Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the reply filed 02/05/2026 and the supplemental reply filed 03/10/2026.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/05/2026 has been entered.
Claim Amendments
Applicant’s amendment to the claims filed on 12/30/2025 is acknowledged. Claim 1 has been amended.
Applicant’s amendment to the claims filed on 03/10/2026is acknowledged. New claims 15-18 have been added.
Claims 1-18 are pending and under examination.
Priority
The instant application 17/745,314 was filed on 05/16/2022. This application is a divisional (DIV) of U.S. Application No. 16/473,535 filed 06/25/2019 (now, U.S. Patent No. 11,364,259), which is a national stage of international application PCT/JP2017/046906 filed 12/27/2017, claiming priority based on Japanese patent applications JP2016-252488, filed 12/27/2016, and JP2016-252487, filed 12/27/2016.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 in U.S. Application No. 16/473,535. Verified English-language translations of applicant’s priority documents, JP2016-252488 and JP2016-252487, have been filed on 12/30/2025 in U.S. Application No. 17/745,314.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 10/06/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. Applicant’s remarks in the reply filed 12/30/2025 and the supplemental reply 03/10/2026 have been carefully considered but are moot in view of the new grounds of rejection set forth below.
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 17-18 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.
This rejection is newly applied, necessitated by amendment.
The limitation “the chemical modification” in line 6 of claim 17 lacks antecedent basis.
Claim 17 first recites that “the chemical modification is performed on the 5’-terminus or 3’terminus of the sequence of the RNA oligomer” and then recites “the RNA oligomer is chemically unmodified.” The recitations are contradictory.
Dependent claim 18 recites “[t]he method of claim 17, wherein 1 to 5 RNA oligomers hybridize with a single mRNA molecule.” The limitation is indefinite because there is no nexus with the method of claim 17. It is unclear if the 1 to 5 RNA oligomers of claim 18 are loaded into the carrier of claim 17 or whether the single mRNA molecule of claim 18 is the same mRNA of claim 17. Generally, it is unclear how dependent claim 18 further limits any feature found in claim 17. Rather, the claim simply recites that 1-5 RNA oligomers hybridize with a single mRNA molecule with no connection or link to the method of claim 17.
For these reasons, with respect to claims 17-18, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 102
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 1-4, 10-15, 17-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2015/0267192 A1 to Heartlein et al.
This rejection is newly applied, necessitated by amendment.
Heartlein discloses methods of stabilizing mRNA, characterized by resistance to nuclease digestion, increased half-life and/or produce increased amounts of protein encoded thereby. See, e.g., Abstract. The method comprises contacting the mRNA with an RNA oligomer consisting of a sequence complementary to a sequence of the mRNA, such that the RNA oligomer hybridizes with the mRNA. See, e.g., paragraphs 8-10, 23, and Figure 1, reproduced below.
Heartlein further discloses the RNA oligomer is perfectly complementary, or at least about 90% complementary, to a sequence of the mRNA. See, e.g., paragraphs 9-10, 40.
Heartlein further discloses a step of loading the stabilized mRNA (i.e., the hybridized mRNA-oligomer complex) in a carrier. See, e.g., paragraphs 56-57, 61 and 76.
Accordingly, Heartlein teaches a method comprising allowing a carrier to load therein an mRNA encoding a target gene and at least one RNA oligomer hybridizing with the mRNA, wherein the RNA oligomer comprises (a) a sequence consisting of a sequence of nucleotides complementary to the sequence of the mRNA or (b) a sequence having at least 90% identity to a sequence of nucleotides complementary to the sequence of the mRNA.
Claim 1 further recites that the RNA oligomer is chemically unmodified or is chemically modified; dependent claims 4 and 14 and new claim 15 recite that the RNA oligomer is chemically modified; and dependent claim 13 recites the RNA oligomer is chemically unmodified. With respect to new claim 17, the claim is indefinite under 35 U.S.C. 112(b) regarding whether the RNA oligomer contains a chemical modification or is chemically unmodified, as set forth above. For examination purposes under 35 U.S.C. 102, new claim 17 has been interpreted as comprising an RNA oligomer that is chemically unmodified.
