DETAILED ACTIONNotice 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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/24/25 has been entered.
Application Status and Election
Claims 1, 2, 6, 9-11, 13-14, 17-19, 22, 25-26, 29, and 30 are pending. Claim 1 is amended. Claim 3 cancelled. Claims 12, 15, 16, 29, and 30 remain withdrawn. Applicant’s election without traverse of group 1 (currently pending claims 1, 2, 6, 9-14, 17-19, 22, and 25-26) in the reply filed on May 14 2024 remains acknowledged. Applicant elected the species of oligomeric compound of SEQ ID NO: 54 with the modifications indicated in claim 25.
Examination on the merits commences on claims 1, 2, 6, 9-11, 13-14, 17-19, 22, and 25-26.
Claim Rejections - 35 USC § 112(d) - NEW
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 25 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 25 recites, “The composition of claim 1, wherein the oligomeric compound comprises a sequence selected from the group consisting of… wherein an * between two nucleosides indicates a phosphorothioate, the absence of an * between two nucleosides indicates a phosphorodiester, the capitalized letters A, C, G, and T indicate tc-DNA nucleosides; the lowercase letters a, u, g, and t indicate 2'-O-methyl-RNA nucleosides, the nucleobase at all C positions is 5-methylcytosine, the nucleobase at all c positions is cytosine, and s represents a -O-CH2-CH2-CH2-O- (1,3-propanediol) non-nucleoside.” Examiner notes that not all the sequences recited in claim 25 contain one or more 2'-modified ribonucleic acid (2'-modified-RNA) nucleosides such as “5'- C*A*T*C*C*T*G*G*A*G*T*T*C*C*T-3' (SEQ ID NO:88).”
However, claim1 recites, “A composition comprising an oligomeric compound, the compound comprising one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and one or more 2'-modified ribonucleic acid (2'-modified-RNA) nucleosides joined by a plurality of internucleoside linkages…”
Thus, claim 25 does not incorporate all the limitations from the claim from which it depends.
Claim Rejections - 35 USC § 112(a) – Written Description - NEW
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.
Claim(s) 1, 2, 6, 9-11, 13-14, 17-19, 22, and 26 is/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.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims are drawn to “an oligomeric compound, the compound comprising one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and one or more 2'-modified ribonucleic acid (2'-modified-RNA) nucleosides joined by a plurality of internucleoside linkages; wherein the ratio of monomers to multimers of oligomeric compound in the composition ranges from 5:1 to 250:1 as determined by size exclusion chromatography or by capillary electrophoresis; and wherein one or more 2'-modified-RNA nucleosides are incorporated in positions such that self-complementary binding under physiological conditions is prevented; and wherein the melting temperature (Tm) of the oligomeric compound is at least 65 °C.”
The specification has not adequately described the entire genus of “oligomeric compound” for the following reasons.
Size and Breadth of the Genus
The claims are drawn to an “oligomeric compound.” However, the claimed language does not sufficiently limit the structure of the oligomeric compounds in length, specific modification, secondary/tertiary structure, or further function, and therefore could encompass any means, directly or indirectly, for targeting. The genus of “oligomeric compound” is broad and diverse in the art. Oligomeric compounds can be single stranded or double stranded, partly DNA or partly RNA, modified with 2’, 5’, and 3’ modifications, etc. Single stranded oligomeric compounds may have a double stranded region, and double stranded oligomeric compounds may have a single stranded region. Some oligomeric compounds include structural genes, genes containing control and termination regions, self-replicating systems such as viral or plasmid DNA, single-stranded and double-stranded siRNA and other RNA interference reagents (RNAi or iRNA agents), shRNA, antisense oligos. Nucleotide, ribozyme, microRNA, microRNA mimetic, supermir, aptamer, antimir, antagomir, Ul adapter, triplex-forming oligonucleotide, G-quadruplex oligonucleotide, RNA activator, immunostimulatory oligo, and decor oligonucleotides, among others.
