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 . 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.
Priority
The instant application is a 371 of PCT/US2021/042469 filed on 07/21/2021 and claims domestic benefit to US provisional application no. 63/144,603 filed on 02/02/2021 and US provisional application no. 63/060,715 filed on 08/04/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/02/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 09/19/2023 is acknowledged. Claims 6, 9, 14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are amended. Claims 2, 5, 7-8, 11, 15, 17-19, 23-27, 29-30, 32, 34-35, 38-40, and 42 are cancelled.
Accordingly, claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are pending and being examined on the merits herein.
Nucleotide and/or Amino Acid Sequence Disclosures
The specification filed on 02/02/2023 recites a nucleotide sequence in paragraph 0203 and 0204 but these sequences do not have a sequence identifier.
The specification filed on 02/02/2023 recites “… is 2 Kilobytes in size” in paragraph 0001 last line. The size of the text file should be recited in bytes.
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 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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 § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a L group in the formula I structure, and also recites that LA is independently PG1 or -L-ligand. Furthermore, claim 1 recites that L is a recited group.
Claim 1 is indefinite because it is not clear if the L group in the formula I structure and the L group in -L-ligand of LA have to be the same L group or if the two recited L groups can have different recited groups.
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.
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.
Claim(s) 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (US20170305956A1 in PTO-892) in view of Nair et al. (WO2019217459A1 in PTO-892).
Brown discloses double-stranded nucleic acids that are conjugated to a ligand (Abstract). Brown discloses their ligand-modified oligomers can be suitably formulated and introduced into the environment of the cell by any means that allows for a sufficient portion of the sample to enter the cell to induce gene silencing (paragraph 0549).
Brown discloses that their conjugates can contain the following ligand-conjugated phosphoramidite synthon structure, Formula XIV shown below (paragraph 0210):
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This compound meets all of the limitation of the formula I recited in instant claim 1 except for the recited Ligand group. Here, the O on the sugar unit is the recited Z when Z is -O-. The 1’ position contains the recited nucleobase. The 2’ position contains a recited L group because the position contains a straight hydrocarbon chain that is 9 carbon long and the first and sixth carbons are substituted with -O-, the third carbon is substituted with a triazole moiety that meets the recited -Cy-, and the last carbon unit is replaced with -N(R)-C(O) wherein R is hydrogen. It is noted that the 4-carbon alkyl chain and sugar unit to the right of the amide bond is not a part of the recited L group because Brown further discloses these positions as a spacer and ligand as seen in Formula V on paragraph 0173. The 3’ position contains a recited X1, wherein X1 is -O-, and a recited PG2, wherein PG2 is a phosphoramidite analogue. Lastly, the 4’ / 5’ position contains hydrogen at the recited R1 and R2 as well as a protecting DMT group for when the recited LA group is PG1.
The difference between Brown and the claimed invention is that Brown does not disclose a recited Ligand group at the 2’ position.
Nair discloses a method of gene silencing comprising administering to a cell or subject an effective amount of lipophilic moieties-conjugated double- stranded iRNAs at one or more internal positions on at least one strand, optionally via a linker or carrier (Abstract).
Nair discloses that their siRNA contained the following conjugated structures shown below (paragraph 0866):
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Here, the 2’ position has an amide alkyl linker to link the lipophilic moieties such as C16, C10, and others (also see paragraph 0013). Nair discloses additional suitable lipophilic moieties include saturated or unsaturated C4-C30 hydrocarbon chains and others (paragraph 0010).
Nair discloses that the conjugation of the lipophilic moiety correlates to the relative hydrophobicity of the double-stranded iRNA agent, which can positively correlate to the silencing activity of the double-stranded iRNA agent (paragraph 0101). Nair further discloses and demonstrates in Figure 24 that the siRNAs conjugated with lipophilic moieties increased the hydrophobicity of the siRNA and also increased the TTR knockdown ability of the siRNA, illustrating the impact of hydrophobicity on the gene silencing activity of siRNAs (paragraph 0865).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the 4-carbon alkyl chain and sugar unit to the right of the amide bond at the 2’s position of the Brown Formula XIV compound shown above with lipophilic moieties such as C10 or C16 as disclosed in Nair to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to use lipophilic moieties because Nair discloses that increasing the hydrophobicity of gene silencing nucleic acids led to increased effectiveness of the gene silencing activity. One of ordinary skill in the art would have a reasonable expectation of success because both Brown and Nair disclose gene silencing nucleic acid conjugates where a sugar unit at the 2’ position is conjugated with similar amide linkers to link either a sugar or lipophilic moiety.
