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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-5, 7, 12, 18-26, 33, and 65 (Group I) in the reply filed on 11/19/2025 is acknowledged. Regarding the species election requirement, Applicant further elected SEQ ID NOs: 43 and 44. Following a search of the prior art, the species election requirement is withdrawn.
Claims 47 and 57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/19/2025.
Accordingly, claims 1-5, 7, 12, 18-26, 33, and 65 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/979,833, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Provisional application 62/979,833 (filed 02/21/2020) discloses sense and antisense sequences of dsRNA agents targeting MCJ, as in the instant application. However, this application does not disclose all of the sequences recited at instant claim 1, as the provisional application discloses only up to SEQ ID NO: 170. These sequences were subsequently disclosed in WO 2021/168373 A1, which was published on 08/26/2021 and filed on 02/20/2021. Accordingly, the earliest effective filing date to which instant claim 1 is entitled as a whole is 02/20/2021. All other claims of the instant claim set directly or indirectly depend from instant claim 1 or otherwise require the subject matter of instant claim 1.
Furthermore, provisional application 62/979,833 (filed 02/21/2020) is silent as to the targeting ligand species recited at instant claim 21 (Mito-F). However, this species was subsequently disclosed in WO 2021/168373 A1, which was published on 08/26/2021 and filed on 02/20/2021.
Finally, as set forth in greater detail below, the instant application does not comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. Accordingly, the earliest effective filing date to which the instant application is entitled is the actual filing date, which is 02/20/2021.
Information Disclosure Statement
Receipt of an information disclosure statement on 01/31/2023 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Specification
The disclosure is objected to because of the following informalities:
When listing the length of overhangs envisioned by the instant application, the instant specification lists “at least e1, 2, 3, 4, 5, 6, or more nucleotides” (page 20, line 24; bolded emphasis added). The bolded “e” appears to be a simple typographical error. It would be remedial to amend the instant specification such that the bolded “e” is deleted.
The term “complementary” is misspelled as “complimentary” at line 27 of page 18 of the specification filed on 08/19/2022. As is known to those of ordinary skill in the art, the terms “complementary” and “complimentary” are not interchangeable. Accordingly, it would be remedial to amend the instant specification such that the term “complementary” is properly spelled throughout.
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 5, and 33 are objected to because of the following informalities:
Instant claim 1 recites “a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ) wherein the dsRNA agent comprises…”, which is grammatically improper. In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to amend the instant claim such that a comma properly separates “methylation-controlled J-protein (MCJ)” and “wherein the dsRNA agent comprises…”.
The preamble of instant claim 5 recites “the dsRNA of claim 1,” which is inconsistent with the preambles of instant claims 2-4, 7, and 18-25, all of which recite “the dsRNA agent of claim 1” (bolded emphasis added). The recitation of a dsRNA agent is consistent both with the recitation of the body of instant claim 1 and of the preambles of instant claims 2-4, 7, and 18-25. Thus, for purposes of internal consistency and clarity, it would be remedial to amend instant claim 5 such that the preamble recites “the dsRNA agent of claim 1” (bolded emphasis added).
With regard to instant claim 33, line 4 of instant claim 33 is grammatically improper. There is an improper comma separating “(dsRNA) agent of claim 1” and “to inhibit expression of the MCJ gene in the cell.” In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to remove the comma separating these phrases.
Appropriate correction is required.
Improper Markush Grouping
Claims 1-5, 7, 12, 18-26, 33, and 65 are rejected on the basis that they contain an improper Markush grouping of alternatives.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of dsRNA agents (instant claims 1, 3, and 4) and sequences targeted by the same (instant claim 2) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the listed alternatives all comprise different sequences that display variable efficacy in reducing MCJ expression, as evidenced by the variable knockdown outcomes disclosed at Table 3 of the instant specification. Therefore, different dsRNA agent sequences targeting different regions of MCJ are considered to have different effects and therefore uses, meaning the Markush grouping of instant claims 1-4 is improper. All other claims in the instant claim set directly or indirectly depend from claim 1 or otherwise require the dsRNA agent of claim 1 and therefore inherit the rejection thereof that is set forth above.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 7, 12, 18-26, 33, and 65 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.
Claim 1 is drawn to a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ), wherein the dsRNA agent comprises a sense strand and an antisense strand, said antisense strand comprising a region of complementarity to an MCJ RNA transcript of at least 15 contiguous nucleotides (meaning the antisense strand itself must comprise at least 15 contiguous nucleotides). Claims 2-5, 7, 12, and 18-25 directly or indirectly depend from claim 1, while claims 26, 33, and 65 all require the dsRNA agent of claim 1. The rejected claims thus comprise a dsRNA agent comprising an antisense strand, wherein said antisense strand comprises up to an unlimited number of contiguous nucleotides.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes antisense sequences of the instantly claimed dsRNA agents with up to 21 contiguous nucleotides at Tables 1 and 6. No description is provided of a dsRNA agent comprising an antisense strand, wherein said antisense strand comprises up to an unlimited number of contiguous nucleotides.
It is known that the length of dsRNA agents (such as siRNAs) has an impact on silencing efficiency. While there is some debate over the “best length” for such dsRNA agents, agents with lengths of 19-29 nucleotides have been found to effectively silence their targets. Effective siRNA design includes considering the length of the agent, as shorter lengths may lead to unspecific binding, while longer lengths can induce immune responses in mammals (Fakhr et al., 2016: page 75, column 1, paragraph 1). The prior art is silent as to any dsRNA agent (such as an siRNA) comprising an antisense strand, wherein said antisense strand comprises up to an unlimited number of contiguous nucleotides.
In view of the disclosed examples and the accepted principles in the field reflected in the prior art and set forth above, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-5, 7, 12, 18-26, 33, and 65.
As set forth above, claims 24 and 25 directly depend from instant claim 1 and therefore inherit the rejection thereof, as they do not resolve the basis of the rejection. Additionally, both claims 24 and 25 are drawn to the dsRNA agent of claim 1, wherein at least one strand comprises a 3’ overhang of at least 1 nucleotide or of at least 2 nucleotides, respectively. The rejected claims thus comprise a dsRNA agent comprising at least one 3’ overhang, wherein said 3’ overhang comprises up to an unlimited number of nucleotides.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification does not clearly disclose the number of nucleotides in the 3’ overhang(s) of the dsRNA agents taught therein, but it does envision nucleotide overhangs of at least 1, 2, 3, 4, 5, 6, or more nucleotides (page 20, line 24). However, no description is provided of a dsRNA agent comprising at least one 3’ overhang, wherein said 3’ overhang comprises up to an unlimited number of nucleotides.
As set forth above regarding instant claim 1, it is known that the length of dsRNA agents (such as siRNAs) has an impact on silencing efficiency (reviewed in Fakhr et al., 2016). The overhangs of instant claims 24 and 25 are necessarily part of the length of the claimed dsRNA agents. Accordingly, overhangs comprising up to an unlimited number of nucleotides would necessarily generate dsRNA agents comprising up to an unlimited number of nucleotides. As set forth above, effective siRNA design includes considering the length of the agent, as shorter lengths may lead to unspecific binding, while longer lengths can induce immune responses in mammals (Fakhr et al., 2016: page 75, column 1, paragraph 1). The prior art is silent as to any dsRNA agent (such as an siRNA) comprising at least one 3’ overhang, wherein said 3’ overhang comprises up to an unlimited number of nucleotides.
