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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/JP2022/039960, filed on 10/26/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/25/20245 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
Claims 1-23 are pending and are under examination.
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.
Claims 16 and 18-20 are 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 16 recites the limitation "(a)" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 18 recites the limitation "the wing" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitations "the 5’ wing" in lines 3-4 and “the 3’ wing” in line 5. There is insufficient antecedent basis for these limitations in the claim.
Claim 20 recites the limitations "the 5’ wing" in line 4 and “the 3’ wing” in line 6. There is insufficient antecedent basis for these limitations in the claim.
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 and 11-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
Claims 1-6 encompass a broad genus of antisense oligonucleotides consisting of 15 to 30 nucleotides and complementary to at least 10 consecutive bases in at least one of numerous target regions encompassing substantially the entire SARS-CoV-2 genomic RNA, wherein the antisense oligonucleotide has an antiviral effect against SARS-CoV-2, SARS-CoV-1, or MERS-CoV. Claim 1 therefore encompasses substantial variation in (1) the length and nucleotide sequence of the antisense oligonucleotide, (2) the location of the target sequence throughout the approximately 30,000-nucleotide SARS-CoV-2 genome, and (3) the virus against which the claimed antiviral effect must occur.
The specification does disclose numerous particular antisense oligonucleotide species. In particular, the specification compares the reference genomic RNA sequences of SARS-CoV-2 (NC_045512.2; SEQ ID NO: 1) and SARS-CoV-1 (NC_004718.3) to identify conserved regions and prepares test substance gapmers G1-G176, corresponding to SEQ ID NOs. 2-177, directed to selected sequences within those conserved regions. The specification reports knockdown and/or viral suppression data for these particular species.
However, the disclosure of these particular species does not reasonably convey possession of the full genus recited in claims 1-6. The specification states that the test substances are predominantly 5-10-5 gapmers and expressly identifies only limited alternative gapmer configurations, including 4-10-5, 5-10-4, 4-10-4, 5-9-4, and 4-9-4 configurations. The specification further states that the test substances were prepared by targeting sequences in conserved regions identified by comparison of the SARS-CoV-2 and SARS-CoV-1 reference genomes. Thus, the experimental disclosure is concentrated on a relatively limited collection of particular sequences and gapmer architectures rather than representative species spanning the full structural and functional diversity encompassed by the claimed 15-30 nucleotide genus.
Moreover, the specification itself recognizes that antisense activity depends upon the particular target sequence. For example, the specification reports differing levels of knockdown activity among the individual test substance gapmers and describes the antiviral effect by reference to particular target sequences. The disclosure therefore does not establish that an antisense oligonucleotide directed to an arbitrary at-least-10-nucleotide sequence within each of the numerous recited regions will necessarily exhibit the claimed antiviral effect. Nor does the specification establish a known structure-function correlation that would allow a skilled artisan to predict, from the disclosed species, which substantially different antisense sequences throughout the claimed target regions would retain antiviral activity.
This deficiency is particularly significant because claims 1-6 are not limited to SARS-CoV-2 having the particular reference sequence SEQ ID NO: 1. The specification expressly states that the invention encompasses SARS-CoV-2, SARS-CoV-1, and MERS-CoV and further describes the contemplated viruses as including mutants. The specification also describes the invention as capable of exerting an effect on mutants of SARS-CoV-2, SARS-CoV-1, and other SARS-related coronaviruses. However, the experimental disclosure does not provide a representative number of antisense oligonucleotide species directed to the corresponding mutated viral sequences, nor does it establish a structure-function correlation demonstrating that the disclosed antisense oligonucleotides will retain antiviral activity against the broad collection of mutant sequences encompassed by the claims.
Accordingly, although the specification provides numerous individual SARS-CoV-2 antisense oligonucleotides, those species are not representative of the entire genus recited in claims 1-6, which extends beyond the disclosed sequences to substantially different 15-30 nucleotide sequences targeting arbitrary at-least-10-nucleotide portions of numerous regions of the viral genome and further extends to SARS-CoV-1, MERS-CoV, and mutants thereof. Where there is substantial variation within a claimed genus, a representative number of species must reflect that variation, or the specification must provide a reasonable structure-function correlation demonstrating possession of the genus.
