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 .
Claims 63-99 are pending.
Claim Rejections - 35 USC § 112
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 63 is 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. This is a written description rejection.
Claim 63 recites:
A double-stranded nucleic acid complex comprising a first nucleic acid strand and a second nucleic acid strand, wherein the first nucleic acid strand is capable of hybridizing to at least part of a target gene or a transcription product thereof, and has an antisense effect on target gene or a transcription product, and second nucleic acid strand comprises a base sequence complementary to said first nucleic acid strand, and comprises one or more 2'-modified nucleoside.
The broad claim encompasses the large genus: the double-stranded nucleic acid complex that has antisense effect to any target gene or on the processing of pre-mRNA or mRNA of any target gene.
An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc).
The specification as filed fails to provide adequate written description of the claimed genera because it does not provide adequate written description of i) double stranded double acid complex that has antisense effect on target genes, and ii) antisense effect on processing of pre-mRNA or mRNA of target genes.
The written description requirement for a claimed genus may be satisfied by providing sufficient description of representative number of species using descriptive means such as words, structure, figures, diagrams and formulas that fully set for the claimed invention (see MPEP 2163). A "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 specification as filed disclosed a limited number of target genes and transcription products. Paragraph 0017 of the specification discloses exon 23/intron 23 boundary region of Dystrophin pre-mRNA and also provides mouse and human DMPK mRNA sequences as SEQ ID NOs 7 and 8. The specification further discloses that sequence and transcription products can be obtained from publicly available database such as NCIB. Thus, the specification identifies particular target genes and transcript productions but does not provide representative species or common structural characteristics sufficient to support the broad genus encompassed by the claimed invention.
The specification of instant application identifies SR-B1, Malat1, Mapt, BACE1, DMPK, and dystrophin as target genes and transcription products. However, the specification provides complete nucleotide sequence for only the mouse and human DMPK mRNA as SEQ ID NOs 7 and 8, respectively. Although specification of instant application provides complete nucleotide sequence of DMPK mRNA, Mahadevan et al. 1993 (Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene, Human Molecular Genetics, 2:299-304, “Mahadevan”) discloses that these genes in human and murine are different. Mahadevan compare the genomic sequences of the human and murine DMPK genes, including their respective exon/intron structures, and demonstrated that the human and murine DMPK gene comprise different species-specific genomic sequences. For the remaining target genes and transcription products, the specification provides either a particular target region, such as the identified dystrophin exon 23/intron 23 region, or sequence of antisense oligonucleotides designed to hybridized to a portion of the target, rather than the complete nucleotide sequence. Furthermore, the specification does not provide any other identifying characteristics of the claimed genus of target gene or transcription products except that the double-stranded nucleic acid complex with antisense effect regulates or inhibit expression of target genes or transcription products.
The state of the prior art teaches that antisense oligonucleotides may be designed to target a wide variety of genes. For example, the art of Crooke et al. 2021 (Antisense technology: an overview and prospectus, Nature Reviews Drug Delivery, 20:427-453) teaches that antisense technology is broadly applicable to numerous RNA targets and across many diseases indicating the complex and large number of genes that are targeted by antisense oligonucleotides. Another art by Moumne et al. 2022 (Oligonucleotide Therapeutics: From Discovery and Development to Patentability, Pharmaceutics, 14:260) provided an extensive review on oligonucleotide-based therapy between 1998 and 2021 and reported that oligonucleotide therapeutic target 66 genes belonging to 14 different therapeutic areas.
Because there are large number of target genes involved in antisense therapy with varying structure and function, disclosure of only a limited number of target genes is not reasonably representative of the full scope of the claimed genus. Furthermore, the specification does not identify any common structural features shared across the claimed genus of target genes or transcription products that would allow and artisan to recognize that the inventors and/or applicant were in possession of the entire claimed genus at the time of filing.
