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 .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification in Table 1, 3, and 5 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Regarding Tables 3 and 5, it is unclear if the Column titled “No.” is referring to the SEQ ID NO for each of the sequences present in the table or if the numbering is not related to the SEQ ID NOs present in the tables.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings, specifically in FIG. 10, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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)(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.
Claim(s) 1, 7, 9, and 11 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019).
Regarding claim 1, Khvorva is directed towards an invention concerned with sequence specific gene silencing though the use of designed siRNA technology (Abstract). Khvorva teaches that siRNA molecules are inhibitory RNA duplexes that comprise an antisense that is complementary to a target mRNA molecule of interest and a sense strand that forms a duplex with the antisense strand (i.e., the sense strand is complementary to the antisense strand) and induce the RNA interference pathway ([0100]). Khvorva teaches that the RNA molecule that induces the RNA interference pathway may comprise a duplex region and no overhang regions (i.e., the siRNA molecule may comprise a blunt end at the 5’ end of the antisense strand and the 3’ end of the sense strand) (pg. 79; see Claim 42). Khvorva teaches that a useful target gene to be silenced by the siRNA complex is RORB (i.e., (ROR)-beta) ([0540]; see Table VIII).
Regarding claim 7, Khvorva teaches that the siRNA molecules may contain substituted nucleotides, including a common OCH3 substitution at the 2’ position of a ribose present in the siRNA (i.e., an -OH group at a 2’ carbon position of a sugar structure of a ribose nucleotide in the sense or antisense strand ([0122])) ([0404]). Khvorva teaches that the siRNA may comprise nucleotide analogs that comprise phosphorothioate linkages ([0116]).
Regarding claims 9 and 11, Khvorva teaches that the siRNAs may comprise multiple substituted nucleotides (i.e., Khvorva teaches that multiple -OH groups at a 2’ carbon position of a sugar structure of a ribose nucleotide present in the sense or antisense strand) ([0404]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019) as applied to claims 1, 7, 9, and 11 above, and further in view of Rao (US Patent No. 8,048,864 B1).
Regarding claims 3-6, Khvorva anticipates claims 1, 7, 9, and 11 as described above. Khvorva further teaches that the siRNA molecule may be 18-30 base pairs in length (i.e., the antisense strand may have a length of 18-23 nucleotides) ([0128]). Khvorva teaches that the term siRNA encompasses an siRNA duplex that may have unpaired overhanging bases on the 5’ or 3’ end of the sense strand or the antisense strand ([0100], see Claim 42).
Khvorva does not teach or suggest that the sense strand has a length of 15 nucleotides to 17 nucleotides (Claim 2).
However, one of ordinary skill in the art would have considered the teachings of Rao as both references are common fields of endeavor pertaining to the use of siRNA molecules that can inhibit target genes of interest, including RORB.
Rao is directed towards an invention concerned with the modulation of NFAT activity (Abstract). Rao teaches the use of an RNAi agent, selected from an siRNA molecule, that can modulate the expression of a gene of interest present in Table 1 (Col. 33, lines 26-33). Rao teaches that RORB is a target gene of interest present in Table 1 (Col. 55-56; see Table 1). Rao teaches the use of an siRNA molecule that comprises 15-28 nucleotides in length (i.e., Rao teaches the use of a sense strand that is 15-17 nucleotides in length (Col. 24, lines 12-29).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the siRNA sense strand that can be utilized to target RORB, as described in Khvorva, for the siRNA sense strand that can be utilized to target RORB, as described in Rao. A person of ordinary skill in the art would have had a reasonable expectation of success because Khvorva teaches that the siRNA molecule may comprise overhangs and Rao teaches that siRNA molecules with sense strands that are 15-17 nucleotides in length can be utilized to target RORB.