Claim 6 further recites numerous relatively broad genomic intervals, many of which encompass substantially more sequence possibilities than the particular 19- to 20-nucleotide antisense oligonucleotide species actually exemplified in the specification. For example, claim 6 encompasses target regions such as positions 43-89, 13458-13502, 15063-15140, 17015-17051, 17564-17600, 26287-26325, 28744-28784, and 29102-29130 of SEQ ID NO: 1. The disclosure of individual antisense oligonucleotides directed to particular sequences within these regions does not, without more, demonstrate possession of the full genus of antisense oligonucleotides complementary to any at-least-10-consecutive-base portion of the recited intervals. The specification does not identify which portions of these broader intervals can be targeted while retaining the claimed antiviral effect, nor does it provide a representative number of active species across the full breadth of the recited intervals.
Claims 11-15 are further directed to sequence genera that are not adequately described. Claim 11 requires an antisense oligonucleotide complementary to at least 15 consecutive bases of a target region, thereby broadening the disclosed target sequences beyond the particular sequences tested in the specification. Claims 12-15 further encompass sequence variants of the specifically disclosed SEQ ID NOs. through additions, deletions, substitutions, or at least 80% sequence identity.
For example, SEQ ID NO: 20 is a disclosed 20-nucleotide antisense oligonucleotide. An 80% sequence identity limitation applied to a 20-nucleotide sequence encompasses sequences having up to four differing nucleotide positions, depending upon the particular sequence-identity calculation. The specification does not identify which substitutions preserve the antiviral or knockdown function of SEQ ID NO: 20, which substitutions destroy that function, whether the location of the substitutions affects activity, or whether combinations of multiple substitutions preserve activity. Nor does the specification provide experimental data demonstrating that a representative number of such sequence variants retain the claimed antiviral effect.
The specification also expressly provides that “several” additions, deletions, or substitutions may include 2, 3, 4, 5, 6, 7, 8, 9, or 10 bases. Thus, claims 12-15 encompass substantial sequence variation beyond the specifically disclosed sequences. The specification does not establish a structure-function correlation sufficient to demonstrate possession of this entire sequence-variant genus.
The lack of an established sequence-function correlation is particularly significant in view of the state of the art. Antisense oligonucleotide activity is dependent upon sequence-specific interactions between the oligonucleotide and its target RNA, and the effect of mismatches is not uniformly predictable. Magner et al. (“Influence of mismatched and bulged nucleotides on SNP-preferential RNase H cleavage of RNA-antisense gapmer heteroduplexes,” Scientific Reports 7, 12532, 2017), evaluated more than 120 gapmers and demonstrated that the type and position of mismatches can materially affect RNase H-mediated cleavage. The authors reported that different arrangements and positions of mismatches produced different cleavage selectivity and that certain mismatch arrangements could enhance or reduce cleavage of particular target RNAs.
Likewise, the review by Hagedorn PH, et al., (“Managing the sequence-specificity of antisense oligonucleotides in drug discovery,” Nucleic Acids Res. 2017 Mar 17;45(5):2262-2282) describes sequence-dependent mismatch tolerance in 20-nucleotide gapmers. The review reports that a 20-nucleotide phosphorothioate gapmer containing seven mismatches was unable to cleave its target RNA, whereas the fully matched version reduced the target RNA by greater than 90%. The review also reports a 20-nucleotide TNF gapmer for which a six-mismatch version retained only partial activity relative to the fully matched gapmer, while a separate 20-nucleotide gapmer containing three mismatches retained substantial activity against another target. These results demonstrate that retention of antisense activity following sequence changes is dependent upon the particular sequence and mismatch arrangement and cannot be inferred merely from a general percentage-identity threshold.
Accordingly, the prior art does not establish a general rule that an antisense oligonucleotide having at least 80% sequence identity to an active 20-nucleotide gapmer will necessarily retain the claimed antiviral or target-RNA knockdown activity. Rather, the prior art demonstrates sequence- and position-dependent effects of mismatches on antisense activity. This evidence therefore supports the conclusion that the specification’s disclosure of individual active antisense oligonucleotide sequences does not provide a known or disclosed structure-function correlation sufficient to demonstrate possession of the full genus encompassed by claims 12-15.
Claims 16 and 17 depend from claim 1 and therefore retain the deficiencies discussed above. Claim 16 further recites the sequence of claim 11 without narrowing the claim to a sufficiently representative species or otherwise providing a structure-function correlation for the broad genus inherited from claim 1. Claim 17 limits the antisense oligonucleotide to 20 nucleotides but continues to encompass the broad target-region and viral genera of claim 1. The limitation to 20 nucleotides therefore does not cure the deficiencies of claim 1 because the claimed genus still encompasses numerous possible 20-nucleotide sequences directed to numerous regions and viruses for which the specification does not demonstrate possession.