In view of the disclosed examples and the accepted principles in the field reflected in the prior art and set forth above, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 24 and 25.
Claim Rejections - 35 USC § 112(b)
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 1-5, 7, 12, 18-26, 33, and 65 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.
With regard to claim 1, which recites “the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an MCJ RNA transcript, which comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1 or Table 6” (bolded emphasis added), as well as claims 3 and 4, which both recite “the dsRNA agent comprises a[/an]…sequence set forth in Table 1 or Table 6” (bolded emphasis added), and claim 2, which recites “any one of the target regions of SEQ ID NO: 2 provided in Table 2” (bolded emphasis added), per MPEP § 2173.05(s), claims are to be complete in themselves-meaning, incorporation by reference to a specific figure or table is only permitted in exceptional circumstances. In the instant application, the claimed sequences may easily be clearly and definitely recited in the claim language itself. It would be remedial to amend the claim language to recite the claimed sequences rather than incorporating them by reference, as in the instant claims. Given that all other claims of the instant claim set directly or indirectly depend from instant claim 1 or otherwise require the subject matter of instant claim 1 and do not resolve the basis of the indefiniteness rejection set forth above, all other claims inherit the rejection thereof. Accordingly, claims 1-5, 7, 12, 18-26, 33, and 65 are rejected under 35 U.S.C. 112(b).
With specific regard to claim 2, which recites “the MCJ RNA transcript is any one of the target regions of SEQ ID NO: 2 provided in Table 2,” this recitation is nonsensical to those of ordinary skill in the art. A single RNA transcript, such as the instantly claimed MCJ RNA transcript comprises multiple target regions, as set forth in Table 2 of the instant specification. However, none of these target regions constitute an MCJ RNA transcript, as is instantly recited. It would be remedial to amend the instant claim language such that the recitation of claim 2 properly reflects that a single RNA transcript comprises multiple target regions and not that each target region is an RNA transcript, for example by reciting “the region of complementarity of the antisense strand to the MCJ RNA transcript is any one of the target regions of SEQ ID NO: 2 defined by SEQ ID NOs: 115-170 and 299-306” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting.
With specific regard to claim 12, the term “substantially all” in claim 12 is a relative term which renders the claim indefinite. The term “substantially all” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the instant specification defines the terms “substantially complementary” and “substantially identical” (page 18, line 13-page 19, line 13), there is no definition of “substantially all.” Based on the disclosure of the instant specification, it is not clear to those of ordinary skill in the art what percentage of nucleotides that are modified in the instantly claimed sequences would infringe on the bounds of protection sought by the instant claim set. In order to ensure one of ordinary skill in the art would be reasonably apprised of the scope of the invention, it would be remedial to clearly define what threshold of percentage of nucleotides that are modified qualifies as “substantially all.”
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, 2, 24-26, and 33 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2017/011356 A2 (hereinafter Rincon; as cited in the IDS filed 01/31/2023), as evidenced by Fakhr et al., 2016 (hereinafter Fakhr).
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With regard to instant claim 1, which recites “a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ)[,] wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an MCJ RNA transcript, which comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1 or Table 6, optionally comprising a targeting ligand,” Rincon discloses compounds for inhibiting MCJ, including double-stranded siRNA molecules (abstract; page 2, lines 21-23; page 8, lines 49-50; page 21, lines 26-29). These siRNA molecules are presented showing one strand, but the disclosure explicitly states that this practice is standard in the art and that the siRNA molecules disclosed therein are nonetheless double-stranded (page 9, lines 1-16; page 21, lines 26-29). This disclosure is consistent with the teachings of Fakhr, which teaches that siRNAs are double-stranded RNA molecules for RNA interference, wherein one strand is the antisense strand that is complementary to the target gene, and the other strand is the sense strand that is cleaved after delivering the antisense strand to its targeted sequence (Figure 1).
As shown in the alignments above, SEQ ID NO: 12 of Rincon (disclosed to correspond to an siRNA molecule targeting MCJ (page 9, lines 1-16; page 21, lines 26-29)) aligns with instant SEQ ID NO: 16 with 2 different terminal nucleotides (i.e. less than 3 different nucleotides), which is an MCJ-targeting antisense sequence disclosed at Table 1 of the instant specification and recited at instant claim 1. While Rincon appears to only disclose the sense strand of the siRNA molecules taught therein based on the above alignments with instant SEQ ID NO: 2 (the MCJ RNA transcript), as set forth above, Rincon explicitly discloses that only one strand of the double-stranded siRNA molecules taught therein is presented (page 9, lines 1-16; page 21, lines 26-29). Thus, based on the disclosure of Rincon, one of ordinary skill in the art would be aware that the other strand that is not presented therein must be complementary to the presented strand, as is further evidenced by the teachings of Fakhr set forth above. Thus, it is considered that Rincon anticipates each and every limitation of instant claim 1.
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With regard to instant claim 2, which recites that the antisense strand targets “the MCJ RNA transcript…[at] any one of the target regions of SEQ ID NO: 2 provided in Table 2,” as shown in the alignments above, instant SEQ ID NO: 16 targets nucleotides 542-560 of instant SEQ ID NO: 2, while SEQ ID NO: 12 of Rincon targets nucleotides 540-560 of instant SEQ ID NO: 2. Therefore, one of ordinary skill in the art may reasonably conclude that instant SEQ ID NO: 16 targets the region of the MCJ RNA transcript defined as instant SEQ ID NO: 121, as confirmed in the alignment below.
Given that both instant SEQ ID NO: 16 and SEQ ID NO: 12 of Rincon target the entirety of nucleotides 542-560 of instant SEQ ID NO: 2 (defined as instant SEQ ID NO: 121), it is considered that Rincon anticipates each and every limitation of instant claim 2.
With regard to instant claims 24 and 25, which respectively recite “the dsRNA agent of claim 1, wherein at least one strand comprises a 3’ overhang of at least 1 nucleotide” or of “at least 2 nucleotides,” as set forth above, Rincon anticipates the dsRNA agent of claim 1. Rincon further discloses that the siRNAs taught therein comprise 3’ overhangs of 2 nucleotides (page 21, lines 26-29). An overhang of 2 nucleotides reads on the instantly claimed “at least 1 nucleotide” and “at least 2 nucleotides” recited at instant claims 24 and 25. Thus, it is considered that Rincon anticipates each and every limitation of instant claims 24 and 25.
With regard to instant claim 26, which recites “a composition comprising a dsRNA agent of claim 1, optionally further comprising a pharmaceutically acceptable carrier, and optionally further comprising one or more additional therapeutic agents,” as set forth above, Rincon anticipates the dsRNA agent of claim 1. Rincon further discloses that the siRNA compounds taught therein may be administered as a pharmaceutical composition (page 30, lines 15-25; page 31, lines 5-18) that comprises pharmaceutically acceptable carriers and therapeutic agents (page 32, lines 7-25). Thus, it is considered that Rincon anticipates each and every limitation of instant claim 26.