In regards to instant claim 3, it would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the triazole-amide linker at the 2’ position seen in the Brown Formula XIV compound above with the amide alkyl linker at the 2’ position as disclosed in Nair to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (triazole-amide linker for another (alkyl amide linker) to obtain predictable results because both linker types are both suitable to use in nucleic acid conjugates at the 2’ position to link a ligand moiety.
Claim(s) 4, 6, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (US20170305956A1 in PTO-892) in view of Nair et al. (WO2019217459A1 in PTO-892).
The teachings of Brown are as described above.
Furthermore, the compound in Formula XIV shown above in Brown meets the formula I-d structure in instant claim 4 except for the recited Ligand group. Here, the recited PG1, PG2, X1, and B groups are met as described above. Furthermore, the triazole amide linker meets the V-W-L2-amide structure when V is -O-, W- is the triazole moiety, R4 is H, and L2 is 5 carbon long with substitution of a carbon at the third position with -O-.
Brown also teaches that 2’ position linker can be a PEG-based linker as shown below (paragraph 0207):
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Here, n can be 1-20 (paragraph 0199), and this PEG-amide linker meets the structure shown in formula I-Ib in instant claim 6.
The difference between Brown and the claimed invention is that Brown does not disclose a recited Ligand group at the 2’ position.
The teachings of Nair are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the 4-carbon alkyl chain and sugar unit to the right of the amide bond at the 2’s position of the Brown Formula XIV compound shown above with lipophilic moieties such as saturated C4-C30 hydrocarbon chain as disclosed in Nair to arrive at the claimed invention.
One of ordinary skill in the art would been motivated to use lipophilic moieties because Nair discloses that increasing the hydrophobicity of gene silencing nucleic acids led to increased effectiveness of the gene silencing activity. One of ordinary skill in the art would have a reasonable expectation of success because both Brown and Nair disclose gene silencing nucleic acid conjugates where a sugar unit at the 2’ position is conjugated with similar amide linkers to link either a sugar or lipophilic moiety.
In regards to instant claim 6, it would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the triazole-amide linker at the 2’ position seen in the Brown Formula XIV compound above with the PEG-amide linker at the 2’ position as disclosed in Brown to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (triazole-amide linker) for another (PEG-amide linker) to obtain predictable results because both linker types are suitable to use in nucleic acid conjugates at the 2’ position to link a ligand moiety.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because Nair discloses that their lipophilic moieties can be saturated C4-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
Claim(s) 10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (US20170305956A1 in PTO-892) in view of Nair et al. (WO2019217459A1 in PTO-892).
The teachings of Brown are as described above. Furthermore, Brown discloses their ligand-modified oligomers can be suitably formulated and introduced into the environment of the cell by any means that allows for a sufficient portion of the sample to enter the cell to induce gene silencing (paragraph 0549), and further discloses their conjugates can be included in oral compositions with excipients (paragraph 0554).
Brown discloses the following Duplex L7, in which one of the sugar groups along the strand is conjugated to a ligand as shown below (page 127):
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This Duplex L7 meets all of the limitation of the recited formula II in instant 10, the recited II-b formula in instant claim 12, the recited II-d formula in instant claim 13, the recited II-Id formula in instant claim 14, and the recited II-Ib in instant claim 16 except for the recited conjugated chemistry and Ligand group at the 2’ position.
Here, the Duplex contains a sense strand that is 35 nucleotides in length and a complementary antisense strand that is 22 nucleotides in length, meeting the oligonucleotide limitations recited in instants claims 21-22. Furthermore, the O on the conjugated sugar unit is the recited Z when Z is -O-. The 1’ position contains the recited nucleobase. The 3’ position contains a recited X1, wherein X1 is -O-, the recited Y2, wherein Y2 is an internucleotide linking group attaching the 5’ terminal of a nucleoside. The 4’ / 5’ position contains the recited R1 and R2 when R1 and R2 is hydrogen, and the recited Y is
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, wherein X2 and X3 is O and R3 is H, and the Y1 is a linking group attaching to the 3’ terminal of a nucleoside. It is noted that the Duplex shown above does not explicitly show the recited phosphate Y group, however the Y group is necessarily present because nucleotide sequences are interconnected via phosphate groups.