Claim 18 depends from claim 1 and further recites 2′-OMe and/or 2′-MOE modifications in the wing regions. Although the specification expressly describes these modifications, claim 18 retains the broad sequence, target-region, and viral scope of claim 1. The disclosed modified gapmers therefore do not constitute a representative disclosure of the full genus encompassed by claim 18, for the same reasons discussed above with respect to claims 1-6.
Claims 19 and 20 depend from claim 17 and specify particular phosphodiester/phosphorothioate internucleoside-linkage arrangements. The specification expressly describes gapmers having phosphodiester bonds at selected positions in the 5′ and 3′ wing regions while the remaining bonds are phosphorothioate bonds. Nevertheless, claims 19 and 20 retain the broad target-region and viral scope of claim 1. The specification does not demonstrate that the disclosed linkage patterns, although specifically described as chemical structures, confer the claimed antiviral effect across the entire sequence and viral genus encompassed by those claims. Thus, the specific linkage limitations do not cure the lack of written description support for the broader functional and sequence genus inherited from claim 1.
Claims 21-23 likewise depend, directly or indirectly, upon the antisense oligonucleotide of claim 1 and therefore retain the same broad genus of antisense oligonucleotides, target regions, and viruses. Merely reciting the pharmaceutical composition or administration of an antisense oligonucleotide having the broad scope of claim 1 does not cure the lack of written description support for the underlying genus. Accordingly, claims 21-23 are rejected for the same reasons set forth above.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-18 and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Crooke S, et al., (US20050100885A1).
Regarding claims 1, 3-5, 11, and 21-23 Crooke teaches antisense oligonucleotides and pharmaceutical compositions thereof consisting of 15 to 30 nucleotides or a pharmaceutically acceptable salt or hydrate thereof for the treatment and/or prevention of infection with a virus selected from the group consisting of SARS-CoV-2, SARS- CoV-1, and MERS-CoV ([0053]: “The present invention provides oligomeric compounds comprising from…15 to about 30 nucleobases…the compound is…an antisense oligonucleotide,” [0217]: “the oligomeric compounds of the invention can encompass any pharmaceutically acceptable salts,” and abstract: “The present invention provides design and synthesis of oligomeric compounds and compositions that can be administered to reduce the activity of SARS virus in vivo or in vitro, to prevent or treat SARS virus-associated disease, to detect AARS virus, and to diagnose SARS virus-associated diseases,” and claim 46: “A method of treating an individual having a disease or condition associated with a coronavirus comprising administering to the individual a therapeutically or prophylactically effective amount of the compound of claim 25 so that the propagation of the coronavirus is inhibited as a result of modulation of the frameshift site of said coronavirus.”). Crooke further teaches the 15 to 30 nucleotides being complementary to a nucleic acid comprising at least 10 consecutive bases or at least 15 consecutive bases in at least one target region selected from the group consisting of 5' UTR region, nsp 1 region, nsp3 region, nsp4 region, 3C-like proteinase region, nsp6 region, nsp7 region, nsp8 region, nsp9 region, nsp 10 region, RNA-dependent RNA polymerase region, helicase region, 3'-to-5' exonuclease region, endoRNase region, 2'-O-ribose methyltransferase region, S region comprising Si region and S2 region, ORF3a region, E region, M region, ORF7b region, N region, ORF10 region, and 3' UTR region in genomic RNA of SARS-CoV-2 ([0053]: “the compound comprises from…15 to about 30 nucleobases…the compound has at least …95% complementarity with the nucleic acid molecule encoding SARS virus,” [0070]: “The oligomeric compounds of the present invention can comprise at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100% sequence complementarity to a target region,” [0396]: “all compounds…are 20 nucleotides in length,” [0087]: “target regions include, but are not limited to, the 5′ untranslated region (5′ UTR)…and the 3′ untranslated region (3′ UTR),” claim 37: “the compound of claim 25 having at least 95% complementarity with the frameshift site of viral RNA, the compound specifically hybridizing to the frameshift site and modulating the function of the frameshift site,” [0034]: “the frameshift site in coronaviruses is in between ORFs 1a and 1b. ORF 1a contains a number of proteins, including proteases, and ORF 1b contains the RNA-dependent-RNA-polymerase,” Example 18: “antisense Inhibition of the SARS-CoV with Oligonucleotides Complementary to the Positive Strand of the Virus,” and see tables 3-16 oligonucleotides targeting SARS-CoV). As shown below, Crooke teaches antisense oligonucleotides 20 nucleotides in length that align with 100% to the instant SEQ ID NO: 1 of the SARS-CoV-2 genome. Absent evidence to the contrary, the antisense nucleotides of Crooke are considered targeted to the SARS-CoV-2 genome.