Heartlein discloses that the RNA oligomer may comprise at least one modification, e.g., one or more chemically modified nucleobases or modified inter-nucleotide bonds. See, e.g., paragraphs 15-17, and 20. Accordingly, Heartlein teaches or fairly suggests that the RNA oligomer is chemically modified or chemically unmodified, as claimed in claims 1, 4, 13-14 and 17
Claims 1, 11-12 further recite that the RNA oligomer has a complementary sequence of 12-40 nucleotides in length; dependent claim 2 and new claims 15 and 17 recite the RNA sequence consists of a sequence of 15-23 nucleotides; and dependent claim 3 recites the RNA sequence consists of a sequence of 17 nucleotides.
Heartlein discloses that the RNA oligomer consists of a sequence of 15 nucleotides complementary to the mRNA. See, e.g., paragraphs 9, 23; and as depicted in Figure 1. The RNA oligomer is also, for example, about 15-50 nucleotides in length, or the RNA oligomer may be 40, 35, 30, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13 or 12 nucleotides in length. See, e.g., paragraphs 34 and 36. Paragraph 39 further depicts an RNA oligomer consisting of 17 nucleotides.
"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (citing In re Petering, 301 F.2d 676, 682, 133 USPQ 275, 280 (CCPA 1962)) (emphasis in original). "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023). See MPEP 2131.03.
In this case, Heartlein discloses at least one point within the claimed ranges of 12-40 nucleotides (claims 1, 11-12), 15-23 nucleotides (claims 2, 15 and 17), and 17 nucleotides (claim 3), as outlined above. Therefore, the claimed ranges of claims 1 and dependent claims 2-3 are anticipated by Heartlein.
Claims 1, 15 and 17 further recite that the position in the mRNA, with which the RNA oligomer hybridizes, is not a poly-A tail in a 3’ UTR of said mRNA and wherein the position in the mRNA, with which the RNA oligomer hybridizes, is a coding region of the target gene.
Heartlein teaches, in a first embodiment, that the RNA oligomer hybridizes to one or more non-coding regions of the mRNA selected from the group consisting of the 3’ UTR, the poly-A tail, the 5’ UTR and a 5’ terminal cap. See, e.g., par. 9, 23, 40; fig. 1. In a second embodiment, the RNA oligomer hybridizes to a region spanning or comprising both a fragment of the coding region and a fragment of the non-coding region of the mRNA. See, e.g., par. 11, 13, 21. In a third embodiment, the RNA oligomer hybridizes to the coding region of the mRNA. See, e.g., par. 13, 21. See also paragraph 41:
As used herein, the phrase “coding region” generally refers to that portion or region of the polynucleotide or a gene that when expressed, transcribed, translated or otherwise processed results in the production of an expression product, such as an amino acid, polypeptide, protein or enzyme. It should be understood that while certain embodiments disclosed herein contemplate the hybridization of complementary stabilizing oligonucleotides to the non-coding region of a polynucleotide transcript, the present invention need not be limited to such embodiments. Rather, the present invention also contemplates the hybridization of the complementary stabilizing oligonucleotides to regions of the polynucleotide transcript (e.g., mRNA) comprising or spanning both the coding and non-coding regions. For example, a stabilizing oligonucleotide may be prepared Such that it targets and/or is complementary (e.g., perfectly complementary) to a fragment of the coding region of an mRNA polynucleotide transcript and a fragment of the non-coding 3' UTR located downstream of the coding region. The foregoing therefore provides a means of specifically targeting a particular region of the polynucleotide, such as the region located immediately downstream of the coding region. Additionally, the foregoing also provides means of controlling or otherwise affecting the degree to which a stabilizing oligonucleotide hybridizes to a complementary region of the polynucleotide. In certain embodiments where the stabilizing oligonucleotide targets the coding region (or a fragment thereof) preferably the hybridization of the stabilizing oligonucleotide to such coding region (or fragment thereof) does not interfere with the expression (e.g., transcription or translation) of such polynucleotide. Similarly, in embodiments where the stabilizing oligonucleotide targets the coding region (or a fragment thereof) preferably the hybridization of the stabilizing oligonucleotide to Such coding region (or fragment thereof) does not substantially interfere with the expression (e.g., transcription or translation) of such polynucleotide.