In this case, the claims encompass the genus of oligomeric compounds, where there is substantial variation within the genus, even upon further limitations of claim 1 wherein the compound comprises one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and one or more 2'-modified ribonucleic acid (2'-modified-RNA) nucleosides joined by a plurality of internucleoside linkages; wherein the ratio of monomers to multimers of oligomeric compound in the composition ranges from 5:1 to 250:1 as determined by size exclusion chromatography or by capillary electrophoresis; and wherein one or more 2'-modified-RNA nucleosides are incorporated in positions such that self-complementary binding under physiological conditions is prevented; and wherein the melting temperature (Tm) of the oligomeric compound is at least 65 °C.
As such, the genus of “oligomeric compounds” is extensive and diverse.
Species disclosed in the Specification
The specification discloses a variety of nucleic acids that can serve as oligomeric compounds. The specification teaches in [00205], an “oligomeric compound" and "oligonucleotide" refer to short polynucleotides that contain nucleotide monomeric subunits. The length of an oligonucleotide may be denoted by the number of nucleotide monomeric subunits concatenated to the term "-mer." For example, an oligonucleotide containing ten nucleotide monomeric subunits is a 10-mer (or decamer), and an oligonucleotide containing 25 nucleotide monomeric subunits is a 25-mer. Oligonucleotides and oligomeric compounds of the present disclosure are listed from left to right following the order of the 5' to the 3' end, respectively.” The Specification also teaches [00206], the oligomeric compound may be an "antisense oligonucleotide" that is capable of interacting with and/or hybridizing to a pre-mRNA or an mRNA having a complementary nucleotide sequence thereby modifying gene expression and which contains a variety of internucleoside linkages and chemical modification patterns.
Although the specification discloses several embodiments of “oligomeric compound,” the specification fails to teach representative species of oligomeric compounds which sufficiently describe the full genus capable of targeting gene expression.
Species Disclosed in the Art
The genus of “oligomeric compound” is broad and diverse in the art. Oligomeric compounds can be single stranded or double stranded, DNA or RNA, modified with 2’, 5’, and 3’ modifications. Single stranded oligomeric compounds may have a double stranded region, and double stranded oligomeric compounds may have a single stranded region. Some oligomeric compounds include structural genes, genes containing control and termination regions, self-replicating systems such as viral or plasmid DNA, single-stranded and double-stranded siRNA and other RNA interference reagents (RNAi or iRNA agents), shRNA, antisense oligos. Nucleotide, ribozyme, microRNA, microRNA mimetic, supermir, aptamer, antimir, antagomir, Ul adapter, triplex-forming oligonucleotide, G-quadruplex oligonucleotide, RNA activator, immunostimulatory oligo, and decor oligonucleotides, among others.
Regarding nucleic acid oligomeric compounds as gene modulators, Wang teaches that the ability to predict nucleic acid hybridization (i.e., via “rational design”) is generally limited to the use of unmodified nucleic acids, and that many broadly employed chemical modifications to DNA and RNA have not been included in predictive models (pg. 2, para. 1 and pg. 14, para. 1; Wang et al., 2022, PLOS ONE, 17(5), e0268575). Wang teaches thermodynamic models of hybridization for nucleic acid molecules with phosphorothioate linkages, where each linkage modification decreases duplex stability (pg. 13, para. 4) Wang teaches that backbone and sugar ring modifications, in conjunctions with nucleotide sequence, would likely require a combinatorially large (and synthetically intractable) set of duplexes to fully characterize (pg. 13, para. 3). Therefore, it is unpredictable that nucleic acid hybridization without a rational design incorporating thermodynamics, phosphorothioate linkages or backbone/sugar ring modifications would successfully promote nucleic acid binding.
Regarding oligomeric compounds such as nucleic acid ligands for G-4 quadruplex structures, Kruisselbrink teaches the existence of 376,000 potentially mutagenic G4 (G-4 quadruplex) DNA sites in the human genome (pg 900 para 1; Kruisselbrink, Evelien, et al. Current Biology 18.12 (2008): 900-905) and that those G4 DNA sequences that have the potential to fold into replication blocking quadruplex structures are intrinsically mutagenic in live animals (pg 903 col 2 para 5). Kruisselbrink teaches the instability of G4 complexes requires a specialized genome-protection mechanism to prevent massive genome rearrangements at G4 DNA sites (pg 903 col 2 para 5). Thus, the instability and mutagenesis of G-4 structures undermines the predictability of any non-specific oligomeric compounds able to hybridize a G-4 complex so as to interfere with translational events.
