comprises at least one anti-viral drug such as acyclovir.
Swayze et al. teaches antisense compounds and methods for decreasing HBV mRNA, DNA and protein expression to treat, prevent, or ameliorate HBV-related diseases, disorders or conditions [abstract]. In certain embodiments, compounds useful for modulating expression of HBV mRNA and protein are antisense oligonucleotides [page 2, fourth full paragraph]. Swayze et al. also teaches that antisense compounds having a gapmer motif are considered chimeric antisense compounds [page 89, last paragraph].
Bhat et al. teaches modified oligomeric compounds and compositions of oligomeric compounds capable of modulating gene expression [abstract]. Bhat et al. teaches that antiviral drugs such as acyclovir may be combined in the pharmaceutical composition [0278].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an anti-viral drug as taught by Bhat et al. in the composition of Swayze with a reasonable expectation of success. One would have been motivated to do so because Swayze et al. taught antisense compounds to treat HBV-related diseases, disorders, or conditions and Bhat et al. taught that compositions comprising oligonucleotides and an antiviral drug such as acyclovir are capable of modulating gene expression.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637