Accordingly, the second embodiment (when the poly-A tail is not selected) and the third embodiment, as disclosed by Heartlein and outlined above, are found to anticipate the instantly claimed limitation wherein the position in the mRNA, with which the RNA oligomer hybridizes, is not a poly-A tail in a 3’ UTR of said mRNA and wherein the position in the mRNA, with which the RNA oligomer hybridizes, is a coding region of the target gene.
Heartlein further discloses the carrier is a lipid nanoparticle, liposome or micelle, as claimed in dependent claim 10 and new claims 15 and 17. See, e.g., paragraphs 56-57.
With respect to new claim 18, the claim is indefinite under 35 U.S.C. 112(b) regarding the nexus of the recited “1 to 5 RNA oligomers [that] hybridize with a single mRNA molecule” and the method according to claim 17, as set forth above. For examination purposes under 35 U.S.C. 102, new claim 18 has been interpreted as reciting that 1 to 5 RNA oligomers hybridize with the mRNA initially recited in line 3 of claim 17 (“an mRNA encoding a target gene and at least one RNA oligomer hybridizing with the mRNA”). Heartlein discloses hybridizing one or more complementary RNA oligomers to the target mRNA. See, e.g., par. 13, 32.
Therefore, for the reasons set forth above, the methods according to claims 1-4, 11-15, 17-18 are anticipated by Heartlein.
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.
Claims 5-6 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0267192 A1 to Heartlein et al., as applied to claims 1-4, 11-15, 17-18 above; in view of Bramsen et al. (2011) "Chemical modification of small interfering RNA" In: van Rij, R. (eds) Antiviral RNAi, Methods in Molecular Biology, vol 721, Humana Press.
This rejection is newly applied, necessitated by amendment.
Heartlein does not disclose that the chemical modification is performed on the 5'-terminus or 3'-terminus of the sequence of the RNA oligomer via an overhang sequence consisting of 1-5 or 2 nucleotides, as claimed in claims 5-6 and 16
Prior to the effective filing date of the instantly claimed invention, Bramsen discloses that a terminal 3’ overhang consisting of 2 nucleotides enhances nuclease resistance of RNA oligomers. See, e.g., page 81-82, and 94.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a RNA oligomer, as found in Heartlein, to contain a terminal 3’ overhang consisting of 2 nucleotides, as taught by Bramsen, with a reasonable expectation of success because the nucleotide overhang enhances nuclease resistance.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0267192 A1 to Heartlein et al., as applied to claims 1-4, 11-15, 17-18 above; in view of Alterman et al. (2015) “Hydrophobically modified siRNAs silence huntingtin mRNA in primary neurons and mouse brain” Molecular therapy Nucleic acids, 4, e266, 12 pages.
This rejection is newly applied, necessitated by amendment.
Heartlein does not disclose that the chemical modification is a modification with a hydrophobic group or a cholesterol modification, as claimed in claims 7-8.