Regarding oligomeric compounds as nucleic acids, “Guide RNA” is a known RNA that binds to an RNA-guided nuclease and binds to a target site, where for example, E. coli have naturally occurring CRISPR/Cas systems and therefore E. coli cells contain guide RNAs (Diez-Villasenor et al., Microbiology (2010), 156: 1351-1361). The RNA “staple nucleic acid” is also described in the art. Wilner et. al., teaches that appropriate selection of staple units may lead to predesigned nanoscale 2D or 3D shapes and patterns of DNA (Figure 10; Wilner, Ofer I., and Itamar Willner. Chemical reviews 112.4 (2012): 2528-2556.). Wilner teaches one of the challenges in the self-assembly of DNA-origami-based nanostructures involves the appropriate design of the staple strands (pg 2537 col 2 para 2). Wilner teaches the design of programmed origami-based DNA assemblies provide the basis to organize ordered systems of nanoparticles, nanotubes, and proteins on origami scaffolds (pg 2537 col 2 para 2). Figure 1 of Wilner teaches schematic structural and functional features of staple nucleic acids including (A) single-stranded sticky end; (B) duplex hybridization; (C) hairpin nanostructure; (D) G-quadruplex; (E) triplex hybrid; (F) DNAzyme structure; (G) metal-bridged duplex; and (H) aptamer nanostructure (pg 2529 para 1).
As the prior art establishes, there is substantial variation within the genus of oligonucleotides. Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus. Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus of “oligomeric compound” and lack of predictability of undefined modifications, secondary structure, or function, the specification disclosure is not sufficient to show that the Applicant was in possession of “oligomeric compounds” at the time the invention was filed.
Dependent claims
Other than claim 25, which recites the specific sequence with length and modifications of the oligomeric compound, the dependent claims of claim 1 do not further limit the genus of cargo molecules so as to resolve the issues above, and therefore lack adequate written description for the reason outlined for claim 1.
Claim Rejections - 35 USC § 103 - Modified Maintained
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
This is a modified rejection necessitated by amendment to claim 1 which incorporates melting temperature limitations from cancelled claim 3, with claim 1 now reciting, “wherein the melting temperature (Tm) of the oligomeric compound is at least 65 °C.”
Claim(s) 1, 2, 6, 9-11, 13, 14, 17, 18, 19, 22, and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Puri (Puri, N., US20100222414A1) of record, in view of Chung (Chung, Hyun Jung, et al. Bioconjugate chemistry 22.2 (2011): 299-306.) of record, and González (Ballarin-Gonzalez, Borja, and Kenneth Alan Howard. Advanced drug delivery reviews 64.15 (2012): 1717-1729.) of record, and Goyenvalle (Goyenvalle, Aurélie, et al. "Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers." Nature medicine 21.3 (2015): 270-275.) of record, and Jackson (Jackson, Aimee L., et al. Rna 12.7 (2006): 1197-1205.) of record, and Ittig (Ittig, Damian, et al. Artificial DNA: PNA & XNA 1.1 (2010): 9-16.) of record.
Regarding claim 1, Puri teaches an oligomeric compound with a tricyclo deoxynucleotide and a 2’-modified RNA nucleoside [0009] linked by internucleoside linkages [0114] used in a method of reducing off-target phenotypic effects in RNAi ([0001]).
Puri does not teach wherein the ratio of monomers to multimers of oligomeric compound in the composition ranges from 5:1 to 250:1 as determined by size exclusion chromatography or by capillary electrophoresis.
Chung teaches multimeric siRNA conjugates linked by cleavable disulfide bonds for enhancing gene silencing efficiency (pg 299 col 2 para 1). Chung teaches enhanced multimeric siRNA consists of a mixture of monomer, dimer, trimer, tetramer, and other oligomeric siRNA species with single-strand overhangs on both ends (pg 299 col 2 para 1). Chung teaches monomers and multimers able to be differentially detected by gel electrophoresis (pg 300 col 2 para 4). Chung teaches that since the multimeric siRNA had high charge density and chain flexibility, they showed greatly enhanced complex stability and efficiency as compared to monomeric siRNA, when using the less cytotoxic linear polyethylenimine (LPEI) as a condensing carrier (pg 299 col 2 para 1).