With regard to instant claim 33, which recites “a method of inhibiting the expression of a methylation-controlled J-protein (MCJ) gene in a cell, the method comprising: preparing a cell comprising an effective amount of a double-stranded ribonucleic acid (dsRNA) agent of claim 1, to inhibit expression of the MCJ gene in the cell,” as set forth above, Rincon anticipates the dsRNA agent of claim 1. Rincon further discloses administration of an effective amount of an inhibiting compound (such as the siRNAs taught therein) to a cell for purposes of disrupting/reducing MCJ expression through RNA interference (page 2, lines 3-5; page 11, lines 5-9; page 22, lines 9-22; page 25, lines 20-26; page 28, line 18-page 29, line 4; Figure 7). Thus, it is considered that Rincon anticipates each and every limitation of instant claim 33.
Claims 1, 2, 5, 7, 12, 18-20, 22-26, 33, and 65 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0190785 A1 (hereinafter Tremblay; earliest effective filing date is 03/30/2020).
As set forth above, the Examiner notes that provisional application 62/979,833 (filed 02/21/2020) discloses sense and antisense sequences of dsRNA agents targeting MCJ, as in the instant application. However, this application does not disclose all of the sequences recited at instant claim 1, as the provisional application discloses only up to SEQ ID NO: 170. These sequences were subsequently disclosed in WO 2021/168373 A1, which was published on 08/26/2021 and internationally filed on 02/20/2021. Accordingly, the earliest effective filing date to which instant claim 1 is entitled is 02/20/2021. All other claims of the instant claim set directly or indirectly depend from instant claim 1 or otherwise require the subject matter of instant claim 1. Therefore, SEQ ID NO: 290 is entitled to an effective filing date of 02/20/2021, which post-dates the earliest effective filing date of Tremblay (03/30/2020).
With regard to instant claim 1, which recites “a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ)[,] wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an MCJ RNA transcript, which comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1 or Table 6, optionally comprising a targeting ligand,” Tremblay discloses dsRNA compositions targeting the DNAJC15 gene (which reads on the instantly claimed MCJ gene as set forth at page 7, lines 26-30 of the instant specification) (abstract). Table 2A of Tremblay discloses exemplary siRNA sequences, including an antisense strand corresponding to SEQ ID NO: 113. As shown in the alignment below, SEQ ID NO: 113 of Tremblay aligns with every residue of instant SEQ ID NO: 290, with the exception of the two terminal nucleotides.
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Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 1, as the antisense strand taught therein comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1.
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With regard to instant claim 2, which recites that the antisense strand targets “the MCJ RNA transcript…[at] any one of the target regions of SEQ ID NO: 2 provided in Table 2,” as shown in the alignment below, SEQ ID NO: 113 of Tremblay targets the same region of the MCJ RNA transcript as instant SEQ ID NO: 290 (which is defined as SEQ ID NO: 302 per table 2 of the instant specification).
Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 2.
With regard to instant claim 5, which recites “the dsRNA agent [of claim 1] comprises at least one modified nucleotide,” Tremblay further discloses that the dsRNA agents targeting DNAJC15 taught therein comprise at least one modified nucleotide (abstract; paragraph [0033]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 5.
With regard to instant claim 7, which recites “the dsRNA agent of claims 1…comprises at least one phosphorothioate internucleoside linkage,” Tremblay further discloses that the dsRNA agents targeting DNAJC15 taught therein comprise at least one phosphorothioate linkage (abstract; paragraph [0045]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 7.
With regard to instant claim 12, which recites “all of substantially all of the nucleotides of the sense strand and the antisense strand [of the dsRNA agent of claim 1] are modified nucleotides,” as set forth above, Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein comprise at least one modified nucleotide (abstract; paragraph [0033]). Tremblay explicitly discloses that all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand may comprise a nucleotide modification (paragraph [0033]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 12.
With regard to instant claim 18, which recites “the dsRNA agent of claim 1…comprises at least one modified nucleotide and further comprises one or more targeting groups or linking groups,” as set forth above, Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein comprise at least one modified nucleotide (abstract; paragraph [0033]). Tremblay further discloses that the dsRNA agents taught therein may comprise a ligand such as GalNAc (paragraph [0036]), which reads on the instantly claimed targeting group per the instant specification (page 26, lines 15-16). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 18.
With regard to instant claim 19, which recites “the one or more targeting groups or linking groups [of the dsRNA agent of claim 18] are conjugated to the sense strand,” as set forth above, Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein comprise at least one modified nucleotide and a ligand such as GalNAc (abstract; paragraphs [0033] and [0036]). Tremblay further discloses that said ligand may be conjugated to either the 3’ or 5’ end of the sense strand (paragraph [0036]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 19.
With regard to instant claim 20, which recites “the targeting group of linking group [of the dsRNA agent of claim 18] comprises N-acetyl-galactosamine (GalNAc),” as set forth above, Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein may comprise a ligand such as GalNAc (abstract; paragraph [0036]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 20.
With regard to instant claim 22, which recites “the dsRNA agent of claim 1…comprises a targeting group that is conjugated to the 5’-terminal end of the sense strand,” as set forth above, Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein comprise at least one modified nucleotide and a ligand such as GalNAc (abstract; paragraphs [0033] and [0036]). Tremblay further discloses that said ligand may be conjugated to either the 3’ or 5’ end of the sense strand (paragraph [0036]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 22.
With regard to instant claim 23, which recites “the dsRNA agent of claim 1…has two blunt ends,” Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein may be blunt ended, wherein both ends of the dsRNA molecule are blunt, with no nucleotide overhang at either end (abstract; paragraph [0083]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 23.
With regard to instant claims 24 and 25, which respectively recite “at least one strand [of the dsRNA agent of claim 1] comprises a 3’ overhang of at least 1 nucleotide” or “at least 2 nucleotides,” Tremblay discloses that the dsRNA agents targeting DNAJC15 taught therein may comprise an overhang of at least 1 nucleotide or of at least 2 nucleotides at least at one strand of said molecule (abstract; paragraph [0043]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claims 24 and 25.
With regard to instant claim 26, which recites “a composition comprising a dsRNA agent of claim 1, optionally further comprising a pharmaceutically acceptable carrier, and optionally further comprising one or more additional therapeutic agents” Tremblay further discloses that the dsRNA agents targeting DNAJC15 taught therein may be delivered as part of a pharmaceutical composition that comprises a pharmaceutically acceptable carrier (abstract; paragraphs [0013] and [0068]). Other known agents effective in treating DNAJC15-related diseases or disorders may also be administered with the dsRNA agents taught in Tremblay (paragraph [0502]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 26.
With regard to instant claim 33, which recites “a method of inhibiting the expression of a methylation-controlled J-protein (MCJ) gene in a cell, the method comprising: preparing a cell comprising an effective amount of a double-stranded ribonucleic acid (dsRNA) agent of claim 1…to inhibit expression of the MCJ gene in the cell,” as set forth above, Tremblay discloses dsRNA agents targeting DNAJC15 (abstract). Tremblay further discloses that these dsRNA agents may be used to inhibit expression of DNAJC15 in a cell by contacting the cell with an effective amount of the dsRNA agent taught therein (or a pharmaceutical composition comprising the same) and maintaining the cell produced by said process such that expression of the DNAJC15 gene is inhibited (abstract; paragraphs [0011], [0012], [0017]-[0019], [0106], and [0535]).
