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
Applicant’s claim to priority from International Application PCT/JP2020/028421
filed July 24, 2020 and Japanese Patent Application No. 2019-136414, filed July 24, 2019 is hereby acknowledged. This Application is a national stage entry under § U.S.C. 371 of International Patent Application No. PCT/JP2020/028421 filed July 24, 2020.
Application Status
Amendments to claims dated 10/28/2025 are hereby acknowledged. Claims 3, 5-9 are cancelled. claims 1 and 10 is currently amended.
Claims 16-19 are withdrawn after restriction requirements and election of Group I invention. Therefore, claims 1-2, 4, and 10-15 are under consideration in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and is therefore withdrawn.
Claim Interpretation
Regarding claim 1, it recites "wherein the nuclease cleaves the target nucleic acid at a fusion part of the first nucleic acid or a derivative thereof and the second nucleic acid or a derivative thereof to form two target nucleic acid fragments with a melting temperature Tm of 38 °C or lower".
Claim 1 refers to the target nucleic acid after cleavage and its property or the property of fragments derived from the target nucleic acid, i.e. having a Tm of 38 °C or lower, the target nucleic acid is not the product to which the claim is drawn to, neither are its fragments. The claimed structure/product is the chimeric molecule. Therefore, adding this property does not further limit on the structure of the chimeric molecule, rather, the limitation is an intended use of said chimeric molecule.
The following rejections are new and necessitated by Applicant’s amendments:
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 non-obviousness.
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 1-2, 4, and 10-15 are rejected under 35 U.S.C. §103 as being unpatentable over Yokota (Yokota, T. et al. WO 2014/132671 A1, published September 4, 2014; previously cited), in view of Dimitrov (Dimitrov, R.A. et al. “Prediction of hybridization and melting for double-stranded nucleic acids”. Biophysical Journal, Vol. 87 (2004), pp: 215-226), Baba (baba, M. et al.” Effects of neutral salts and pH on the activity and stability of human RNAse H2”. Journal of Biochemistry, Vol. 162, No. 3 (2017), pp: 211-219), and Ohtani (Ohtani, N. et al. “Junction ribonuclease: a ribonuclease HII orthologue from Thermus thermophilus HB8 prefers the RNA-DNA junction to the RNA/DNA heteroduplex”. Biochemistry Journal, Vol. 412 (2008), pp: 517-526).
Regarding claim 1, Yokota teaches a chimeric molecule resulting from fusion of a first nucleic acid with a second nucleic acid (see [0017], a first wing region comprising 1-10 nucleotides and a center region comprising at least 5 nucleotides. Yokota teaches that the chimeric polynucleotide can hybridize to an RNA polynucleotide (see [0017], page 5, section (3)). Yokota teaches that the chimeric antisense polynucleotide comprises DNA or derivatives (see [0017], page 5, section (4), and page 37, claims 4-6). Therefore, since DNA comprises a main chain that is a sugar-phosphate skeleton, the chimeric molecule has a main chain skeleton that is anionic.
Regarding claims 1(lines 5-6) and 2, Yokota teaches that the chimeric molecule can have bridged nucleic acids with an amide, therefore a neutral skeleton (see page 37, claim 13). Yokota also teaches a complementary strand to the chimeric molecule that can be selected from RNA, DNA, PNA (peptide nucleic acid) and BNA (bridged nucleic acid, e.g. LNA) (see [0069]).
Regarding claim 1 (lines 7-8), Yokota also teaches a chimeric molecule wherein the first 5’-wing region joined to the 5’ end of the second (center region) nucleic acid (see [0017], see page 36, claim 1).
Regarding claims 1(lines 9-10) and 10, Yokota teaches a chimeric molecule wherein the target nucleic acid bound to the chimeric molecule specifically binds to a nuclease, that can cleave the duplex and that is a ribonuclease H (see [0004], [0017](3), and page 36, claim 3).
Regarding the recitation “the nuclease cleaves the target nucleic acid at a fusion part of the first nucleic acid or a derivative thereof and the second nucleic acid or a derivative thereof”, Yokota teaches the use of RNAse H , stating “The chimeric antisense polynucleotide of items (1 or 2), wherein the center nucleotide region comprises nucleotides that, when hybridized to an RNA polynucleotide, the center nucleotide region/RNA polynucleotide duplex is recognized by RNAse H” (see page 5, section (3)). Yokota does not teach which subtype of RNAse H can be used.