Although Chung teaches the higher charge density of multimers allows greater stability, González teaches that charge density of RNAi particles influences other biological properties such as endosomolytic activity (pg 1721 col 2 para 3) and that lower charge density of RNAi compositions can be used to avoid membrane disruption, immune complement activation, and cellular inflammatory response (pg 1722 table 2).
Goyenvalle teaches that even though oligomeric compound multimerization has been shown to enhance cellular internalization, it is not known whether self-assembly of tcDNA is maintained in vivo and thereby responsible for increased potency (pg 273 col 2 para 1). Therefore, Goyenvalle teaches potency of tcDNA containing multimer RNAis in vivo is not well known.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Puri’s tcDNA/2'-RNA composition to include multimeric forms in a ratio such as between 5:1 and 250:1 monomer to multimer as determined by gel electrophoresis in place of capillary electrophoresis. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Puri uses the tcDA/2’RNA composition to enhance RNAi. Chung teaches that multimer combinations of RNAi oligomers demonstrate enhanced effectiveness based on increased stability and that monomers and multimers can be differentially detected by gel electrophoresis. However, Chung also teaches the increased stability comes with increased charge density of the linked multimers and González teaches that increased charge density can increase toxicity by influencing membrane disruption, immune complement activation, and cellular inflammatory response. Thus, the skilled artisan would have had a reasonable expectation that while the presence of multimers within the composition would benefit RNAi effectiveness, higher levels of multimers as effectively distinguished by gel electrophoresis would pose a toxicity risk, particularly with tcDNA containing oligomers. Given that Goyenvalle teaches potency of tcDNA containing multimer RNAis is not well known and that González teaches highly charge dense multimers pose a toxicity risk, it would be obvious to optimize the ratio of monomer and multimers in Puri’s tcDNA/2’RNA composition to a ratio of monomer to multimer which can contain the risk of toxicity with still enhanced stability so as to optimize overall effectiveness of the oligomer composition. Note that the optimization of compositions (i.e., 5:1 – 250:1 monomer to multimer ratio) would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Regarding the claim 1 recitation of, “wherein one or more 2'-modified-RNA nucleosides are incorporated in positions such that self-complementary binding under physiological conditions is prevented”, Puri does not teach wherein the one or more 2'-modified-RNA nucleosides are incorporated in positions such that self-complementary binding under physiological conditions is prevented.
However, Jackson teaches 2’-O methyl ribosyl groups used to prevent binding partially perfect matches where position-specific, sequence-independent chemical modifications of 2’-O-methyl reduce silencing of partially complementary transcripts through limited complementarity to the RNA duplex (abstract). Jackson teaches off-target transcript silencing of siRNAs is mediated through miRNA-like mechanism where 2’-O-methyl modification distinguishes off-target silencing from silencing of perfectly matched targets and that that miRNA-like transcript silencing is differentially sensitive to 2’-O-methyl modification position. (pg 1203 col 1 para 1). Jackson teaches off-target transcript silencing is widespread and mediated largely by limited target sequence complementarity to the seed region of the siRNA guide strand (pg 1197 col 1 para 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have employed 2’O methyl group positioning within Puri’s tcDNA/2’O modified monomer/multimer composition according to the teachings of Jackson so as to prevent self-complementary binding under physiological conditions. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that specifically positioned 2’-O-methyl RNA nucleosides could modify the oligomer to prevent self-complementary binding because Jackson teaches the positional use of 2’-O methyl groups to modulate perfect and partial complementarity. The skilled artisan would be motivated to employ 2’O-methyl modifications within Puri’s tcDNA composition to control off-target silencing by preventing self-complementary binding.
Further regarding claim 1 and the newly amended melting temperature, the teachings of Puri, Chung, González, Goyenvalle, and Jackson as applied above for claim 1 do not teach wherein the melting temperature (Tm) of the oligomeric compound is at least 65 0C.