Claim 99 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for decreasing central nervous system toxicity by directly administrating to the site of toxicity a double stranded nucleic acid complex wherein said double-stranded nucleic acid has antisense effect on transcription of Mapt, Malat1, and BACE1 genes and their transcription product, does not reasonably provide enablement for treating any central nervous system disease, in any subject, and targeting any genes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
There are many factors to assess when determining there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “reasonable” or “undue” (see MPEP 2164.01). These factors are: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claim: the claim as currently drafted is broad and it encompass a method of treating any central nervous system disease, in any subject, by administrating double stranded nucleic acid complex with antisense effect which is targeted to any genes. Consequently, the breadth of this claim is broad.
The nature of the invention: the claimed invention pertains to a double-stranded nucleic acid complex where the first strand is antisense strand capable of hybridizing to at least part of a target gene, and second strand with a base sequence complementary to said first strand, and comprises one or more 2'-modified nucleoside. The invention further comprises a method of treating central nervous system disease by administrating pharmaceutical composition comprising the double strand nucleic acid complex. Successful implementation of claimed method requires not only hybridization and target gene suppression but also effective delivery to the central nervous system and therapeutic efficiency in a subject. Therefore, to make such a claimed method perform as described, there will be undue burden as it will require undue experimentation.
The state of the prior art: Successful treatment of central nervous system disease by using antisense therapy depends on many factors including target gene selection, chemical modification, sequence optimization, blood-brain barrier, and therapeutic efficiency etc. There are more than 600 neurological diseases (see Nervous System Diseases | Neurologic Diseases | MedlinePlus) which demonstrates the diversity and complexity of diseases affecting central nervous system. Delivery of antisense drugs or RNA based drugs to the central nervous system is the biggest challenge in the development of therapeutics for central nervous system disease. The art of Holm et al. 2021 (Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases, RNA Biology, 19:594-608, “Holm”) teaches that treating central nervous system disease using RNA therapy requires overcoming numerous technical challenges including effective delivery to the central nervous system. Holm teaches that chemically modified antisense oligonucleotides have increased target affinity, however, these modifications have not sufficiently enhanced the delivery of drugs to brain. Holm further teaches that blood-brain barrier is a major constrains in developing antisense based therapy targeting central nervous system diseases.
The specification of instant application provides working examples directed to Mapt, Malat1, and BACE1 genes (examples 1-3, paragraph 0169-0199)-. Example 1 demonstrates the effect using an HDO targeting mouse Mapt mRNA; Example 2 demonstrates the effect using an HDO targeting mouse BACE1 mRNA; and Example 3 demonstrates the effect using an HDO targeting mouse Malat1 non-coding RNA. In each example, the HDO is administered to mice and central nervous system toxicity is assessed using behavioral tolerability and motor-function evaluations.
However, the state of art teaches that central nervous system disease involve numerous disease-specific target genes with specific biological functions. For example, Luo et al. 2022 (Delivering the Promise of Gene Therapy with Nanomedicines in Treating Central Nervous System Diseases, Advanced Science, 9:2201740, “Luo”) teaches numerous implicated genes associated with different central nervous system disease including but not limited to IDH, EGFR, FGFR, TERT, APOE, APP, PSEN, GBA, and many others. All of these genes have different biological mechanism and therapeutic considerations.
In summary, existence of more than 600 neurological diseases and difficult in delivery of antisense-based therapy targeting central nervous system diseases, particularly due to blood-brain barrier creates significant uncertainty in practicing the full scope of the claimed invention. Therefore, treating central nervous system disease by administrating pharmaceutical composition comprising the double strand nucleic acid complex is unpredictable and practicing the full scope of the claimed invention would require undue experimentation.
The level of one of ordinary skill: due to the unpredictable nature of the claimed method and the broad scope of the claims, an artisan would still be required to perform experimentations to identify appropriate target genes, optimize antisense sequence, chemical modification, determine effective pharmaceutical formulation, evaluate blood-brain barrier penetration, and demonstrate therapeutic efficiency in vivo. Such experimentation would require undue experimentation.
The level of predictability in the art: in view of state of the art and the level of skill in the art, the claimed method of treating central nervous system disease by administrating pharmaceutical composition comprising the double strand nucleic acid complex is unpredictable.
The amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure: the applicant has not provided sufficient direction to practice the full scope of the claimed invention. The enablement requirement is met when the specification teaches a person of ordinary skill in the art how to make and use the full scope of the claimed invention without undue experimentation. In the present case, the specification does not provide sufficient guidance or representative working examples to enable the full scope of the claimed method of treating central nervous system diseases. Although the specification includes a limited number of in vivo examples involving particular target genes (e.g., Mapt, Malat1, and BACE1) in mice, these examples do not reasonably enable treatment of the broad range of central nervous system diseases encompassed by the claims using double-stranded nucleic acid complexes targeting any gene.
MPEP 2164.01(a) states that “a conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. That conclusion is justified by our analysis presented above. The Wands Factors have been analyzed which also supported undue experimentations would be required to practice the invention as claimed due to the amount of experimentation necessary, state of the prior arts and its predictability, the high level of skill required to practice the alleged invention, and the limited amount of guidance provided by the applicant in the form of varied working examples in the specification.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(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 63-64, 68-73, 76, 78-89, and 92-99 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Pre-Grant Publication (US-PGPUB) Number US20140302603A1 (Published October 9, 2014 “US2014”).
Claim 63 recites a double-stranded nucleic acid complex comprising a first nucleic acid strand and a second nucleic acid strand, wherein first nucleic acid strand is capable of hybridizing to at least part of a target gene or a transcription product thereof, and has an antisense effect on said target gene or a transcription product thereof, and second nucleic acid strand comprises a base sequence complementary to said first nucleic acid strand, and comprises one or more 2'-modified nucleoside.
Regarding claim 63, US2014 teaches a double-stranded nucleic acid complex comprising (a) and (b) [see paragraph 0019] wherein (a) and (b) are instant first nucleic acid strand annealed to a second nucleic acid strand, wherein the first nucleic acid strand hybridizes to a target transcription product (target RNA) and the second nucleic acid strand is complementary to the first strand. The reference explains that the duplex functions as a double-stranded antisense complex for reducing expression of the target RNA (abstract, paragraph 0004).
Regarding 2’-modified nucleoside in the second nucleic acid strand of the complex, US2014 teaches that modification is 2’-O-methylation and/or phosphorothioation (see paragraph 0026).
US2014 discloses locked nucleic acid (LNA) as an example of a 2’-modified nucleoside (see formula 1 and paragraphs 0121-0123). The structure shown in formula 1 is shown below.
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Regarding claim 64, US2014 teaches first strand (antisense strand) which contains a central region and modified nucleic acid regions at 5’ and 3’ end, wherein the modified nucleic acid is LNA (paragraph 0020, 0023). Figure 6a, 6b, 9, 15 of US2014 teaches antisense strand with LNA-DNA-LNA i.e, a gapmer (DNA) having modified wing region flanking the central region.
Regarding claims 68 and 69, figures 10 and 15 of US2014 show the complementary RNA strand having modified nucleosides at the both terminal regions and the modification is 2'-O-methylation and/or phosphorothioation (paragraph 0026). US2014 teaches the structure of cRNA(m/s) in figure 10, where all of the nucleosides are modified including 3’-and 5’-end.
Regarding claim 70, US2014 teaches first nucleic acid strand is an antisense nucleic acid that is complementary to the transcription product of the target gene and contains a region comprising a DNA of four or more contiguous bases (paragraph 0020). US2014 further teaches that antisense strand comprises modified nucleic acid which is disposed on the 5'-terminal side and the 3'-terminal side of the central DNA region. Figures 3, 6, and 9 of US2014 show modified nucleosides (LNA) on 3’ and 5’ region of the central DNA region. For example, figure 6A shows-
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Regarding claims 71 and 72, US2014 teaches when the complementary nucleic acid strand or the second strand is RNA, the region complementary to the modified nucleic acid region of the antisense strand (first strand) is also modified (paragraph 0025, 0026). The modified regions of the antisense strand correspond to 5′ and/or 3′ LNA wing regions, which comprise 2′-modified nucleosides. Therefore, the corresponding region of the second nucleic acid strand are complementary to the 5′ and/or 3′ wing regions of first strand like comprise 2′-modified nucleosides.