Claim(s) 3-6 is/are rejected under 35 U.S.C. 103 as being unpatentable Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019) as applied to claims 1, 7, 9, and 11 above, and further in view of Rao (US Patent No. 8,048,864 B1) and NCBI Reference Sequence XM_003822192.4 “Sequence XM_003822192.4” (5 June 2020).
Regarding claims 3-6, Khvorva anticipates claims 1, 7, 9, and 11 as described above. Khvorva further teaches that the siRNA molecule may be 18-30 base pairs in length (i.e., the antisense strand may have a length of 18-23 nucleotides) ([0128]). Khvorva teaches that the term siRNA encompasses an siRNA duplex that may have unpaired overhanging bases on the 5’ or 3’ end of the sense strand or the antisense strand ([0100], see Claim 42). Khvorva teaches that siRNA molecules can be rationally designed to target a gene of interest ([0471]).
Khvorva does not teach or suggest that the sense strand comprises a sequence selected from the claimed SEQ ID NOs: 27, 29, 51, and 109 (Claims 3-4). Khvorva does not teach or suggest that the antisense strand comprises a sequence selected from the claimed SEQ ID NOs: 28, 30, 52, and 110 (Claims 5-6).
However, one of ordinary skill in the art would have considered the teachings of Rao and Sequence XM_003822192.4 as both references are common fields of endeavor pertaining to the use of siRNA molecules that can inhibit target genes of interest, including RORB.
Rao is directed towards an invention concerned with the modulation of NFAT activity (Abstract). Rao teaches the use of an RNAi agent, selected from an siRNA molecule, that can modulate the expression of a gene of interest present in Table 1 (Col. 33, lines 26-33). Rao teaches that RORB is a target gene of interest present in Table 1 (Col. 55-56; see Table 1). Rao teaches the use of an siRNA molecule that comprises 15-28 nucleotides in length (i.e., Rao teaches the use of a sense strand that is 15-17 nucleotides in length (Col. 24, lines 12-29). Rao teaches that siRNA molecules that have a targeting region that comprise at least 25-75% G/C content can be designed in order to target specific mRNA sequences of interest (Col 31, lines 38-67).. Rao teaches that analysis of sequence databases, including but are not limited to the NCBI, BLAST, Derwent and GenSeq as well as commercially available oligosynthesis software such as Oligoengine®, can also be used to select siRNA sequences against EST libraries to ensure that only one gene is targeted (Col 31, lines 38-67).
Sequence XM_003822192.4 is directed towards a DNA sequence encoding a Pan paniscus RORB gene (pg. 1). Sequence XM_003822192.4 teaches that the RORB gene comprises a DNA sequence that is reverse complementary to an mRNA sequence having 100% identity to the claimed SEQ ID NO: 51-52 (i.e., the DNA sequence of Sequence XM_003822192.4 is transcribed into an mRNA molecule with 100% identity to the claimed SEQ ID NOs: 51-52) (pg. 2; see sequence “ta cccaacttgt ttaccta” in base pairs 1349-1367). Sequence XM_003822192.4 teaches that the RORB gene comprises a DNA sequence that is reverse complementary to an mRNA sequence having 100% identity to the claimed SEQ ID NOs: 109-110 (i.e., the DNA sequence of Sequence XM_003822192.4 is transcribed into an mRNA molecule with 100% identity to the claimed SEQ ID NO: 109) (pg. 2; see sequence “gtccaga agcttcagga aa” in base pairs 1924-1939). Sequence XM_003822192.4 teaches that the RORB gene comprises a DNA sequence that is reverse complementary to an mRNA sequence having 100% identity to the claimed SEQ ID NOs: 27-28 (i.e., the DNA sequence of Sequence XM_003822192.4 is transcribed into an mRNA molecule with 100% identity to the claimed SEQ ID NO: 27-28) (pg. 2; see sequence “ggag gagccagcag aacaa” in base pairs 886-905). Sequence XM_003822192.4 teaches that the RORB gene comprises a DNA sequence that is reverse complementary to an mRNA sequence having 100% identity to the claimed SEQ ID NOs: 29-30 (i.e., the DNA sequence of Sequence XM_003822192.4 is transcribed into an mRNA molecule with 100% identity to the claimed SEQ ID NOs: 29-30) (pg. 2; see sequence “aggag gagccagcag aac” in base pairs 889-903).