However, Ittig teaches Tc-DNA possesses both high affinity to RNA as well as high nuclease resistance which suggests that tc-nucleotide spiked siRNAs may enhance the functional half-life of siRNA by protecting them against exo- and endonucleolytic degradation (pg 12 col 1 para 2). Ittig teaches four consecutive tc-pyrimidine replacements demonstrates slightly higher stability at 65°C (pg 12 col 2 para 2), i.e. at least 65°C. Therefore, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention that Puri’s tc modified siRNA would have a melting temperature of at least 65°C. Furthermore, Examiner notes that the melting temperature of the oligomeric compound could vary based on the routine optimization of doses/concentrations (i.e., ratio of monomer to dimer) such that it would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Therefore, claim 1 is obvious and is properly rejected under 35 U.S.C. 103.
Regarding claim 2 and 13, Puri teaches the modified oligomeric compound having 15 to 30 nucleotides, a region of continuous complementarity to the passenger (sense) oligomeric compound of at least 12 nucleotides; the guide strand further having complementarity to at least a portion of a target mRNA. [0008], i.e. about 10-20 nucleotides wherein the oligomeric compound is complementary to a target sequence.
Regarding claim 6, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Puri’s tcDNA/2'-RNA composition to include multimeric forms in a ratio of at least 100 to 1 monomer to multimer for the obviousness rational provided above for claim 1.
Regarding claims 9-11, Puri does not teach wherein the one or more 2'-modified-RNA nucleosides are incorporated in at least two adjacent positions that form self-complementary Watson-Crick base pairs. However, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have employed 2’O methyl group positioning within Puri’s tcDNA/2’O methyl modified monomer/multimer composition according to the teachings of Jackson so as to form self-complementary Watson-Crick base pairs, given the obviousness rational provided above for claim 1 regarding the self-complementary binding reduction and given the teachings of Jackson.
Regarding claim 14, Puri teaches use of 2′-O-methyl-modified RNA as the 2'-modified-RNA nucleoside within the siRNA composition [0019].
Regarding claim 17, Puri teaches the internucleoside linkages of the composition can be phosphodiester bonds [0126].
Regarding claims 18, 19, and 22, Puri teaches the internucleoside linkages of the composition can be phosphorothioate bonds [0126]. Internucleoside phosphorothioate linkages are well known in the art such that optimization of doses/concentrations (i.e., ratio of phosphorothioate linkages within the composition) would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Regarding claim 26, Puri teaches the compositions of the invention can be in delivered in any method or combination as would be known to one of ordinary skill in the art [0184], i.e. within a pharmaceutical composition.
Claim(s) 1 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wakayama (Wakayama, T., US20180179538A1) of record, in view of Puri (Puri, N., US20100222414A1) of record, and Chung (Chung, Hyun Jung, et al. Bioconjugate chemistry 22.2 (2011): 299-306.) of record, and González (Ballarin-Gonzalez, Borja, and Kenneth Alan Howard. Advanced drug delivery reviews 64.15 (2012): 1717-1729.) of record, and Goyenvalle (Goyenvalle, Aurélie, et al. Nature medicine 21.3 (2015): 270-275) of record, and Jackson (Jackson, Aimee L., et al. Rna 12.7 (2006): 1197-1205.) of record, and Ittig (Ittig, Damian, et al. Artificial DNA: PNA & XNA 1.1 (2010): 9-16.) of record, as applied to claim 1.
Wakayama teaches SEQ ID NO: 33 as an antisense oligomeric compound with the identical base sequence to Applicant’s SEQ ID NO: 54 in a method of influencing exon 51 gene expression in the human dystrophin gene [0069].
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Wakayama does not teach the tcDNA/2’O methyl/5-methylcytosine modifications according to Applicant’s SEQ ID NO: 54:
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, wherein an * between two nucleosides indicates a phosphorothioate, the absence of an * between two nucleosides indicates a phosphorodiester, the capitalized letters A, C, G, and T indicate tc-DNA nucleosides; the lowercase letters a, u, g, and t indicate 2'-O-methyl-RNA nucleosides, the nucleobase at all C positions is 5-methylcytosine, the nucleobase at all c positions is cytosine.
The teachings of Puri, Chung, González, Goyenvalle, Jackson, and Ittig, as applied above for claim 1 are incorporated here.
Additionally, Puri teaches nucleotides in the tcDNA/2’O methyl modified composition can include the use of 5-methylcytosine [0128]. Puri also teaches the systematic arrangement of nucleic acids of the composition within arrays to screen for hybridization [0200]. Puri also teaches arrangements and permutations and combinations of the modifications of the invention, for example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB or BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth [0103], using “sequence-independent modification,” based on modification format patterns [0104].