Regarding claims 2 and 17-18, Crooke teaches the antisense oligonucleotide is a gapmer comprising a center gap region and two wing regions flanking the gap region, and that the gapmer is 20 bases ([0389]: “the compounds can be “gapmers” 20 nucleotides in length,” [0396]: “All compounds in Table 3 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of ten 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′ directions) by five-nucleotide “wings.”). Crooke further teaches that the wing regions comprise a 2'-OMe (2'-O-CH3) group and/or a 2'-O-MOE (2'-O-CH2CH20CH3) group ([0389]: “The wings are composed of 2′-O-methoxyethyl nucleotides, also known as 2′-MOE.”).
Regarding claim 6, Crooke teaches SEQ ID NO: 13,403, which is a 20mer that aligns with at least 10 consecutive bases with 100% identity to the target region of positions 13458 to 13502, see alignment below:
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Regarding Claim 7, Crooke teaches SEQ ID NO: 13,087, which is a 20mer that aligns with at least 10 consecutive bases with 100% identity to the target region of positions 13153 to 13172, see alignment below:
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Regarding Claim 8, Crooke teaches SEQ ID NO: 14,818, which is a 20mer that aligns with at least 10 consecutive bases with 100% identity to the target region of positions 14879 to 14898, see alignment below:
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Regarding Claims 8-10, Crooke teaches SEQ ID NO: 16,127, which is a 20mer that aligns with at least 10 consecutive bases with 100% identity to the target region of positions 16195 to 16214, see alignment below:
Note: sequence search in ABSS started at position 15,001 and so the positions in the alignment need 15,00 added to them.
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Regarding claims 12-15, Crooke teaches SEQ ID NO: 6341, which is an antisense oligonucleotide according to claim 1, wherein the antisense oligonucleotide comprises a base sequence with 100% identity to instant SEQ ID NO: 12. See alignment below:
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Regarding claim 16, this claim is indefinite so it is rejected for the same reasons as claim 11 above from which it depends.
Claims 1-18 and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beigelman L, et al., (US20210317457A1, in IDS).
Regarding claims 1-5 and 11 Beigelman teaches antisense oligonucleotides (ASOs) that are gapmer ASO comprising a 5′-wing region (A′), a central region (B′), and a 3′-wing region (C′) that together comprise 8 to 22 total nucleotide units, wherein: (a) a central region (B′) comprising 6 or more contiguous nucleotide units, (b) a 5′-wing region (A′) comprising 2 to 6 locked nucleotide units, 2′ substituted nucleotide units, or a combination thereof, and (c) a 3′-wing region (C′) comprising 2 to 6 locked nucleotide units, 2′ substituted nucleotide units, or a combination thereof; and wherein the ASO is complementary or hybridizes to a viral target RNA sequence in a coronavirus (see claim 1, [0093], and [0095]). Beigelman teaches the ASO comprise at least 10 consecutive bases with 100% identity in at least one target region selected from the group consisting of 5' UTR region, nsp 1 region, nsp3 region, nsp4 region, 3C-like proteinase region, nsp6 region, nsp7 region, nsp8 region, nsp9 region, nsp 10 region, RNA-dependent RNA polymerase region, helicase region, 3'-to-5' exonuclease region, endoRNase region, 2'-O-ribose methyltransferase region, S region comprising Si region and S2 region, ORF3a region, E region, M region, ORF7b region, N region, ORF10 region, and 3' UTR region in genomic RNA of SARS-CoV-2 (see claims 18-19, 21-26, 32-33, [0020], [0022-0025], [0033-0034]). Beigelman teaches that the “specific ASOs that are effective against a broad spectrum of coronaviruses, and especially the β-coronaviruses, including SARS-CoV-2, the causative agent of COVID-19,” see abstract. Beigelman teaches the ASOs have an antiviral effect on a virus selected from the group consisting of SARS-CoV-2, SARS- CoV-1, and MERS-CoV, see [0195-0196] and table 4.