Therefore, regarding claims 3-4, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to substitute the sense strand siRNA sequence of Khvorva for an siRNA sense strand that comprised 100% sequence identity to the claimed SEQ ID NOs: 27, 29, 51, and 109, as described by Rao and Sequence XM_003822192.4. A person of ordinary skill in the art would have recognized that Khvorva recognized a need in the art to target a RORB gene with an siRNA molecule. A person of ordinary skill in the art would have recognized that there are a finite number of possible siRNA molecules that could be generated using well-known oligonucleotide synthesis softwares that comprise a targeting sequence that comprise at least 25-75% G/C, as described by Rao, and could hybridize to the mRNA sequence of finite length that is described by Sequence XM_003822192.4. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued because Khvorva teaches that siRNA molecules can be rationally designed to target a gene of interest, including RORB, Rao teaches that utilizing siRNA sense strands of 15-17 nucleotides in length can be utilized to target a RORB gene, and Sequence XM_003822192.4 teaches that the claimed SEQ ID NOs: 27, 29, 51, and 109 were known to be sequences present within RORB mRNA.
Therefore, regarding claims 5-6, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to substitute the antisense strand siRNA sequence of Khvorva for an siRNA antisense strand that comprised 100% sequence identity to the claimed SEQ ID NOs: 28, 30, 52, and 110, as described by Rao and Sequence XM_003822192.4. A person of ordinary skill in the art would have recognized that Khvorva recognized a need in the art to target a RORB gene with an siRNA molecule. A person of ordinary skill in the art would have recognized that there are a finite number of siRNA molecules that can be designed in order to target a RORB gene of interest that has a finite length, as described by Sequence XM_003822192.4. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued because Khvorva teaches that siRNA molecules can be rationally designed to target a gene of interest and comprise an antisense strand of 18-23 nucleotides in length and comprise an overhang at the antisense’ 3’ end, Rao teaches that utilizing siRNA antisense strands of 18-23 nucleotides in length can be utilized to target a RORB gene, and Sequence XM_003822192.4 teaches that the claimed SEQ ID NOs: 28, 30, 52, and 110, were known to be complementary to sequences present within RORB mRNA.
Claim(s) 7-8 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019) as applied to claims 1, 7, 9, and 11 above, and further in view of Strapps (PG Pub No. WO 2015/070158 A1).
Regarding claims 7-8 and 14, Khvorva anticipates claims 1, 7, 9, and 11 as described above.
Khvorva does not teach or suggest the linkage of a lipophilic compound to the sense or antisense strand of the siRNA (Claim 7). Khvorva does not teach or suggest that the lipophilic compound is cholesterol (Claim 8). Khvorva does not teach or suggest that the RNAi inducing nucleic acid molecule has cell-penetrating ability (Claim 14).
However, one of ordinary skill in the art would have considered the teachings of Strapps as both references are common fields of endeavor pertaining to the use of siRNA molecules to silence genes of interest.
Strapps is directed towards an invention concerned with the in vivo delivery of siRNA molecules to cells of interest (Abstract). Strapps teaches that it is well-known in the art that siRNA molecules can be conjugated to a lipophilic molecule such as cholesterol or to a cell-penetrating peptide (i.e., a peptide that has a cell-penetrating ability) (Abstract; pg. 2, lines 22-26). Strapps attaches that conjugating siRNA molecules to the cholesterol or cell-penetrating peptides allows for a systematic delivery system of the siRNA to certain tissues of interest (pg. 2, lines 22-26).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the siRNA molecule anticipated by Khvorva such that it was linked to a lipophilic compound selected from cholesterol or a cell-penetrating peptide, as described by Strapps. A person of ordinary skill in the art would have been motivated to do so in order to deliver the siRNA to a tissue of interest. A person of ordinary skill in the art would have had a reasonable expectation of success because both Khvorva and Strapps teach the use of siRNA molecules that can target genes of interest in cells.