Briefly, Jackson teaches 2’-O methyl ribosyl groups used to prevent binding partially perfect matches where position-specific, sequence-independent chemical modifications of 2’-O-methyl reduce silencing of partially complementary transcripts through limited complementarity to the RNA duplex (abstract).
It would It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Wakayama’s known antisense oligomeric compound base sequence with Puri’s tc-DNA/5-methylcytosine/2’-O-methyl-RNA monomer/multimer system according to Jackson’s positional teachings of 2’O methyl so as to construct the same modification pattern as Applicant’s SEQ ID NO: 54. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that modifying Wakayama’s oligo according to the modification pattern of Puri and Jackson would enhance oligo gene silencing functionality because Puri teaches these positional modifications enhance RNAi efficacy. The skilled artisan would be motivated to modify Wakayama’s oligomeric compound with such modifications in order to enhance the overall influence of exon 51 in the human dystrophin gene.
Double Patenting – Modified Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claim 1, 2, 6, 9-11, 13-14, 17-19, 22, and 25-26 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-22 of US Patent US11118179B2 in view Puri (Puri, N., US20100222414A1) and Chung (Chung, Hyun Jung, et al. Bioconjugate chemistry 22.2 (2011): 299-306.) and González (Ballarin-Gonzalez, Borja, and Kenneth Alan Howard. Advanced drug delivery reviews 64.15 (2012): 1717-1729.) and Goyenvalle (Goyenvalle, Aurélie, et al. Nature medicine 21.3 (2015): 270-275, and Jackson (Jackson, Aimee L., et al. Rna 12.7 (2006): 1197-1205.) of record, and Ittig of record (Ittig, Damian, et al. Artificial DNA: PNA & XNA 1.1 (2010): 9-16.), as applied to claim 1, and Wakayama (Wakayama, T., US20180179538A1) of record, as applied to claim 25.
Regarding instant claims 1-6, 9-11, 13-14, 17-19, 22, and 25-26, references claims 1 teaches an oligomeric compound comprising: one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and one or more 2′-modified ribonucleic acid (2′-modified-RNA) nucleosides, and optionally including one or more non-nucleosides; which are joined by a plurality of internucleoside linkages; wherein the oligomeric compound is a monomer as determined by non-denaturing gel electrophoresis.
Reference claim 2 teaches the oligomeric compound of reference claim 1, comprising from about 10 to about 20 nucleotides.
Reference claim 3 teaches oligomeric compound of reference claim 1, wherein the melting temperature (Tm) of the oligomeric compound is at least 50° C.
Reference claim 4 teaches the oligomeric compound of reference claim 1, wherein the one or more 2′-modified-RNA nucleosides are incorporated in positions such that self-complementary binding under physiological conditions is prevented.
Reference claim 5 teaches the oligomeric compound of reference claim 1, wherein the one or more 2′-modified-RNA nucleosides are incorporated in at least one position that forms self-complementary Watson-Crick base pairs.
Reference claim 6 teaches the oligomeric compound of reference claim 1, wherein the one or more 2′-modified-RNA nucleosides are incorporated in at least two adjacent positions that form self-complementary Watson-Crick base pairs.
Reference claim 7 teaches the oligomeric compound of reference claim 1, wherein the one or more 2′-modified-RNA nucleosides are incorporated at three or more adjacent positions that form self-complementary Watson-Crick base pairs.
Reference claim 8 teaches the oligomeric compound of reference claim 1, wherein the oligomeric compound does not contain a direct tc-DNA to tc-DNA phosphorothioate internucleoside linkage.
Reference claim 9 teaches the oligomeric compound of reference claim 1, which is complementary to a target sequence.
Reference claim 10 teaches the oligomeric compound of reference claim reference 1, wherein the one or more 2′-modified-RNA nucleosides are 2′-O-methyl-RNA nucleosides.
Reference claim 11 teaches the oligomeric compound of reference claim 1, wherein the one or more 2′-modified-RNA nucleosides are 2′-fluoro-RNA nucleosides.