Regarding Claims 6-10, Beigelman teaches SEQ ID NO: 4519, which is a 20mer that aligns with at least 10 consecutive bases with 100% identity to the target region of positions 6406 to 6427, see alignment below:
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Regarding claims 12-15 and 17, Beigelman teaches SEQ ID NO: 4520, which is an antisense oligonucleotide comprising 20 nucleotides according to claims 1 and 17, wherein the antisense oligonucleotide comprises a base sequence with 100% identity to instant SEQ ID NO: 12. See alignment below:
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Regarding claim 16, this claim is indefinite so it is rejected for the same reasons as claim 11 above from which it depends.
Regarding claim 18, Beigelman teaches the wing regions comprise a 2'-OMe (2'-O-CH3) group and/or a 2'-O-MOE (2'-O-CH2CH20CH3) group (see [0100-0103]).
Regarding claim 21, Beigelman teaches “the present disclosure also encompasses pharmaceutical compositions comprising ASOs of the present disclosure. One embodiment is a pharmaceutical composition comprising one or more ASO of the present disclosure, and a pharmaceutically acceptable diluent or carrier,” see [0130].
Regarding claim 22-23, Beigelman teaches “any of the foregoing specific embodiments can be used to treat or prevent viral infections, such as coronavirus infections (e.g., COVID-19) pursuant to the methods and uses disclosed herein,” namely by administering to a subject an effective amount of the ASO, see [0038], [0129-0174], and claims 45 and 59.
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 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Crooke S, et al., (US20050100885A1) as applied to claims 1-18 and 21-23 above, and further in view of Vargeese C, et al., (US20210032620A1).
The teachings of Crooke are incorporated herein by reference to the respective 102 rejection above.
Crooke dos not teach the specific patterns phosphodiester (PO) and phosphorothioate (PS) internucleoside linkages in the 5’ and 3’ wings as recited in instant claims 19-20. Claim 19 requires an alternating PS/PO pattern in wings in the configuration of PS-PO-PS-PO-PS; whereas, claim 20 requires a PS-PO-PO-PO-PS configuration for the 5’ and 3’ wings.
Vargeese teaches gapmer antisense oligonucleotides comprising a 5’ wing and a 3’ wing, see [0111], [0143], [0145], [1390], and [1674]. Vargeese further teaches that the 5’ and 3’ wings can have a mixture of phosphodiester (O) and phosphorothioate (S) internucleoside linkages in the required configurations of instant claim 19 (i.e., “SOSOS” [0540-0541]) and 20 (i.e., “SOOOS” [0540-0541]), see [0145] and [0540-0541]. Vargeese further teaches that the wings having “an asymmetric format are capable of improving the target specificity, target binding, stability, deliverability, efficacy, and/or other useful characteristic of an oligonucleotide,” see [0142] and [0154-0155].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to employ the internucleoside linkage configurations, SOSOS and SOOOS, for the 5’ and 3’ wings as taught by Vargeese in Crooke’s gapmer ASOs targeting SARS-CoV-2. A PHOSITA would have been motivated to do so in order to improve target specificity, target binding, stability, deliverability, efficacy, and/or other useful characteristics. A PHOSITA would have had a reasonable expectation of success because these modification patterns were standard practice in the art and known to confer advantageous results when employing the gapmer ASOs in vivo as a pharmaceutical composition.
Claims 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Beigelman L, et al., (US20210317457A1, in IDS) as applied to claims 1-18 and 21-23 above, and further in view of Vargeese C, et al., (US20210032620A1).
The teachings of Beigelman are incorporated herein by reference to the respective 102 rejection above.
Regarding claims 19-20, Beigelman teaches the 5’ and 3’ wings each comprise at least 2, 3, 4, 5, or 6 phosphorothioate-linked nucleosides.
Beigelman dos not teach the specific patterns phosphodiester (PO) and phosphorothioate (PS) internucleoside linkages in the 5’ and 3’ wings as recited in instant claims 19-20. Claim 19 requires an alternating PS/PO pattern in wings in the configuration of PS-PO-PS-PO-PS; whereas, claim 20 requires a PS-PO-PO-PO-PS configuration for the 5’ and 3’ wings.