Claim(s) 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019).
Regarding claim 9-10, Khvorva anticipates claims 1, 7, 9, and 11 as described above.
Khvorva does not specifically disclosure that the sense strand may comprise at least one chemical modification selected from the substitution of an -OH group at the 2’ carbon position of a sugar structure of at least 2 nucleotides with methoxy (-OCH3) (Claim 10). Khvorva does not specifically disclosure that the antisense strand may comprise at least one chemical modification selected from the substitution of an -OH group at the 2’ carbon position of a sugar structure of at least 2 nucleotides with methoxy (-OCH3) (Claim 10).
However, as described above, Khvorva teaches that the siRNA molecules may contain substituted nucleotides, including a common OCH3 substitution at the 2’ position of a ribose present in the siRNA (i.e., an -OH group at a 2’ carbon position of a sugar structure of a ribose nucleotide in the sense or antisense strand ([0122])) ([0404]). Khvorva teaches that the siRNAs may comprise multiple substituted nucleotides (i.e., Khvorva teaches that multiple -OH groups at a 2’ carbon position of a sugar structure of a ribose nucleotide present in the sense or antisense strand) ([0404]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to modify the siRNA of Khvorva such that either the sense or antisense strand of the siRNA molecule comprised a chemical modification selected from the substitution of an -OH group at the 2’ carbon position of a sugar structure of at least 2 nucleotides with methoxy (-OCH3), as described by Khvorva. A person of ordinary skill in the art would have recognized that Khvorva recognized a need in the art to target a RORB gene with an siRNA molecule that comprised multiple substituted nucleotides. A person of ordinary skill in the art would have recognized that there are a finite number of possible positions that an -OH group at a 2’ carbon position of a sugar structure with a methoxy group because the siRNA molecules of Khvorva are of finite length. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued because Khvorva teaches that siRNA molecules can be rationally designed to comprise modified nucleotides, including the substitution of a methoxy group at multiple 2’ carbon positions of a sugar structure within the siRNA molecules of the disclosure.
Claim(s) 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019) as applied to claims 1, 7, 9, and 11 above, and further in view of Rao (US Patent No. 8,048,864 B1), NCBI Reference Sequence XM_003822192.4 “Sequence XM_003822192.4” (5 June 2020), and Ly (Molecular Therapy Nucleic Acids 21 (September 2020): 991-1005) and Podbevsek (Nucleic acids research 38.20 (2010): 7298-7307).
Regarding claims 12-13, the applicable teachings of Khvorva, Rao, and Sequence XM_003822192.4 with regard to the claimed SEQ ID NOs: 51-52 are discussed above as applied to claims 3-6.
Neither Khvorva, Rao, nor Sequence XM_003822192.4 teach the use of the antisense strand (b) present in claim 13 or the sense strand (C) in claim 14 (see Claims 13-14).
However, one of ordinary skill in the art would have considered the teachings of Ly and Podbevsek as both references are common fields of endeavor pertaining to the use of siRNA molecules and the modification of the siRNA molecules.
Ly is directed towards a study concerned with how phosphorothioate (PS)-modified, chemically stabilized, cholesterol-conjugated siRNAs support rapid cellular uptake and efficient mRNA silencing both in cultured cells and in vivo (Abstract). Ly teaches that siRNA molecules that have phosphorothioate linkages present at the terminal ends have enhanced stability and better cellular uptake efficiency compared to unmodified siRNAs (pg. 991). Ly teaches that different amounts of terminal PS modifications, ranging from 1-7 linkages, in both the sense and antisense strands of an siRNA molecule that was linked to a cholesterol were able to be detested and their ability to be efficiency delivered into a cell of interest measured (pg. 992-993, 995; see Figure 1 and Table 1).