With regard to instant claim 65, which recites “the dsRNA agent [of the method of claim 33] comprises at least one modified nucleotide,” as set forth above, Tremblay further discloses that the dsRNA agents targeting DNAJC15 taught therein may be used to decrease expression of an MCJ gene (i.e. DNAJC15) in a cell and may comprise at least one modified nucleotide (abstract; paragraph [0011], [0012], [0017]-[0019], [0033], [0106], and [0535]). Thus, it is considered that Tremblay anticipates each and every limitation of instant claim 65.
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 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/011356 A2 (hereinafter Rincon; as cited in the IDS filed 01/31/2023), as evidenced by Fakhr et al., 2016 (hereinafter Fakhr) as applied to claim 1 above, and further in view of RU 2644675 C1 (hereinafter Vasilevich; machine translation attached), Eckstein, 2014 (hereinafter Eckstein), and Watts et al., 2008 (hereinafter Watts).
The disclosure of Rincon (as evidenced by Fakhr) is described above and applied as before. However, this disclosure does not teach the terminal 2’-deoxythymidine-3’-phosphate residues of the sense and antisense sequences of instant claims 3 and 4.
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With regard to instant claim 3, which recites “the dsRNA agent of claim 1…comprises a sense strand sequence set forth in Table 1 or Table 6,” as set forth above, SEQ ID NO: 12 of Rincon is presented as one strand of a double-stranded siRNA molecule targeting MCJ (abstract; page 2, lines 21-23; page 8, lines 49-50; page 9, lines 1-16; page 21, lines 26-29). As shown in the alignments above, SEQ ID NO: 12 of Rincon appears to correspond to the sense strand of the siRNA molecules taught therein, which is supported by the alignment below showing that SEQ ID NO: 12 of Rincon aligns with instant SEQ ID NO: 15, which is the sense strand corresponding to the antisense strand of instant SEQ ID NO: 16 as listed in Table 1.
However, Rincon does not disclose the terminal 2’-deoxythymidine-3’-phosphate residues of the sense sequences recited at instant claim 3. This deficiency is cured by Vasilevich and Eckstein. Vasilevich discloses siRNA duplexes comprising a terminal 2’-deoxythymidine-3’-phosphate residue and a 2’-deoxythymidine-3’-phosphorothioate residue 5’ of said terminal residue for purposes of increasing siRNA resistance to nucleases (abstract; paragraph [0056] of machine translated document). While 2’-deoxythymidine-3’-phosphorothioate does not comprise a 3’-phosphate group, it does comprise a 3’-phosphorothioate, which is a known modification of the phosphate group to generate a phosphorothioate linkage that increases nuclease resistance (Eckstein: abstract). Watts further discloses that acceptance of phosphorothioate linkages in siRNA molecules depends on strand architecture, with different regions of different molecules displaying varying levels of acceptance (page 845, column 2, paragraph 2-page 846, column 1, paragraph 1). Based on this disclosure, one of ordinary skill in the art would reasonably be motivated to generate and test multiple siRNA molecules with varying numbers of phosphorothioate linkages (including 0) at varying locations within said siRNA molecules (including the termini) via routine experimentation in order to maximize the nuclease resistance of said siRNA molecules. Thus, as set forth in greater detail below, it is considered that Vasilevich, Eckstein, and Watts collectively disclose each and every additional limitation of instant claim 3.
With regard to instant claim 4, which recites “the dsRNA agent of claim 1…comprises an antisense strand sequence set forth in Table 1 or Table 6,” as set forth above, SEQ ID NO: 12 of Rincon is presented as one strand of a double-stranded siRNA molecule targeting MCJ (abstract; page 2, lines 21-23; page 8, lines 49-50; page 9, lines 1-16; page 21, lines 26-29). As shown in the alignments above, SEQ ID NO: 12 of Rincon appears to correspond to the sense strand of the siRNA molecules taught therein, which is supported by the alignment above showing that SEQ ID NO: 12 of Rincon aligns with instant SEQ ID NO: 15, which is the sense strand corresponding to the antisense strand of instant SEQ ID NO: 16 as listed in Table 1.
Additionally, as set forth above, Fakhr teaches that sense and antisense strands of siRNA must be complementary and form a proper duplex (page 75, column 1, paragraph 5). Therefore, one of ordinary skill in the art would be aware that the antisense strand complement of the sense strand presented as SEQ ID NO: 12 in Rincon must correspond to the antisense sequence of instant SEQ ID NO: 16, as set forth above regarding instant claim 1.
However, Rincon does not disclose the terminal 2’-deoxythymidine-3’-phosphate residues of the sense sequences recited at instant claim 3. This deficiency is cured by Vasilevich and Eckstein. Vasilevich discloses siRNA duplexes comprising a terminal 2’-deoxythymidine-3’-phosphate residue and a 2’-deoxythymidine-3’-phosphorothioate residue 5’ of said terminal residue for purposes of increasing siRNA resistance to nucleases (abstract; paragraph [0056] of machine translated document). While 2’-deoxythymidine-3’-phosphorothioate does not comprise a 3’-phosphate group, it does comprise a 3’-phosphorothioate, which is a known modification of the phosphate group to generate a phosphorothioate linkage that increases nuclease resistance (Eckstein: abstract). Watts further discloses that acceptance of phosphorothioate linkages in siRNA molecules depends on strand architecture, with different regions of different molecules displaying varying levels of acceptance (page 845, column 2, paragraph 2-page 846, column 1, paragraph 1). Based on this disclosure, one of ordinary skill in the art would reasonably be motivated to generate and test multiple siRNA molecules with varying numbers of phosphorothioate linkages (including 0) at varying locations within said siRNA molecules (including the termini) via routine experimentation in order to maximize the nuclease resistance of said siRNA molecules. Thus, as set forth in greater detail below, it is considered that Vasilevich, Eckstein, and Watts collectively disclose each and every additional limitation of instant claim 4.
Given that Rincon discloses siRNA compounds targeting MCJ for inhibition of expression of the same as set forth regarding instant claim 1, that Vasilevich discloses siRNA duplexes comprising a terminal 2’-deoxythymidine-3’-phosphate residue and a 2’-deoxythymidine-3’-phosphorothioate residue 5’ of said terminal residue for purposes of increasing siRNA resistance to nucleases, that Eckstein teaches that phosphorothioate linkages are known modifications of the phosphate group of nucleotides for increasing nuclease resistance, and that Watts teaches that different regions of different siRNA molecules display varying levels of acceptance of phosphorothioate linkages based on strand architecture, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to generate and test multiple siRNA molecules with varying numbers of phosphorothioate linkages (including 0) at varying locations within said siRNA molecules (including the termini) to predictably identify an effective siRNA molecule displaying maximal nuclease resistance, which is also conferred by 2’-deoxythymidine-3’-phosphate, as set forth above. One would have been motivated to make such a modification in order to receive the expected benefit of maximizing the nuclease resistance of therapeutic siRNA molecules.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0190785 A1 (hereinafter Tremblay; earliest effective filing date is 03/30/2020), as applied to claim 1 above, and further in view of RU 2644675 C1 (hereinafter Vasilevich; machine translation attached), Eckstein, 2014 (hereinafter Eckstein), and Watts et al., 2008 (hereinafter Watts).