Regarding claim 73, US2014 teaches that the middle region of complementary strand or second strand is natural or unmodified RNA [RNA(o)] (paragraph 0185) which is complementary to the central region of DNA of first antisense strand (figures 10 and 15). Thus, the purine base (G and A) in the central region are ribonucleosides (building block of RNA).
Regarding claim 76, US2014 teaches three different complementary strand structures including cRNA(m/s)] where all the bases in the cRNA strand were chemically modified to be resistant to cleavage by RNase (see paragraph 0185). This will satisfy the (d) option and other options have not been considered because they have been listed as alternatives.
Regarding claim 78, US2014 teaches first antisense strand having a central DNA gap region comprising four or more contiguous bases (paragraph 0020). The complementary strand anneals to the antisense strand and contains an RNA central region complementary to the central DNA gap region. Therefore, the complementary strand necessarily comprises at least four consecutive ribonucleosides complementary to the at least four consecutive deoxyribonucleosides of the first strand, as required by claim 78. Figure 3A further illustrates this complementary DNA-gap/RNA central region arrangement.
Regarding claim 79 and 80, US2014 teaches the cRNA 13-mer (SEQ ID NO 7) as the complementary strand to the ASO 13-mer (SEQ ID NO 5). The specification teaches that lowercase nucleoside represents 2’-O-methyl modified RNA, while uppercase represents RNA (see paragraph 0200). As shown by SEQ ID NO 7, the nucleoside in the 5’ end is guanosine as recited by (i) option of claims 79 and 80.
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Regarding claims 81 and 82, US2014 teaches that when the complementary strand is RNA, the region complementary to the modified nucleic acid of the antisense strand is also modified (paragraph 0025). Furthermore, US2014 teaches that complementary RNA strand contains 2'-O-methyl modified nucleosides in the modified region (paragraph 0025-0026). Those modified regions will contain adenine or pyrimidine bases as recited in claim 81 and pyrimidine base as recited in claim 82.
Regarding claim 83, US2014 teaches three different complementary strand structures (see figure 10) including a cRNA(m/s) where all the bases are modified (paragraph 0185). Since all the bases in cRNA(m/s) are modified, it does not comprise natural ribonucleoside comprising a pyrimidine base, as recited in claim 83. Figure 10 from US2014 shows –
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Regarding claim 84, US2014 teaches that all the bases in cRNA(m/s) are chemically modified (2’-O-methylated and phosphorothioated) (see paragraph 0185). Since all bases in cRNA(m/s) are chemically modified, all pyrimidine nucleosides in the second nucleic acid strand are 2’-modified nucleosides
Claim 85 recites that the 20% or more of the nucleoside in the second nucleic acid strand are modified. As describe above, all the bases of cRNA(m/s) are chemically modified. Also, SEQ ID NO 4 of US2014 shows that all the bases are modified. Since, 100% of the nucleosides are modified in cRNA(m/s), US2014 teaches the limitation of claim 85 requiring 20% or more of nucleosides in second nucleic acid strand are 2'-modified nucleosides.
Claim 86 recites that all of the nucleosides other than 2’-modified nucleosides in second nucleic acid strand are deoxyribonucleosides. US2014 teaches three complementary strand structure (see paragraph 0185). Of these three structures, cRNA(m/s) contains all bases which are chemically modified by 2'-O-methylation. Since there are no non-modified bases in cRNA(m/s), this satisfies the limitation of claim 86.
Claim 87 recites all of the nucleosides in a region in said second nucleic acid strand which consists of a base sequence complementary to the first nucleic acid strand are 2'-modified nucleosides. cRNA(m/s) contains all bases which are chemically modified by 2'-O-methylation (see paragraph 0185). Because the second strand hybridize with to the first strand, the entire region of cRNA(m/s) with 2’-modified nucleosides hybridize with the first strand.