Reference claim 12 teaches the oligomeric compound of reference claim 1, wherein the one or more 2′-modified-RNA nucleosides are locked nucleic acid RNA nucleosides.
Reference claim 13 teaches the oligomeric compound of reference claim 1, wherein each of the plurality of internucleoside linkages is independently selected from a phosphorothioate linkage, a phosphorodithioate linkage, and a phosphorodiester linkage, a phosphotriester linkage, an aminoalkylphosphotriester linkage, a methyl phosphonate linkage, an alkyl phosphonate linkage, a 5′-alkylene phosphonate linkage, a phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, an 3′-aminophosphoramidate linkage, an aminoalkyl phosphoramidate linkage, a thionophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a selenophosphate linkage, or a boranophosphate linkage.
Reference claim 14 teaches the oligomeric compound of reference claim 1, wherein the internucleoside linkages comprise a plurality of phosphorothioate linkages and a plurality of phosphorodiester linkages.
Reference claim 15 teaches the oligomeric compound of reference claim 14, wherein no more than 50% of the plurality of internucleoside linkages are phosphorothioate linkages.
Reference claim 16 teaches the oligomeric compound of reference claim 14, wherein no more than 33% of the plurality of internucleoside linkages are phosphorothioate linkages.
Reference claim 17 teaches the oligomeric compound of reference claim 14, wherein no more than 25% of the plurality of internucleoside linkages are phosphorothioate linkages.
Reference claim 18 teaches the oligomeric compound of reference claim 14, wherein at least 50% of the plurality of internucleoside linkages are phosphorodiester linkages.
Reference claim 19 teaches the oligomeric compound of reference claim 14, wherein at least 66% of the plurality of internucleoside linkages are phosphorodiester linkages.
Reference claim 20 teaches the oligomeric compound of reference claim 14, wherein at least 75% of the plurality of internucleoside linkages are phosphorodiester linkages.
Reference claim 21 teaches the oligomeric compound of reference claim 1 teaches SEQ ID NO: 55 which is identical in sequence and modification to instant claim 25 SEQ ID NO: 54.
Reference claim 22 teaches pharmaceutical composition comprising an oligomeric compound molecule according to reference claim 1.
The teachings of Puri, Chung, González, Goyenvalle, Jackson, Ittig, and Wakayama as applied above for claim 1 are incorporated here.
The patented claims do not recite the limitations of the ratio of monomers to multimers of oligomeric compound in the composition ranges from 5:1 to 250:1 as determined by size exclusion chromatography or by capillary electrophoresis, however, the patented Specification indicates, “the invention provides an oligomeric compound comprising a plurality of tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and a plurality of 2'-modified ribonucleic acid (2'-modified-RNA) nucleosides joined by a plurality of internucleoside linkages, wherein the oligomeric compound exhibits a monomer to multimer ratio of at least about 100 to 1 as determined by size-exclusion chromatography.” (col 4 line 23). The reference specification also teaches, “acute toxicity may be triggered upon bolus administration of some phosphorothioate tc-DNA oligomeric compounds through activation of the complement cascade, possibly as the result of multimer formation.” (Col 2 line 26). Therefore, the reference specification teaches that multimers of tc-DNA can cause toxicity such as through complement cascade. It would be obvious to a skilled artisan to limit the presence of multimers in the reference application’s composition to such as between 5:1 and 250:1 monomer to multimer in order to limit toxicity of the tc-DNA modified oligomer. It would similarly have been obvious to modify the reference patent claims to limit the ratio of monomer to dimer as detected by well-known techniques in the art to within the range of 5:1 and 250:1 for the obviousness rational provided in the above 35 U.S.C. 103 rejection of claim 1.
Claim 1 is rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1 and 4 of US patent US11872239 in view Puri (Puri, N., US20100222414A1) and Chung (Chung, Hyun Jung, et al. Bioconjugate chemistry 22.2 (2011): 299-306.) and González (Ballarin-Gonzalez, Borja, and Kenneth Alan Howard. Advanced drug delivery reviews 64.15 (2012): 1717-1729.) and Goyenvalle (Goyenvalle, Aurélie, et al. Nature medicine 21.3 (2015): 270-275) and Jackson (Jackson, Aimee L., et al. Rna 12.7 (2006): 1197-1205.) and Ittig of record (Ittig, Damian, et al. Artificial DNA: PNA & XNA 1.1 (2010): 9-16.), as applied to claim 1.