Prior to the effective filing date of the instantly claimed invention. Alterman discloses that hydrophobic modifications promote biodistribution, stability and cellular uptake of RNA oligomers. The hydrophobic modification is a cholesterol moiety. See, e.g., Abstract; pages 1-2, and Figure 1a.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a RNA oligomer, as found in Heartlein, to contain a hydrophobic group or cholesterol modification, as taught by Alterman, with a reasonable expectation of success because the modification promotes biodistribution, stability and cellular uptake of RNA oligomers.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0267192 A1 to Heartlein et al., as applied to claims 1-4, 11-15, 17-18 above; in view of Winkler, J. (2015) “Therapeutic oligonucleotides with polyethylene glycol modifications” Future medicinal chemistry, 7(13), 1721-1731.
This rejection is newly applied, necessitated by amendment.
Heartlein does not disclose that the chemical modification is a polyethylene glycol (PEG) modification, as claimed in claim 9.
Prior to the effective filing date of the instantly claimed invention, Winkler discloses that the attachment of PEG is a well-established strategy to prevent enzymatic degradation and avoid renal elimination in the field of oligonucleotide drugs. See, e.g., Abstract; and Figure 1.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a RNA oligomer, as found in Heartlein, to contain a polyethylene glycol (PEG) modification, as taught by Winkler, with a reasonable expectation of success because the PEG modification is a well-established strategy to protect the RNA oligomer from enzymatic degradation and renal elimination.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 11-15, 17-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 16/762,059 (reference to claim listing filed 03/19/2026); in view of US 2015/0267192 A1 to Heartlein et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious in view of the copending claims and secondary references (if any). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This rejection is newly applied.
Copending claim 17 recites an mRNA carrier, which loads therein the complex according to copending claim 1. The complex according to copending claim 1 comprises a target mRNA encoding a target gene and an RNA oligomer, wherein the RNA oligomer comprises:
(a) an RNA sequence comprising a sequence of 17 nucleotides complementary to a sequence of the target mRNA, or
(b) an RNA sequence comprising a sequence having at least 90% identity to 17 nucleotides complementary to a sequence of the target mRNA, and hybridizing with the target mRNA.
The copending claims do not recite a method of stabilizing a carrier comprising a step of allowing a carrier to load therein the mRNA-oligomer complex, as instantly claimed. "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). See MPEP 2144.01. In this case, since copending claim 17 recites an mRNA carrier which loads therein the mRNA-oligomer complex, one of ordinary skill in the art would have been reasonably expected to draw therefrom a method comprising a step of allowing a carrier to load therein the mRNA-oligomer complex, as instantly claimed, in order to arrive at the product of copending claim 17. Accordingly, a method of stabilizing a carrier comprising a step of allowing a carrier to load therein the mRNA-oligomer complex, as instantly claimed, would have been prima facie obvious in view of the copending claims.
The copending claims do not recite that the position in the mRNA, with which the RNA oligomer hybridizes, is not a poly A tail in a 3 'UTR of said mRNA and wherein the position in the mRNA, with which the RNA oligomer hybridizes, is a coding region of the target gene, as instantly claimed.
Heartlein is relevant prior art for disclosing methods of stabilizing mRNA, characterized by resistance to nuclease digestion, increased half-life and/or produce increased amounts of protein encoded thereby. See, e.g., Abstract. The method comprises contacting the mRNA with an RNA oligomer consisting of a sequence complementary to a sequence of the mRNA, such that the RNA oligomer hybridizes with the mRNA. See, e.g., paragraphs 8-10, 23, and Figure 1, reproduced below.