Regarding claim 1 (lines 11-13) reciting “wherein the nuclease cleaves the target nucleic acid at a fusion part of the first nucleic acid or a derivative thereof and the second nucleic acid or a derivative thereof to form two target nucleic acid fragments with a melting temperature Tm of 38 °C or lower”, Yokota does not teach a nuclease that cleaves at the fusion part; Yokota does not teach two target nucleic acid fragments with a melting temperature Tm of 38 ⁰C or lower either.
However, the limitation is directed to an intended use of the claimed chimeric molecule and to properties presented by the target nucleic acid and its fragments. MPEP § 2122 states “ Utility need not be disclosed in reference” and “In order to constitute anticipatory prior art, a reference must identically disclose the claimed compound, but no utility need be disclosed”.
The limitation claimed is directed to the target nucleic acid. However, Dimitrov teaches that the target nucleic acid can have inherent properties (GC composition) that can lead to different Tm under different salt concentrations (see page 224, right column, second paragraph , i.e. salt effect; and Table 1). Table 1 shows different fragments of nucleic acids with different Tm, ranging from 27 ⁰C to 66 ⁰C depending on sequences (see pages 221-222).
Baba teaches that human cells and tissues possess different subtypes of RNAse H, and especially an RNAse H2 which is active between 25 ⁰C and 35 ⁰C, therefore around physiological conditions (see title and abstract). In Figure 6b, Baba shows that under physiological neutral pH, RNAse H2 presents more activity at 30 ⁰C to 35 ⁰C.
Ohtani teaches that RNase H2 orthologue prefers the RNA-DNA junction to the RNA/DNA heteroduplex (see title and abstract).
It would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have substituted the target nucleic acid taught by Yokota, with a specific target nucleic acid such as when cleaved, it gives rise to two fragments with a GC composition compatible with a Tm of 38 ⁰C or lower as taught by Dimitrov. One with ordinary skills in the art motivated in designing a chimeric molecule to target a specific region of target nucleic acid with a composition and structure favorable to RNAse H2 junction-type cleavage, i.e. presenting with lower melting temperature, specifically adapted to human cells, as taught by Baba/Ohtani, could have performed this modification with a reasonable expectation of success, since it would be performing routine optimization of a known method, and arrived at the claimed invention.
Regarding claims 4 and 12, Yokota teaches a second nucleic acid or derivative thereof has a main chain skeleton that is a sugar-phosphate skeleton, i.e. DNA or RNA (see [0017], and page 37, claims 4-9).
Regarding claim 11, Yokota teaches a chimeric molecule with a complementary strand that can be PNA, therefore, the first region of the duplex can also be a hybrid with PNA (see [0069]).
Regarding claim 13, Yokota teaches a target nucleic acid that is an RNA (see [0004], [0017](3), and page 36 claim 3).
Regarding claim 14, Yokota teaches a pharmaceutical composition comprising the chimeric molecule in which the chimeric molecule is capable of treating a patient when administered in an effective amount (see [0016], [0017](41), and claims 41 and 45).
Regarding claim 15, Yokota teaches in some embodiments, a pharmaceutical composition intended to treat and prevent diseases that are associated with, e.g., increased expression of a target gene, such as metabolic diseases, tumors , and infections (see page 28, [0089]).
The obviousness of the combination of references, Yokota, Dimitrov, Baba and Ohtani is described above. Therefore, the combination of references renders the elements of claims 4, 11-15 obvious as well.
Claims 1-2, 4 and 10-15 are rejected under 35 U.S.C. §103 as being unpatentable over Cook (Cook, P.D. US Patent No. 5, 700,922, published December 23, 1997; previously cited) in view of Dimitrov (Dimitrov, R.A. et al. “Prediction of hybridization and melting for double-stranded nucleic acids”. Biophysical Journal, Vol. 87 (2004), pp: 215-226), Saarbach (Saarbach, J. et al. “Peptide nucleic acid (PNA) and its applications in chemical biology, diagnostics, and therapeutics”. Current Opinion in Chemical Biology, Vol. 52 (2019), pp: 112-124; previously cited, and evidentiary reference for rejection of claim 2), Baba (Baba, M. et al.” Effects of neutral salts and pH on the activity and stability of human RNAse H2”. Journal of Biochemistry, Vol. 162, No. 3 (2017), pp: 211-219), and Ohtani (Ohtani, N. et al. “Junction ribonuclease: a ribonuclease HII orthologue from Thermus thermophilus HB8 prefers the RNA-DNA junction to the RNA/DNA heteroduplex”. Biochemistry Journal, Vol. 412 (2008), pp: 517-526)).