Regarding claim 88, US2014 teaches three structures of complementary strand where bases in two structures, cRNA(G) and cRNA(m/s), are chemically modified (2'-O-methylated) (see paragraph 0185).
Claim 89 recites that the first strand of the nucleic acid complex is a mixmer. Figure 3A of US2014 discloses an antisense strand having LNA nucleosides at the 5’ and 3’ terminal region and DNA in the central region (i.e., LNA-DNA-LNA gapmer). Because the first strand contains modified and unmodified nucleosides, the strand is a mixmer as recited in claim 89.
Claim 92 recite that the base length of second nuclei acid strand is shorter than the base length of the first nucleic acid strand. Example 9 of US2014 discloses a 12-mer antisense strand (SEQ ID NO 1) and complementary strand having lengths of 12, 10, and 8 nucleotides. The 10-mer and 8-mer complementary strand are shorter than the 12-mer antisense strand, thereby teaching the limitation of claim 92.
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Regarding claim 93, example 8 of US2014 discloses a 12-mer antisense strand (SEQ ID NO 1) and a complementary 21-mer strand. Because the complementary strand is longer than the antisense strand, nucleotides at one of both terminals necessarily extend beyond the hybridizing region, thereby forming at least one 5’ and/or3’ overhang as recited in claim 93.
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Claim 94 recites that the first and second strand of nucleic acid complex are bound via a linker. US2014 teaches that the first and second strand are attached by a linker (see figure 5B).
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Regarding claims 95-97, US2014 teaches a double stranded nucleic acid complex comprising first and second strand (e.g., figure 3A). Figure 3A further teaches an embodiment in which the second strand is conjugated to a functional moiety X. The specification teaches that X represents a ligand including, for example, a lipid (e.g., cholesterol or tocopherol) (see paragraph 0058). Therefore, US2014 teaches the limitations of claims 95-97.
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Regarding claim 98, US2014 teaches that a pharmaceutical composition which contains the double-stranded nucleic acid complex can be used as an active ingredient to suppress the expression of a target gene by means of an antisense effect (see paragraph 0162).
Regarding claim 99, US2014 teaches that the pharmaceutical composition comprising double stranded nucleic acid complex can be used to treat and prevent diseases that are associated with e.g., increase expression of a target genes. US2014 listed many diseases which can be treated by using the double stranded nucleic acid complex including Alzheimer, Amyotrophic lateral sclerosis (ALS), Brain tumor, Cerebral ischemia, Brain Capillary Multiple sclerosis, Parkinson etc., and all these diseases are central nervous system disease.
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 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over US Pre-Grant Publication (US-PGPUB) Number US20140302603A1 (Published October 9, 2014 “US2014”) in view of Vickers et al. 2001 (Fully modified 2′ MOE oligonucleotides redirect polyadenylation , Nucleic Acid Research, 29:1293-1299, “Vickers”).
The teachings of US2014 with respect to the limitations of claim 63 are presented above.
US2014 teaches a double stranded nucleic acid complex where the all the nucleosides in second strand are modified; however, it does not teach all of nucleosides in the first strand are modified as recited by claim 65, 2’-modified as recited by claim 66, and 2’-O-methoxyethyl-, modified as recited by claim 67.
Vickers et al. 2001 (Fully modified 2′ MOE oligonucleotides redirect polyadenylation, Nucleic Acid Research, 29:1293-1299, “Vickers”) teaches a fully modified 2′-O-methoxyethyl/phosphorothioate oligonucleotides and has antisense effect (see abstract). Because the oligonucleotides are fully modified with 2′-O-methoxyethyl, all nucleosides are 2’ modified nucleosides, and all nucleosides are 2′-O-methoxyethyl-modified nucleosides.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the first nucleic acid strand of US2014 by Vickers because Vickers teaches that fully 2’-O-methoxyethyl-modified oligonucleotides possess improved nuclease resistance and increase binding affinity to the target.