Podbevsek is directed towards a study concerned with a fully alternatively modified 2’-F/2’-OMe dimeric siRNA construct (Abstract). Podbevsek teaches that siRNA molecule duplexes that comprise alternating 2′-F and 2′-OMe nucleotides exhibit several desirable pharmacokinetic properties including a higher melting temperature when compared to an unmodified RNA oligonucleotide (pg. 7299).
Therefore, it would have been obvious to try to modify the siRNA molecules comprising the claimed SEQ ID NOs: 51-52, described above by Khvorva, Rao, and Sequence XM_003822192.4, such that they comprised fully alternating 2′-F and 2′-OMe nucleotides alongside terminal phosphorothioate and cholesterol linkages, as described by Podbevsek and Ly, in order to arrive at the claimed antisense strand (b) present in claim 13 or the sense strand (C) in claim 14. A person of ordinary skill in the art would have recognized that Ly recognized a need in the art to utilize terminal phosphorothioate and cholesterol linkages to enhance cellular uptake of an siRNA molecule while Podbevsek teaches that alternating 2′-F and 2′-OMe nucleotides exhibit several desirable pharmacokinetic properties including a higher melting temperature when compared to an unmodified RNA oligonucleotide. A person of ordinary skill in the art would have recognized that there are a finite number of possible siRNA molecule modifications that could be generated because Ly teaches that siRNAs with different amounts of phosphorothioate linkages in the sense and antisense strand, ranging from 1-7 phosphorothioate linkages, could be created and their cellular uptake measured while Podbevsek teaches that fully alternating 2′-F and 2′-OMe nucleotides in an siRNA molecule was known to be beneficial. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued because Ly teaches that the cellular uptake of siRNAs comprising different amounts of phosphorothioate linkages could be measured and Podbevsek teaches that an siRNA comprising fully alternating 2′-F and 2′-OMe nucleotides could have its melting point and silencing activity measured.
Claim(s) 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable Khvorva (PG Pub No. US 2019/0345573 A1, published 14 November 2019, effectively filed 5 March 2019) as applied to claims 1, 7, 9, and 11 above, and further in view of Nakamura (Elife 6 (2017): e30577).
Regarding claims 15-16, Khvorva anticipates claims 1, 7, 9, and 11 as described above. Khvorva further teaches that the siRNA molecules can be utilized to treat diseases of interest that are caused by overexpression of genes of interest ([0010]).
Khvorva does not teach or suggest a method for treating a retinal disease comprising administering the RNAi-inducing nucleic acid molecule according to claim 1 to a subject (Claim 15), wherein the retinal disease is retinitis pigmentosa (Claim 16).
However, one of ordinary skill in the art would have considered the teachings of Nakamura as both references are common fields of endeavor pertaining to the study of RORB and its role in retinal diseases.
Nakamura is directed towards a study concerned with the regulation of rod gene expression as a potential therapeutic strategy to treat degenerative diseases like retinitis pigmentosa (Abstract). Nakamura teaches that the inhibition of rod photoreceptor genes provides a potential strategy for the treatment of retinitis pigmentosa (Abstract). Nakamura teaches that RORB is a gene that controls rod gene expression and that loss of function RORB mutations reduced rod gene expression in subjects (pg. 7).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the siRNA molecules of Khvorva for the treatment of retinitis pigmentosa, as described by Nakamura. A person of ordinary skill in the art would have been motivated to do so in order to inhibit the expression of rods in a subject’s eye for the treatment of retinitis pigmentosa. A person of ordinary skill in the art would have had a reasonable expectation of success because Khvorva teaches the use of siRNA molecules that can inhibit RORB gene expression while Nakamura teaches that inhibiting genes associated with rod expression, including RORB, is a therapeutic strategy for treating retinitis pigmentosa.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636