Vargeese teaches gapmer antisense oligonucleotides comprising a 5’ wing and a 3’ wing, see [0111], [0143], [0145], [1390], and [1674]. Vargeese further teaches that the 5’ and 3’ wings can have a mixture of phosphodiester (O) and phosphorothioate (S) internucleoside linkages in the required configurations of instant claim 19 (i.e., “SOSOS” [0540-0541]) and 20 (i.e., “SOOOS” [0540-0541]), see [0145] and [0540-0541]. Vargeese further teaches that the wings having “an asymmetric format are capable of improving the target specificity, target binding, stability, deliverability, efficacy, and/or other useful characteristic of an oligonucleotide,” see [0142] and [0154-0155].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to employ the internucleoside linkage configurations, SOSOS and SOOOS, for the 5’ and 3’ wings as taught by Vargeese in Beigelman’s gapmer ASOs targeting SARS-CoV-2. A PHOSITA would have been motivated to do so in order to improve target specificity, target binding, stability, deliverability, efficacy, and/or other useful characteristics. A PHOSITA would have had a reasonable expectation of success because these modification patterns were standard practice in the art and known to confer advantageous results when employing the gapmer ASOs in vivo as a pharmaceutical composition.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 3-11, and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 13-15, and 17-18 of copending Application No. 18/557,883 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because: copending claim 1 recites an antiviral nucleic acid targeting a sequence within a substantially overlapping set of SARS-CoV-2 target regions and the identical group of viruses (SARS-CoV-2, SARS-CoV-1, MERS-CoV) recited in instant claim 1, with copending claim 2's 16-to-30 consecutive base limitation (which is at least 15 consecutive base as in instant claim 11) substantially overlapping instant claim 1's 15-to-30 nucleotide length; instant claim 3's SARS-CoV-2/SARS-CoV-1 limitation is recited verbatim in copending claim 3; instant claims 4 and 5's narrowed target-region subsets are each fully encompassed within the target-region lists of copending claims 1 and 5; instant claims 6-10 each recite a target-region position range that overlaps the position range of positions 6406 to 6427 of SEQ ID NO: 1 recited in copending claim 4 (e.g., instant claim 6's "positions 6406 to 6427," instant claim 7's "positions 6406 to 6425, positions 6407 to 6426, positions 6408 to 6427," and the narrowing "positions 6407 to 6426" recited in instant claims 8-10), such that the progressively narrower position ranges claimed in the instant application are not patentably distinct from the identically-located target region already claimed in copending claim 4; and instant claims 21-23, directed to a pharmaceutical composition and methods of treating/preventing infection by SARS-CoV-2, SARS-CoV-1, or MERS-CoV using the claimed nucleic acid, are not patentably distinct from copending claims 13-15, 17, and 18, which likewise claim a pharmaceutical composition and corresponding treatment/prevention methods for the same group of viruses using the corresponding nucleic acid. The instantly claimed "antisense oligonucleotide" is in each instance merely a species of the genus "nucleic acid" recited in the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 4, 5 and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 11 of copending Application No. 18/845,385 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because: copending claim 1 recites an antisense oligomer of 15 to 30 bases complementary to at least 10 consecutive bases of a SARS-CoV-2 target region selected from a group (5′ UTR, nsp1, nsp10, RNA-dependent RNA polymerase, ORF10, and 3′ UTR regions) that is entirely subsumed within the broader target-region genus recited in instant claim 1, and is directed to the identical group of viruses (SARS-CoV-2, SARS-CoV-1, MERS-CoV), such that copending claim 1 anticipates a species falling within the scope of instant claim 1’s genus; copending claim 4 further evidences that at least 15-consecutive-base targeting within this same region subset was contemplated, overlapping instant claim 1’s 10-consecutive-base minimum; instant claim 3’s SARS-CoV-2/SARS-CoV-1 limitation is recited verbatim in copending claim 11; and instant claims 4 and 5’s narrowed target-region subsets (which include the RNA-dependent RNA polymerase region, and for claim 4 also the ORF10 and 3′ UTR regions) overlap with the target-region group recited in copending claim 1, such that selecting this overlapping subset would have been an obvious matter of design choice to one of ordinary skill in the art. The instantly claimed “antisense oligonucleotide” and the copending “antisense oligomer” are directed to the same genus of compound, differing patentably only insofar as the copending claims elsewhere elect a morpholino-based species (claims 12-14) not recited at the copending claim 1/4/11 level of generality relied upon here. Instant claims 21-23, directed to a pharmaceutical composition and methods of treating/preventing infection by SARS-CoV-2, SARS-CoV-1, or MERS-CoV using the claimed nucleic acid, are not patentably distinct from copending claims 15-17, which likewise claim a pharmaceutical composition and a corresponding method of treating/preventing the same group of viral infectious diseases using the copending antisense oligomer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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