The disclosure of Tremblay is described above and applied as before. However, this disclosure does not teach the terminal 2’-deoxythymidine-3’-phosphate residues of the sense and antisense sequences of instant claims 3 and 4.
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With regard to instant claim 4, which recites “the dsRNA agent of claim 1…comprises an antisense strand sequence set forth in Table 1 or Table 6,” as set forth above, Tremblay discloses dsRNA compositions targeting the DNAJC15 gene (which reads on the instantly claimed MCJ gene as set forth at page 7, lines 26-30 of the instant specification) (abstract). Table 2A of Tremblay discloses exemplary siRNA sequences, including an antisense strand corresponding to SEQ ID NO: 113. As shown in the alignment below, SEQ ID NO: 113 of Tremblay aligns with every residue of instant SEQ ID NO: 290, with the exception of the two terminal nucleotides, which are disclosed to be 2’-deoxythymidine-3’-phosphate residues.
This deficiency is cured by Vasilevich and Eckstein. Vasilevich discloses siRNA duplexes comprising a terminal 2’-deoxythymidine-3’-phosphate residue and a 2’-deoxythymidine-3’-phosphorothioate residue 5’ of said terminal residue for purposes of increasing siRNA resistance to nucleases (abstract; paragraph [0056] of machine translated document). While 2’-deoxythymidine-3’-phosphorothioate does not comprise a 3’-phosphate group, it does comprise a 3’-phosphorothioate, which is a known modification of the phosphate group to generate a phosphorothioate linkage that increases nuclease resistance (Eckstein: abstract). Watts further discloses that acceptance of phosphorothioate linkages in siRNA molecules depends on strand architecture, with different regions of different molecules displaying varying levels of acceptance (page 845, column 2, paragraph 2-page 846, column 1, paragraph 1). Based on this disclosure, one of ordinary skill in the art would reasonably be motivated to generate and test multiple siRNA molecules with varying numbers of phosphorothioate linkages (including 0) at varying locations within said siRNA molecules (including the termini) via routine experimentation in order to maximize the nuclease resistance of said siRNA molecules. Thus, as set forth in greater detail below, it is considered that Vasilevich, Eckstein, and Watts collectively disclose each and every additional limitation of instant claim 4.
Given that Tremblay discloses dsRNA compounds targeting DNAJC15 (i.e. MCJ) for inhibition of expression of the same as set forth regarding instant claim 1, that Vasilevich discloses siRNA duplexes comprising a terminal 2’-deoxythymidine-3’-phosphate residue and a 2’-deoxythymidine-3’-phosphorothioate residue 5’ of said terminal residue for purposes of increasing siRNA resistance to nucleases, that Eckstein teaches that phosphorothioate linkages are known modifications of the phosphate group of nucleotides for increasing nuclease resistance, and that Watts teaches that different regions of different siRNA molecules display varying levels of acceptance of phosphorothioate linkages based on strand architecture, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to generate and test multiple siRNA molecules with varying numbers of phosphorothioate linkages (including 0) at varying locations within said siRNA molecules (including the termini) to predictably identify an effective siRNA molecule displaying maximal nuclease resistance, which is also conferred by 2’-deoxythymidine-3’-phosphate, as set forth above. One would have been motivated to make such a modification in order to receive the expected benefit of maximizing the nuclease resistance of therapeutic siRNA molecules.
Claims 5, 7, 12, 18-20, 22, 23, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/011356 A2 (hereinafter Rincon; as cited in the IDS filed 01/31/2023), as evidenced by Fakhr et al., 2016 (hereinafter Fakhr) as applied to claims 1 and 33 above, and further in view of US 2014/0288158 A1 (hereinafter Rajeev), as evidenced by Watts et al., 2008 (hereinafter Watts), Eckstein, 2014 (hereinafter Eckstein), and Zhu and Mahato, 2010 (hereinafter Zhu).
The disclosure of Rincon (as evidenced by Fakhr) is described above and applied as before. However, this disclosure does not teach the dsRNA agent modifications of instant claims 5, 7, 12, 18-20, and 65.
With regard to instant claim 5, which recites “the dsRNA...agent [of claim 1] comprises at least one modified nucleotide,” as set forth above, Rincon anticipates the dsRNA agent of claim 1. However, Rincon is silent as to the instantly claimed modified nucleotide(s). This deficiency is cured by Rajeev. Rajeev discloses dsRNA agents capable of inhibiting the expression of a target gene (abstract), wherein said dsRNA agents comprise modified nucleotides to enhance gene silencing activity, such as ribose sugar modifications (paragraphs [0011] and [0043]). Rajeev explicitly discloses that every nucleotide of the sense strand and of the antisense strand may be modified, for example with ribose sugar modifications (paragraph [0043]). Watts teaches that nucleotide sugar modifications are widely used in siRNA design to increase binding affinity, nuclease resistance, and potency (page 843, column 2, paragraph 5; page 844, column 2, paragraph 4; Figure 2). Thus, it is considered that Rajeev, as evidenced by Watts, discloses each and every additional limitation of instant claim 5.
With regard to instant claim 7, which recites “the dsRNA agent of claim 1…comprises at least one phosphorothioate internucleoside linkage,” as set forth above, Rincon anticipates the dsRNA agent of claim 1. However, Rincon is silent as to the instantly claimed phosphorothioate internucleoside linkage(s). This deficiency is cured by Rajeev. The dsRNA agents of Rajeev are further disclosed to comprise at least one phosphorothioate linkage, which may occur on any nucleotide of the sense strand or antisense strand or both in any position on the strand (paragraph [0057]). As set forth above, Eckstein teaches that phosphorothioate linkages increase nuclease resistance (abstract). Thus, it is considered that Rajeev (as evidenced by Eckstein) discloses each and every additional limitation of instant claim 7.
With regard to instant claim 12, which recites “all or substantially all of the nucleotides of the sense strand and the antisense strand [of the dsRNA agent of claim 1] are modified nucleotides,” as set forth above, Rincon anticipates the dsRNA agent of claim 1, while Rajeev discloses dsRNA agents comprising modified nucleotides (i.e. modified sugars) (paragraphs [0011] and [0043]) that increase siRNA binding affinity, nuclease resistance and potency per Watts (page 843, column 2, paragraph 5; page 844, column 2, paragraph 4; Figure 2). Additionally, as set forth above, Rajeev explicitly discloses that every nucleotide of the sense strand and of the antisense strand may be modified, for example with ribose sugar modifications (paragraph [0043]). Thus, it is considered that Rajeev (as evidenced by Watts) discloses each and every additional limitation of instant claim 12.