Regarding instant claim 1, reference claim 1 teaches a composition comprising: a. an oligomeric compound comprising one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides, wherein the oligomeric compound comprises from 5 to 40 monomer subunits; and b. a lipid moiety, and a hydroxyl protecting group. Reference claim 4 teaches wherein the monomer subunits are nucleosides, and wherein one or more nucleosides are one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides, and wherein the monomer subunits are linked by a plurality of internucleosidic linkage groups. Examiner is interpreting 5-40 linked monomer subunits as at least one multimer.
The teachings of Puri, Chung, González, Goyenvalle, Jackson, and Ittig as applied above for claim 1 are incorporated here.
The patented claims do not recite one or more 2'- modified ribonucleic acids in the composition, however, the patented Specification indicates “The term “monomer subunit”, as used herein, is meant to include all manner of monomer units that are amenable to oligomer synthesis including, and typically and preferably referring to… in particular tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and 2′-modified ribonucleic acid (2′-modified-RNA) nucleosides.” (col 8 line 63). Additionally in the reference specification, “it was observed that tc-DNA oligomeric compounds with acute toxicity show an additional band in polyacrylamide gel electrophoresis experiments migrating at the level of 40-60 BP. It was proposed that this rather sharp band is a multimer of the oligomeric compound (e.g., duplex, trimer, or larger aggregate). The results of gel electrophoresis experiments are shown in FIG. 9 with no apparent appearance of the multimer band for any of oligomeric compounds studied. For illustration of multimer band, the oligomeric compound SY-0221, which showed toxicity in vivo is also shown.” (col 91 line 25). Therefore, the reference specification illustrates detection of toxic multimers with gel-electrophoresis. Consequently, it would be obvious to a skilled artisan to limit the presence of multimers in the reference application’s composition such as to less than 5:1 monomer to multimer ratio in order to limit toxicity of the tc-DNA modified oligomer. It would similarly have been obvious to modify the reference patent claims to limit the ratio of monomer to dimer as detected by well-known techniques in the art to within the range of 5:1 and 250:1 for the obviousness rational provided in the above 35 U.S.C. 103 rejection of claim 1. Note that Examiner gives little patentable weight to the determination of monomer/dimer ratio by capillary electrophoresis specifically as there is no evidence of a different ratio of monomer to multimer in gel electrophoresis vs capillary electrophoresis.
Response to Arguments
Applicant’s amendments necessitate modifications to the §103 and NSDP rejections of record to address the incorporation of canceled claim 3 limitations into independent claim 1. Applicants argue (Remarks pg 7 and 9) that the cited references do not teach the limitations of the newly amended claim 1 which now recites “wherein the melting temperature (Tm) of the oligomeric compound is at least 65 °C.”. Applicant’s arguments have been thoroughly reviewed and found unpersuasive. As described in the modified §103 rejection above applied to melting temperature of the claimed oligonucleotide, Ittig does in fact teach tc-oligomeric compounds with a melting temperature of at least 65 °C. Specifically, Ittig teaches Tc-DNA possesses both high affinity to RNA as well as high nuclease resistance which suggests that tc-nucleotide spiked siRNAs may enhance the functional half-life of siRNA by protecting them against exo- and endonucleolytic degradation (pg 12 col 1 para 2). Ittig teaches four consecutive tc-pyrimidine replacements demonstrates slightly higher stability at 65°C (pg 12 col 2 para 2), i.e. at least 65°C. Therefore, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention that Puri’s tc modified siRNA would have a melting temperature of at least 65°C. Furthermore, Examiner notes that the melting temperature of the oligomeric compound could vary based on the routine optimization of doses/concentrations (i.e., ratio of monomer to dimer) such that it would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Therefore, claim 1 is obvious and is properly rejected under 35 U.S.C. 103.
Applicants further argue (Remarks pg 8) that the Double Patenting rejections should be withdrawn giving filing of a terminal disclaimer, however, Examiner notes no filing of a terminal disclaimer in the application disclosure, and as such the double patenting rejections remain.
Conclusion
All claims are rejected.
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