Claims 74-75 and 77 are rejected under 35 U.S.C. 103 as being unpatentable over US Pre-Grant Publication (US-PGPUB) Number US20140302603A1 (Published October 9, 2014 “US2014”) in view of Asami et al. 2021 (Efficient Gene Suppression by DNA/DNA Double-Stranded Oligonucleotide In Vivo, Molecular Therapy, 29:839-847, “Asami”).
The teachings of US2014 with respect to the limitations of claim 63 are presented above.
US2014 teaches that the middle region of complementary strand or second strand is natural or unmodified RNA; however, it does not teach that that the central region of the complementary strand which consists of a base sequence complementary to the central region of the first strand are deoxyribonucleosides (building blocks of DNA)
Regarding claim 74, Asami et al. 2021 (Molecular Therapy, 29:839-847, “Asami”) teaches a heteroduplex oligonucleotide, in which the RNA portion of the complementary strand was replaced with DNA, yielding an ASO/DNA double-stranded structure and DNA complement were protected using 2′-O-methyl modifications (abstract). See figure from Asami regarding DNA/DNA double-stranded oligonucleotide.
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the second nucleic acid strand of US2014 by Asami because Asami teaches that DNA/DNA double stranded oligonucleotide demonstrated enhance in vivo inhibitory effect.
Regarding claim 75, Asami teaches that the 2’-modified nucleoside in the second strand of the double stranded oligonucleotide is 2′-O-methyl modified (see figure 1A, and “Toc-HDO (coDNA) Suppresses Apob mRNA More Efficiently Than the 13-mer Parent ASO” section of result).
Regarding claim 77, Asami teaches that all of the bases in the central region which are complementary to the first strand are deoxyribonucleosides as described above for claim 74. Also, Asami teaches that the 5’- and 3-end of the second strand are 2’-modified. See below figure 1A from Asami.
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the second nucleic acid strand of US2014 by Asami because Asami teaches that incorporating 2’-O-methyl-modified nucleosides in to the complementary strand enhance stability against exonuclease digestion, thereby improving the stability of the double-stranded oligonucleotide.
Claims 90-91 are rejected under 35 U.S.C. 103 as being unpatentable over US Pre-Grant Publication (US-PGPUB) Number US20140302603A1 (Published October 9, 2014 “US2014”) in view of United States Patent Number US8329888B2 (published December 11, 2012, “US8329”).
The teachings of US2014 with respect to the limitations of claim 63 are presented above.
Claims 90 and 91 recite that the second nucleic acid strand comprise at least one bulge structure consisting of a base sequence not complementary to the first strand and/or insertion and/or deletion of one of more bases, with respect to the first strand. US2014 teaches that the first and second strand of the double-stranded complex are complementary; however, it does not teach the bulge structure consisting of a base sequence not complementary as recited in claim 90 and presence of insertion and/or deletion of one or more bases as recited in claim 91.
US8329 teaches a pharmaceutical and therapeutic composition which comprise RNA complexes comprising an antisense strand and passenger strand (see abstract). US8329 further teaches that passenger strand comprises an additional nucleobase sequence which is not complementary to the antisense strands, which typically consists of at least one, such as at least two or at least three non-complementary nucleobases (see paragraph 139). US8329 teaches that the passenger strand comprises an additional nucleobase sequence that is not complementary to the antisense strand (paragraph 139). Because those additional nucleobases lack complementary, they remain unpaired within the duplex, thereby forming a bulge structure in the passenger (second) strand. US8329 further teaches the passenger strand comprise at least one, two, or three non-complementary nucleobase which indicates insertion in passenger strand.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the second nucleic acid strand of US2014 by US8329 because US8329 teaches that discontinued passenger strand reduces off-target effect of the complex, thereby improving the efficiency of double-stranded complex in therapeutic treatment.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SURAJ SAPKOTA whose telephone number is (571)270-0842. The examiner can normally be reached Monday-Thursday 7am-5pm.
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Suraj Sapkota
Patent Examiner
AU 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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