With regard to instant claim 18, which recites “the dsRNA agent of claim 1…comprises at least one modified nucleotide and further comprises one or more targeting groups or linking groups,” as set forth above, Rincon anticipates the dsRNA agent of claim 1, while Rajeev discloses dsRNA agents comprising modified nucleotides (i.e. modified sugars) (paragraphs [0011] and [0043]) that increase siRNA binding affinity, nuclease resistance and potency per Watts (page 843, column 2, paragraph 5; page 844, column 2, paragraph 4; Figure 2). Regarding the instantly claimed targeting groups, Rincon discloses that the siRNA molecules taught therein may comprise a targeting agent such as NAcGalactosamine (GalNAc), which facilitates delivery of said siRNA molecules (page 27, lines 19-23). Rajeev also discloses that the dsRNA agents taught therein may comprise a targeting group such as N-acetyl-galactosamine (GalNAc) (paragraph [0180]). Per the instant specification, GalNAc reads on the instantly claimed targeting group (page 26, lines 15-17). Thus, it is considered that Rincon and Rajeev (as evidenced by Watts) collectively disclose each and every additional limitation of instant claim 18.
With regard to instant claim 19, which recites “the one or more targeting groups…[of the dsRNA agent of claim 18] are conjugated to the sense strand,” as set forth above, both Rincon and Rajeev disclose conjugating a targeting group such as GalNAc to the therapeutic siRNA molecules taught therein to facilitate its delivery. Rajeev further discloses that the dsRNA agents taught therein may be conjugated to a ligand (such as GalNAc per paragraph [0180]) at the sense strand, antisense strand, or both strands, at the 3’-end, 5’-end, or both ends (paragraph [0172]). This is supported by the teachings of Zhu, which discloses that conjugation on both the 3’ and 5’ ends of the sense strand is safe and effective (page 2124, column 1, paragraph 1). Based on this disclosure, one of ordinary skill in the art would reasonably be motivated to generate and test siRNA molecules with conjugation of targeting group ligands to different strands and different termini via routine experimentation in order to maximize the efficacy of the targeting group in facilitating siRNA delivery. Thus, as set forth in greater detail below, it is considered that Rincon and Rajeev (as evidenced by Zhu) collectively disclose each and every additional limitation of instant claim 19.
With regard to instant claim 20, which recites “the targeting group…[of the dsRNA agent of claim 18] comprises N-acetyl-galactosamine (GalNAc),” as set forth above, Rincon discloses that the siRNA molecules taught therein may comprise a targeting agent such as NAcGalactosamine (GalNAc), which facilitates delivery of said siRNA molecules (page 27, lines 19-23). Rajeev also discloses that the dsRNA agents taught therein may comprise a targeting group such as N-acetyl-galactosamine (GalNAc) (paragraph [0180]). Thus, it is considered that Rincon and Rajeev collectively disclose each and every additional limitation of instant claim 20.
With regard to instant claim 22, which recites “the dsRNA agent of claim 1…comprises a targeting group that is conjugated to the 5’-terminal end of the sense strand,” as set forth above, both Rincon and Rajeev disclose conjugating a targeting group such as GalNAc to the therapeutic siRNA molecules taught therein to facilitate its delivery. Rajeev further discloses that the dsRNA agents taught therein may be conjugated to a ligand (such as GalNAc per paragraph [0180]) at the sense strand, antisense strand, or both strands, at the 3’-end, 5’-end, or both ends (paragraph [0172]). This is supported by the teachings of Zhu, which discloses that conjugation on both the 3’ and 5’ ends of the sense strand is safe and effective (page 2124, column 1, paragraph 1). Based on this disclosure, one of ordinary skill in the art would reasonably be motivated to generate and test siRNA molecules with conjugation of targeting group ligands to different strands and different termini (i.e. at the 5’ end of the sense strand) via routine experimentation in order to maximize the efficacy of the targeting group in facilitating siRNA delivery. Thus, as set forth in greater detail below, it is considered that Rincon and Rajeev (as evidenced by Zhu) collectively disclose each and every additional limitation of instant claim 22.
With regard to instant claim 23, which recites “the dsRNA agent of claim 1…has two blunt ends,” as set forth above, Rajeev discloses dsRNA agents capable of inhibiting the expression of a target gene (abstract), wherein said dsRNA agents may have two blunt ends (i.e. at both ends of the dsRNA duplex) (paragraph [0026]). Furthermore, Watts teaches that blunt-ended siRNA duplexes are more resistant to 3’-exonucleases (page 846, column 2, paragraph 3). Thus, it is considered that Rajeev (as evidenced by Watts) discloses each and every additional limitation of instant claim 23.
With regard to instant claim 65, which recites “the dsRNA agent [of the method of claim 33] comprises at least one modified nucleotide,” as set forth above, Rincon anticipates the method of instant claim 33. However, Rincon is silent as to the instantly claimed modified nucleotide(s) of the dsRNA agent of said method. This deficiency is cured by Rajeev. Rajeev discloses dsRNA agents capable of inhibiting the expression of a target gene (abstract), wherein said dsRNA agents comprise modified nucleotides to enhance gene silencing activity, such as ribose sugar modifications (paragraphs [0011] and [0043]). Rajeev explicitly discloses that every nucleotide of the sense strand and of the antisense strand may be modified, for example with ribose sugar modifications (paragraph [0043]). Watts teaches that nucleotide sugar modifications are widely used in siRNA design to increase binding affinity, nuclease resistance, and potency (page 843, column 2, paragraph 5; page 844, column 2, paragraph 4; Figure 2). Thus, it is considered that Rajeev, as evidenced by Watts, discloses each and every additional limitation of instant claim 65.
Given that both Rincon and Rajeev disclose therapeutic dsRNA agents, such as siRNA molecules, wherein said dsRNA agents may be conjugated to a targeting group such as GalNAc; that Rajeev specifically discloses that the dsRNA agents taught therein may comprise at least one modified nucleotide (up to and including all nucleotides being modified nucleotides) and/or phosphorothioate linkage(s), that the conjugated targeting group may be attached at either end of the sense or antisense strand, and that the dsRNA agents taught therein may have two blunt ends; and that the various evidentiary references teach that nucleotide sugar modifications are widely used in siRNA design to increase binding affinity, nuclease resistance, and potency (Watts), blunt ends increase exonuclease resistance (Watts), phosphorothioate linkages increase nuclease resistance (Eckstein), and conjugation on both the 3’ and 5’ ends of the sense strand is safe and effective (Zhu), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA agents disclosed in Rincon to have two blunt ends and/or to further comprise nucleotide modifications, phosphorothioate linkages, and conjugation to targeting groups such as GalNAc at the 3’ or 5’ terminus of the sense strand to predictably increase the efficacy of said dsRNA agents by increasing their binding affinity, nuclease resistance, and potency. One would have been motivated to make such a modification in order to receive the expected benefit of increasing the efficacy of therapeutic dsRNA agents (such as siRNAs) by increasing their binding affinity, nuclease resistance, and potency.
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, 26, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 7, and 11 of U.S. Patent No. 10,583,169 B2 in view of WO 2017/011356 A2 (hereinafter Rincon; as cited in the IDS filed 01/31/2023), as evidenced by Fakhr et al., 2016 (hereinafter Fakhr).