Heartlein further teaches, in a first embodiment, that the RNA oligomer hybridizes to one or more non-coding regions of the mRNA selected from the group consisting of the 3’ UTR, the poly-A tail, the 5’ UTR and a 5’ terminal cap. See, e.g., par. 9, 23, 40; fig. 1. In a second embodiment, the RNA oligomer hybridizes to a region spanning or comprising both a fragment of the coding region and a fragment of the non-coding region of the mRNA. See, e.g., par. 11, 13, 21. In a third embodiment, the RNA oligomer hybridizes to the coding region of the mRNA. See, e.g., par. 13, 21. See also paragraph 41:
As used herein, the phrase “coding region” generally refers to that portion or region of the polynucleotide or a gene that when expressed, transcribed, translated or otherwise processed results in the production of an expression product, such as an amino acid, polypeptide, protein or enzyme. It should be understood that while certain embodiments disclosed herein contemplate the hybridization of complementary stabilizing oligonucleotides to the non-coding region of a polynucleotide transcript, the present invention need not be limited to such embodiments. Rather, the present invention also contemplates the hybridization of the complementary stabilizing oligonucleotides to regions of the polynucleotide transcript (e.g., mRNA) comprising or spanning both the coding and non-coding regions. For example, a stabilizing oligonucleotide may be prepared Such that it targets and/or is complementary (e.g., perfectly complementary) to a fragment of the coding region of an mRNA polynucleotide transcript and a fragment of the non-coding 3' UTR located downstream of the coding region. The foregoing therefore provides a means of specifically targeting a particular region of the polynucleotide, such as the region located immediately downstream of the coding region. Additionally, the foregoing also provides means of controlling or otherwise affecting the degree to which a stabilizing oligonucleotide hybridizes to a complementary region of the polynucleotide. In certain embodiments where the stabilizing oligonucleotide targets the coding region (or a fragment thereof) preferably the hybridization of the stabilizing oligonucleotide to such coding region (or fragment thereof) does not interfere with the expression (e.g., transcription or translation) of such polynucleotide. Similarly, in embodiments where the stabilizing oligonucleotide targets the coding region (or a fragment thereof) preferably the hybridization of the stabilizing oligonucleotide to Such coding region (or fragment thereof) does not substantially interfere with the expression (e.g., transcription or translation) of such polynucleotide.
Accordingly, the second embodiment (when the poly-A tail is not selected) and the third embodiment, as disclosed by Heartlein and outlined above, are found to teach or fairly suggest the instantly claimed limitation wherein the position in the mRNA, with which the RNA oligomer hybridizes, is not a poly-A tail in a 3’ UTR of said mRNA and wherein the position in the mRNA, with which the RNA oligomer hybridizes, is a coding region of the target gene.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the copending claims such that the RNA oligomer hybridizes to the coding region of the mRNA, and not the poly-A tail of the mRNA, as taught by Heartlein, with a reasonable expectation of success because Heartlein teaches targeting such regions provide stability and nuclease resistance to the mRNA, and such regions may be targeted without interfering with expression of the mRNA.
Claim 1 further recites that the RNA oligomer is chemically unmodified or is chemically modified; dependent claims 4 and 14 and new claim 15 recite that the RNA oligomer is chemically modified; and dependent claim 13 recites the RNA oligomer is chemically unmodified. With respect to new claim 17, the claim is indefinite under 35 U.S.C. 112(b) regarding whether the RNA oligomer contains a chemical modification or is chemically unmodified, as set forth above. For examination purposes under 35 U.S.C. 102, new claim 17 has been interpreted as comprising an RNA oligomer that is chemically unmodified.
Heartlein discloses that the RNA oligomer may comprise at least one modification, e.g., one or more chemically modified nucleobases or modified inter-nucleotide bonds. See, e.g., paragraphs 15-17, and 20. Accordingly, Heartlein teaches or fairly suggests that the RNA oligomer is chemically modified or chemically unmodified, as claimed in claims 1, 4, 13-14 and 17
Copending claim 18 recites the carrier is a polymeric micelle or a lipidic mRNA carrier, and Heartlein discloses the carrier is a lipid nanoparticle, liposome or micelle, as instantly claimed in dependent claim 10 and new claims 15 and 17. See, e.g., paragraphs 56-57.