Regarding claims 1, 11 and 12, Cook teaches a chimeric molecule resulting from fusion of a first nucleic acid or derivative thereof (see figure 1 and claim 1 of Cook), which has an ability to bind to a target nucleic acid (see column 1, lines 25-34, and claim 14 of Cook), with a second nucleic acid or derivative thereof, which has an ability to bind to the target nucleic acid (see title, abstract, claim 14 and column 1, lines 25-34). Cook teaches a DNA moiety - which is inherently negatively charged because of its sugar-phosphate backbone, also according to Cook, phosphate linkage bears a negative charge (see column 9, lines 10-11) - and a peptide nucleic acid (PNA) moiety or moieties (see column 5, lines 33-40). Cook also teaches that “each peptide nucleic acid subunit and each 2’-deoxynucleotide subunit includes a nucleobase that is capable of specifically hybridizing with like nucleobases on a target RNA molecules or other target molecules including DNA molecules and proteins (see column 6, lines 12-16).
Cook also teaches a chimeric molecule wherein the main chain skeleton of the first nucleic acid or a derivative thereof is an amide skeleton (see claim 1 of Cook).
Regarding claim 1, Cook teaches a chimeric molecule wherein the first nucleic acid or a derivative thereof is fused to the 5’ end of the second nucleic acid or a derivative thereof (see Figure 2 and below).
PNG
media_image1.png
870
626
media_image1.png
Greyscale
Regarding claims 1 and 10, Cook teaches a chimeric molecule wherein a complex composed of the chimeric molecule and the target nucleic acid bound to the chimeric molecule specifically binds to a nuclease, which is ribonuclease H or RNAse H (see Abstract and column 1, lines 25-34).
Regarding the recitation “the nuclease cleaves the target nucleic acid at a fusion part of the first nucleic acid or a derivative thereof and the second nucleic acid or a derivative thereof”, Cook teaches the use of RNAse H. Cook teaches that the 2’-deoxyoligonucleotide portion is believed to elicit a RNAse H response and cleavage of a RNA target strand ( see column 3, lines 62-64).
Regarding claim 1 (lines 11-13) reciting “wherein the nuclease cleaves the target nucleic acid at a fusion part of the first nucleic acid or a derivative thereof and the second nucleic acid or a derivative thereof to form two target nucleic acid fragments with a melting temperature Tm of 38 °C or lower”, Cook does not teach specifically a cleavage at a fusion part, nor two target nucleic acid fragments with a melting temperature Tm of 38 ⁰C or lower.
Cook also does not teach a specific subtype of RNAse H that cleaves at fusion part.
However, the limitation recited in claim 1(lines 11-13) is directed to an intended use of the claimed chimeric molecule, and to properties presented by the target nucleic acid and its fragments. MPEP § 2122 states “ Utility need not be disclosed in reference” and “In order to constitute anticipatory prior art, a reference must identically disclose the claimed compound, but no utility need be disclosed”.
Although the limitation claimed in claim 1 (lines 11-13) is directed to the target nucleic acid, Dimitrov teaches that the target nucleic acid can have inherent properties (GC composition) that can lead to different Tm under different salt concentrations (see page 224, right column, second paragraph , i.e. salt effect; and Table 1). Table 1 shows different fragments of nucleic acids with different Tm, ranging from 27 ⁰C to 66 ⁰C depending on sequences (see pages 221-222).
Ohtani teaches that there is a subtype of RNAse H, RNAse H2, that prefers cutting in junction region when the chimeric oligonucleotide is a RNA/DNA chimera (see title and abstract).
Baba teaches that human cells and tissues possess different subtypes of RNAse H, and especially an RNAse H2 which is active between 25⁰ and 35 ⁰C, therefore around physiological conditions (see title and abstract). In Figure 6b, Baba shows that under physiological neutral pH, RNAse H2 presents more activity at 30⁰ C to 35⁰ C.
It would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have substituted the target nucleic acid taught by Cook, with a specific target nucleic acid such as when cleaved, it gives rise to two fragments with a GC composition compatible with a Tm of 38 ⁰C or lower as taught by Dimitrov. One with ordinary skills in the art motivated in designing a chimeric molecule to target a specific region of nucleic acid with a composition and structure favorable to RNAse H2 cleavage, i.e. presenting with lower melting temperature, specifically adapted to human cells, as taught by Baba/Ohtani, could have performed this modification with a reasonable expectation of success, since it would be performing routine optimization of a known method, and arrived at the claimed invention.