Patent ‘169 is also drawn to methods and compositions that alter MCJ expression (title; abstract). Claim 1 of patent ‘169 recites “a method for treating a metabolic disease or condition in a subject, the method comprising administering…an MCJ-modulating compound that decreases MCJ polypeptide activity…wherein the MCJ-modulating compound comprises an MCJ siRNA.” This method is further limited by claims 4 and 5, which respectively recite “the MCJ-modulating compound is administered in a pharmaceutical composition” that “further comprises a targeting agent.” Additionally, claim 7 recites “a method of increasing mitochondrial metabolism in a liver cell, the method comprising contacting the liver cell with an exogenous MCJ-modulating compound that decreases MCJ polypeptide activity…wherein the MCJ modulating compound comprises an MCJ siRNA.” This method is further limited by claim 11, which further recites that “the MCJ-modulating compound comprises a targeting agent.”
In comparison, instant claim 1 recites “a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ)[,] wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an MCJ RNA transcript, which comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1 or Table 6, optionally comprising a targeting ligand.” Instant claim 26 further recites “a composition comprising a dsRNA agent of claim 1, optionally further comprising a pharmaceutically acceptable carrier, and optionally further comprising one or more additional therapeutic agents.” Additionally, instant claim 33 recites “a method of inhibiting the expression of a methylation-controlled J-protein (MCJ) gene in a cell, the method comprising: preparing a cell comprising an effective amount of a double-stranded ribonucleic acid (dsRNA) agent of claim 1…to inhibit expression of the MCJ gene in the cell.” The instant specification explicitly discloses that the claimed dsRNA agents may be interchangeably referred to as siRNAs (page 8, lines 12-14), as in patent ‘169. Thus, both the instant application and patent ‘169 recite an siRNA with a targeting ligand (or agent) targeting an MCJ gene, which modulates (i.e. decreases) MCJ expression, thereby decreasing associated polypeptide activity.
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While patent ‘169 does not disclose the specific sequences recited at instant claim 1, this deficiency is cured by Rincon. As set forth above (see section Claim Rejections - 35 USC § 102), Rincon discloses compounds for inhibiting MCJ, including double-stranded siRNA molecules (abstract; page 2, lines 21-23; page 8, lines 49-50; page 21, lines 26-29). These siRNA molecules are presented showing one strand, but the disclosure explicitly states that this practice is standard in the art and that the siRNA molecules disclosed therein are nonetheless double-stranded (page 9, lines 1-16; page 21, lines 26-29). This disclosure is consistent with the teachings of Fakhr, which teaches that siRNAs are double-stranded RNA molecules for RNA interference, wherein one strand is the antisense strand that is complementary to the target gene, and the other strand is the sense strand that is cleaved after delivering the antisense strand to its targeted sequence (Figure 1).
As shown in the alignments above, SEQ ID NO: 12 of Rincon (disclosed to correspond to an siRNA molecule targeting MCJ (page 9, lines 1-16; page 21, lines 26-29)) aligns with instant SEQ ID NO: 16 with 2 different terminal nucleotides (i.e. less than 3 different nucleotides), which is an MCJ-targeting antisense sequence disclosed at Table 1 of the instant specification and recited at instant claim 1. While Rincon appears to only disclose the sense strand of the siRNA molecules taught therein based on the above alignments with instant SEQ ID NO: 2 (the MCJ RNA transcript), as set forth above, Rincon explicitly discloses that only one strand of the double-stranded siRNA molecules taught therein is presented (page 9, lines 1-16; page 21, lines 26-29). Thus, based on the disclosure of Rincon, one of ordinary skill in the art would be aware that the other strand that is not presented therein must be complementary to the presented strand, as is further evidenced by the teachings of Fakhr set forth above.
Given that patent ‘169 recites an siRNA with a targeting ligand (or agent) targeting an MCJ gene, which modulates (i.e. decreases) MCJ expression, thereby decreasing associated polypeptide activity, as well as pharmaceutical compositions comprising the same (as in the instant application), and that Rincon discloses an siRNA agent targeting an MCJ gene that comprises an antisense strand meeting the limitations of instant claim 1, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the siRNA disclosed in Rincon in the methods recited in patent ‘169 to predictably modulate (i.e. decrease) MCJ expression, thereby decreasing associated polypeptide activity, as is instantly claimed. One would have been motivated to make such a modification in order to receive the expected benefit of modulating (i.e. decrease) MCJ expression, thereby decreasing associated polypeptide activity for therapeutic purposes.
Claims 1, 26, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, 10, 13, and 14 of U.S. Patent No. 10,655,126 B2 in view of WO 2017/011356 A2 (hereinafter Rincon; as cited in the IDS filed 01/31/2023), as evidenced by Fakhr et al., 2016 (hereinafter Fakhr).
Patent ‘126 is drawn to methods and compounds useful to treat drug-induced diseases and conditions, wherein said compounds are MCJ-inhibiting compounds that decrease MCJ polypeptide activity in cells, tissues, and/or subjects as a treatment for such diseases and conditions (abstract). Claim 1 of patent ‘126 recites “a method for treating…a subject, the method comprising administering…an MCJ-inhibiting compound…wherein the MCJ-inhibiting compound reduces MCJ polypeptide activity…wherein the MCJ-inhibiting compound comprises a[n] MCJ small interference RNA molecule (MCJ siRNA).” This method is further limited by claims 3 and 6, which respectively recite “the MCJ-inhibiting compound further comprises a targeting agent” and “the MCJ-inhibiting compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and optionally comprises one or more of a carrier agent, a delivery agent, a labeling agent, and a targeting agent.”
Similarly, claim 10 of patent ‘126 recites “a method of reducing an acetaminophen-induced disease or condition in a liver cell, the method comprising contacting the liver cell with an MCJ-inhibiting compound in an amount effective to decrease an MCJ polypeptide activity in the liver cell…wherein the MCJ-inhibiting compound comprises an MCJ small interference RNA molecule (MCJ siRNA),” while claims 13 and 14 respectively further limit the claimed method by reciting “the MCJ-inhibiting compound [is] in a pharmaceutical composition…wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and optionally comprises one or more of a carrier agent, a delivery agent, a labeling agent, [and] a targeting agent” and that “the MCJ-inhibiting compound further comprises a targeting agent.”
In comparison, instant claim 1 recites “a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ)[,] wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an MCJ RNA transcript, which comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1 or Table 6, optionally comprising a targeting ligand.” Instant claim 26 further recites “a composition comprising a dsRNA agent of claim 1, optionally further comprising a pharmaceutically acceptable carrier, and optionally further comprising one or more additional therapeutic agents.” Additionally, instant claim 33 recites “a method of inhibiting the expression of a methylation-controlled J-protein (MCJ) gene in a cell, the method comprising: preparing a cell comprising an effective amount of a double-stranded ribonucleic acid (dsRNA) agent of claim 1…to inhibit expression of the MCJ gene in the cell.” The instant specification explicitly discloses that the claimed dsRNA agents may be interchangeably referred to as siRNAs (page 8, lines 12-14), as in patent ‘126. Thus, both the instant application and patent ‘126 recite an siRNA with a targeting ligand (or agent) targeting an MCJ gene, which modulates (i.e. decreases) MCJ expression, thereby decreasing associated polypeptide activity.