With respect to new claim 18, the claim is indefinite under 35 U.S.C. 112(b) regarding the nexus of the recited “1 to 5 RNA oligomers [that] hybridize with a single mRNA molecule” and the method according to claim 17, as set forth above. For examination purposes under 35 U.S.C. 102, new claim 18 has been interpreted as reciting that 1 to 5 RNA oligomers hybridize with the mRNA initially recited in line 3 of claim 17 (“an mRNA encoding a target gene and at least one RNA oligomer hybridizing with the mRNA”). Copending claim 1 recites a complex comprising a plurality of 6-10 types of RNA oligomers, wherein each RNA oligomer comprises a first sequence complementary to the target mRNA sequence linked to a second sequence that is the same as the first sequence. Heartlein discloses hybridizing one or more complementary RNA oligomers to the target mRNA. See, e.g., par. 13, 32.
For these reasons, instant claims 1-4, 11-15, 17-18 would have been prima facie obvious in view of the copending claims and secondary references.
Claims 5-6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 16/762,059; and US 2015/0267192 A1 to Heartlein et al., as applied to claims 1-4, 11-15, 17-18 above; in further view of Bramsen et al. (2011) "Chemical modification of small interfering RNA" In: van Rij, R. (eds) Antiviral RNAi, Methods in Molecular Biology, vol 721, Humana Press.
This rejection is newly applied.
The copending claims do not recite that the RNA oligomer comprises a chemical modification on the 5'-terminus or 3'-terminus of the sequence of the RNA oligomer via an overhang sequence consisting of 1-5 or 2 nucleotides, as claimed by instant claims 5-6.
Prior to the effective filing date of the instantly claimed invention, Bramsen discloses that a terminal 3’ overhang consisting of 2 nucleotides enhances nuclease resistance of RNA oligomers. See, e.g., page 81-82, and 94.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a RNA oligomer, as found in the copending claims, to contain a terminal 3’ overhang consisting of 2 nucleotides, as taught by Bramsen, with a reasonable expectation of success because the nucleotide overhang enhances nuclease resistance.
Claims 7-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 16/762,059; and US 2015/0267192 A1 to Heartlein et al., as applied to claims 1-4, 11-15, 17-18 above; in further view of Alterman et al. (2015) “Hydrophobically modified siRNAs silence huntingtin mRNA in primary neurons and mouse brain” Molecular therapy Nucleic acids, 4, e266, 12 pages.
This rejection is newly applied.
The copending claims do not recite that the RNA oligomer comprises a modification with a hydrophobic group or a cholesterol modification, as claimed by instant claims 7-8.
Prior to the effective filing date of the instantly claimed invention. Alterman discloses that hydrophobic modifications promote biodistribution, stability and cellular uptake of RNA oligomers. The hydrophobic modification is a cholesterol moiety. See, e.g., Abstract; pages 1-2, and Figure 1a.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a RNA oligomer, as found in the copending claims, to contain a hydrophobic group or cholesterol modification, as taught by Alterman, with a reasonable expectation of success because the modification promotes biodistribution, stability and cellular uptake of RNA oligomers.
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 16/762,059; and US 2015/0267192 A1 to Heartlein et al., as applied to claims 1-4, 11-15, 17-18 above; in further view of Winkler, J. (2015) “Therapeutic oligonucleotides with polyethylene glycol modifications” Future medicinal chemistry, 7(13), 1721-1731.
This rejection is newly applied.
The copending claims do not recite that the RNA oligomer comprises a polyethylene glycol (PEG) modification, as claimed by instant claim 9.
Prior to the effective filing date of the instantly claimed invention, Winkler discloses that the attachment of PEG is a well-established strategy to prevent enzymatic degradation and avoid renal elimination in the field of oligonucleotide drugs. See, e.g., Abstract; and Figure 1.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a RNA oligomer, as found in the copending claims, to contain a polyethylene glycol (PEG) modification, as taught by Winkler, with a reasonable expectation of success because the PEG modification is a well-established strategy to protect the RNA oligomer from enzymatic degradation and renal elimination.
Conclusion
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached on (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
Prosecution Insights