Regarding claim 2, Cook teaches a chimeric molecule, wherein the first nucleic acid or a derivative thereof is neutral, since PNA is inherently neutral (see evidentiary reference : Saarbach, page 112, right column, section “Modifications”, first para.).
Regarding claim 4, Cook teaches a chimeric molecule, wherein the second nucleic acid or a derivative thereof is a sugar-phosphate skeleton, since Cook teaches DNA as a moiety (see claim 1 of Cook).
Regarding claim 13, Cook teaches a chimeric molecule wherein the target nucleic acid is RNA (see column 3, lines 36-49; column 4, lines 45-49; column 6, lines 11-15; and column 26, lines 55-57).
Regarding claims 14 and 15, Cook teaches a pharmaceutical composition comprising the chimeric molecule as an active ingredient (see column 13, lines 46-57). Cook also teaches that the pharmaceutical composition can be used for cancer since Cook uses neoplastic cell lines (see columns 25, 27 and 28, Procedures 1-3, 7, 9 and 10). Cook uses the test compounds with the generic structure PNA-DNA-PNA (see Examples 1-17) to treat Hela cells transfected with a vector comprising a mutant Ras oncogene fused to a luciferase reporter gene. Cook use luciferase assays to test the activity of the compounds on Ras oncogene expression, which is an oncogene often mutated in cancer, therefore, it is interpreted that the compositions taught in Examples 1-17 are compositions that are for cancer.
The obviousness of the combination of references Cook, Dimitrov, Saarbach, Baba and Ohtani is described above. Therefore, since Cook also teach elements of claims 2, 4, 13-15, the combination of references also renders elements of these claims obvious.
Response to Arguments
Applicant's arguments filed 10/28/2025 have been fully considered but they are not persuasive.
Applicant argues on pages 10-12 of Remarks that “none of the cited references
teach a chimeric molecule resulting from fusion of a first nucleic acid or a derivative thereof, which has an ability to bind to a target nucleic acid, with a second nucleic acid or a derivative thereof, which has an ability to bind to the target nucleic acid, and in which a main chain skeleton is anionic, wherein the main chain skeleton of the first nucleic acid or a derivative thereof is an amide skeleton, wherein the first nucleic acid or a derivative thereof is fused to the 5' end of the second nucleic acid or a derivative thereof, wherein the chimeric molecule binds to the target nucleic acid to form a complex that specifically binds to a nuclease, wherein the nuclease cleaves the target nucleic acid at a fusion part of the first nucleic acid or a derivative thereof and the second nucleic acid or a derivative thereof to form two target nucleic acid fragments with a melting temperature Tm of 38°C or lower, as recited in amended claim 1”.
In response, the combination of reference Yokota, Dimitrov, Baba and Ohtani as well as the combination of references Cook, Saarbach, Dimitrov, Baba and Ohtani both teach the elements of claim 1, as described in the current rejections above. Examiner would like to remind that the claim is drawn to a product, i.e., ”a chimeric nucleic acid molecule”, and not to a target nucleic acid, nor to a method of using and its end-result.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant did not claim any specific structure, nor enumeration in residues, therefore any combination of references that teach a generic chimeric nucleic acid molecule that can bind a target nucleic acid and RNAse H and can possess the generic structure and function claimed, satisfies the limitations of the amended claim.
Applicant also argues that “One technical effect of the present application is, as indicated in paragraph [0039] of the present specification, that by setting the Tm of both fragments of the target nucleic acid to body temperature (e.g. 38°C) or lower, both fragments of the target nucleic acid generated by cleavage at one site with the nuclease can be rapidly dissociated from the nuclease. On the other hand, the chimeric molecule as claimed is rapidly dissociated from the nuclease after cleavage of the target nucleic acid with the nuclease, and therefore, the chimeric molecule is rapidly used for cleavage of the subsequent target nucleic acid, and highly efficient turnover of the cleavage by the nuclease of the target nucleic acid can be achieved. Therefore, the chimeric molecule of the pending claims unexpectedly cleaves the target nucleic acid at a low concentration, and thus, reduces the off-target effect.”
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “rapid dissociation from the nuclease”, “efficient turnover of the cleavage by the nuclease”, “unexpectedly cleaves the target nucleic acid at a low concentration”, and “reduces the off-target effect”) are not recited in the rejected claim(s). 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).
Also, these activities, or properties attributed to the claimed chimeric molecule, not only are not claimed, but the structures specifically allowing for these functions are not evident in the structure as claimed. These attributes might derive and might be inherent to specific structures. As claimed, the structures responsible for the activities/properties are not clear.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
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, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636