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While patent ‘126 does not disclose the specific sequences recited at instant claim 1, this deficiency is cured by Rincon. As set forth above (see section Claim Rejections - 35 USC § 102), Rincon discloses compounds for inhibiting MCJ, including double-stranded siRNA molecules (abstract; page 2, lines 21-23; page 8, lines 49-50; page 21, lines 26-29). These siRNA molecules are presented showing one strand, but the disclosure explicitly states that this practice is standard in the art and that the siRNA molecules disclosed therein are nonetheless double-stranded (page 9, lines 1-16; page 21, lines 26-29). This disclosure is consistent with the teachings of Fakhr, which teaches that siRNAs are double-stranded RNA molecules for RNA interference, wherein one strand is the antisense strand that is complementary to the target gene, and the other strand is the sense strand that is cleaved after delivering the antisense strand to its targeted sequence (Figure 1).
As shown in the alignments above, SEQ ID NO: 12 of Rincon (disclosed to correspond to an siRNA molecule targeting MCJ (page 9, lines 1-16; page 21, lines 26-29)) aligns with instant SEQ ID NO: 16 with 2 different terminal nucleotides (i.e. less than 3 different nucleotides), which is an MCJ-targeting antisense sequence disclosed at Table 1 of the instant specification and recited at instant claim 1. While Rincon appears to only disclose the sense strand of the siRNA molecules taught therein based on the above alignments with instant SEQ ID NO: 2 (the MCJ RNA transcript), as set forth above, Rincon explicitly discloses that only one strand of the double-stranded siRNA molecules taught therein is presented (page 9, lines 1-16; page 21, lines 26-29). Thus, based on the disclosure of Rincon, one of ordinary skill in the art would be aware that the other strand that is not presented therein must be complementary to the presented strand, as is further evidenced by the teachings of Fakhr set forth above.
Given that patent ‘126 recites an siRNA with a targeting ligand (or agent) targeting an MCJ gene, which modulates (i.e. decreases) MCJ expression, thereby decreasing associated polypeptide activity, as well as pharmaceutical compositions comprising the same (as in the instant application), and that Rincon discloses an siRNA agent targeting an MCJ gene that comprises an antisense strand meeting the limitations of instant claim 1, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the siRNA disclosed in Rincon in the methods recited in patent ‘126 to predictably modulate (i.e. decrease) MCJ expression, thereby decreasing associated polypeptide activity, as is instantly claimed. One would have been motivated to make such a modification in order to receive the expected benefit of modulating (i.e. decrease) MCJ expression, thereby decreasing associated polypeptide activity for therapeutic purposes.
Claims 1 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 11,752,193 B2 in view of WO 2017/011356 A2 (hereinafter Rincon; as cited in the IDS filed 01/31/2023), as evidenced by Fakhr et al., 2016 (hereinafter Fakhr).
Patent ‘193 is drawn to methods and compositions that are useful to modulate metabolic function of cells, said methods and compositions comprising siRNAs targeting MCJ (title; abstract). Claim 1 of patent ‘193 recites “a method of increasing mitochondrial metabolism in a kidney cell, the method comprising contacting the kidney cell with an MCJ-modulating compound comprising an MCJ siRNA that decreases MCJ polypeptide activity,” which is further limited by the recitation of “the MCJ-modulating compound further comprises a targeting agent” at claim 5 of patent ‘193.
In comparison, instant claim 1 recites “a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of methylation-controlled J-protein (MCJ)[,] wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an MCJ RNA transcript, which comprises at least 15 contiguous nucleotides and differs by no more than 3 nucleotides from one of the antisense sequences listed in Table 1 or Table 6, optionally comprising a targeting ligand.” Additionally, instant claim 33 recites “a method of inhibiting the expression of a methylation-controlled J-protein (MCJ) gene in a cell, the method comprising: preparing a cell comprising an effective amount of a double-stranded ribonucleic acid (dsRNA) agent of claim 1…to inhibit expression of the MCJ gene in the cell.” The instant specification explicitly discloses that the claimed dsRNA agents may be interchangeably referred to as siRNAs (page 8, lines 12-14), as in patent ‘193. Thus, both the instant application and patent ‘193 recite an siRNA with a targeting ligand (or agent) targeting an MCJ gene, which modulates (i.e. decreases) MCJ expression, thereby decreasing associated polypeptide activity.
While patent ‘193 does not disclose the specific sequences recited at instant claim 1, this deficiency is cured by Rincon. As set forth above (see section Claim Rejections - 35 USC § 102), Rincon discloses compounds for inhibiting MCJ, including double-stranded siRNA molecules (abstract; page 2, lines 21-23; page 8, lines 49-50; page 21, lines 26-29). These siRNA molecules are presented showing one strand, but the disclosure explicitly states that this practice is standard in the art and that the siRNA molecules disclosed therein are nonetheless double-stranded (page 9, lines 1-16; page 21, lines 26-29). This disclosure is consistent with the teachings of Fakhr, which teaches that siRNAs are double-stranded RNA molecules for RNA interference, wherein one strand is the antisense strand that is complementary to the target gene, and the other strand is the sense strand that is cleaved after delivering the antisense strand to its targeted sequence (Figure 1).
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As shown in the alignments above, SEQ ID NO: 12 of Rincon (disclosed to correspond to an siRNA molecule targeting MCJ (page 9, lines 1-16; page 21, lines 26-29)) aligns with instant SEQ ID NO: 16 with 2 different terminal nucleotides (i.e. less than 3 different nucleotides), which is an MCJ-targeting antisense sequence disclosed at Table 1 of the instant specification and recited at instant claim 1. While Rincon appears to only disclose the sense strand of the siRNA molecules taught therein based on the above alignments with instant SEQ ID NO: 2 (the MCJ RNA transcript), as set forth above, Rincon explicitly discloses that only one strand of the double-stranded siRNA molecules taught therein is presented (page 9, lines 1-16; page 21, lines 26-29). Thus, based on the disclosure of Rincon, one of ordinary skill in the art would be aware that the other strand that is not presented therein must be complementary to the presented strand, as is further evidenced by the teachings of Fakhr set forth above.
Given that patent ‘193 recites an siRNA with a targeting ligand (or agent) targeting an MCJ gene, which modulates (i.e. decreases) MCJ expression, thereby decreasing associated polypeptide activity (as in the instant application), and that Rincon discloses an siRNA agent targeting an MCJ gene that comprises an antisense strand meeting the limitations of instant claim 1, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the siRNA disclosed in Rincon in the methods recited in patent ‘126 to predictably modulate (i.e. decrease) MCJ expression, thereby decreasing associated polypeptide activity, as is instantly claimed. One would have been motivated to make such a modification in order to receive the expected benefit of modulating (i.e. decrease) MCJ expression, thereby decreasing associated polypeptide activity for therapeutic purposes.
Conclusion
No claims are allowed.
Claims 1, 5, and 33 are objected to.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637