Brown discloses that their ligand-modified oligomers form a tetraloop to provide new potent and stable RNA interference agents (Abstract). Brown discloses that examples of RNA tetraloops include the GAAA tetraloop and others (paragraph 0356). Brown further shows in FIG. 37 (page 47) several dsRNA constructs including a construct that has a GAAA tetraloop and a nick on the same side of the antisense strand shown below:
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Here, the construct shown above meets the limitation of the oligonucleotide recited in instant claims 28 and 31 because the construct contains a GAAA tetraloop sequence as well as the sequences being complementary adjacent to the tetraloop. Furthermore, the construct comprises a 3’-overhang sequence that is two nucleotides in length.
Brown discloses that their double stranded nucleic acid contains modified nucleotide wherein the modified nucleotide comprises a sugar modification selected from the group consisting of: 2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro (claims 17-18). Brown discloses that both sense and antisense strands consist of up to 100% chemically modified nucleotides (claim 21), and further discloses that the nucleic acid comprise a region containing at least one phosphorothioate linkage. (claim 20).
As stated above, the difference between the Duplex L7 shown in Brown is the conjugation chemistry and ligand group at the 2’ position.
The teachings of Nair are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the conjugation linker and ligand shown in the Duplex L7 of Brown with the amide alkyl linker and lipophilic moieties such as saturated C4-C30 hydrocarbon chain as disclosed in Nair to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (conjugation linker) for another (amide alkyl linker) to obtain predictable results because both linker types are suitable to use in nucleic acid conjugates at the 2’ position to link a ligand moiety.
One of ordinary skill in the art would been motivated to use lipophilic moieties because Nair discloses that increasing the hydrophobicity of gene silencing nucleic acids led to increased effectiveness of the gene silencing activity. One of ordinary skill in the art would have a reasonable expectation of success because both Brown and Nair disclose gene silencing nucleic acid conjugates where a sugar unit at the 2’ position is conjugated with similar amide linkers to link either a sugar or lipophilic moiety.
In regards to instant claims 13-14, it would have also been prima facie obvious before the effective filing date of the claimed to have substituted the amide alkyl linker as described in the combined teachings of Brown and Nair above with the triazole-amide linker at the 2’ position seen in the Brown compound above to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (amide alkyl linker) for another (triazole-amide linker) to obtain predictable results because both linker types are suitable to use in nucleic acid conjugates at the 2’ position to link a ligand moiety.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because Nair discloses that their lipophilic moieties can be saturated C4-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
In regards to instant claim 16, it would have also been prima facie obvious before the effective filing date of the claimed to have substituted the amide alkyl linker as described in the combined teachings of Brown and Nair above with the PEG-amide linker at the 2’ position as disclosed in Brown to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (triazole-amide linker for another (PEG-amide linker) to obtain predictable results because both linker types are suitable to use in nucleic acid conjugates at the 2’ position to link a ligand moiety.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because Nair discloses that their lipophilic moieties can be saturated C4-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
In regards to instant claims 28 and 31, it would have also been prima facie obvious before the effective filing date of the claimed invention to incorporate the GAAA tetraloop construct shown in Brown into the modified conjugate as disclosed in the combined teachings of Brown and Nair to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results because Brown discloses similar structured gene-silencing ligand-modified nucleic acid constructs that can contain a tetraloop and further discloses / exemplifies a GAAA tetraloop construct.
In regards to instant claims 33 and 36-37, it would have also been prima facie obvious before the effective filing date of the claimed invention to modify the conjugate as disclosed in the combined teachings of Brown and Nair described above such that all nucleotides are modified including a 2’-modification such as 2’-fluoro and also contain a region with at least one phosphorothioate linkage as disclosed in Brown to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results because Brown discloses similar structured gene-silencing ligand-modified nucleic acid constructs that can be modified to contain the described features.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/092,994 (‘994) in view of Nair et al. (WO2019217459A1 in PTO-892) and Brown et al. (US20170305956A1 in PTO-892)
The reference application claims recite a double stranded nucleic acid (dsNA) comprising: a) a sense strand having a length of 36 nucleotides; b) an antisense strand having a length of 22 nucleotides; c) a duplex formed by the sense strand and the antisense strand, the duplex comprising 20 base pairs; and d) a single-stranded 3′-overhang of 2 nucleotides on the antisense strand; wherein the sense strand and antisense strands are separate strands; wherein the sense strand comprises a stem and an RNA tetraloop, wherein the stem has a length of 6 base pairs; wherein N-acetylgalactosamine is conjugated to a sugar of three or four of the nucleotides of the RNA tetraloop via a linker as set forth in Formula VII:
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wherein B is a nucleobase, X is N-acetylgalactosamine, and m and n each independently range from 1 to 20; wherein the antisense strand is sufficiently complementary to a target mRNA along at least 15 nucleotides of the antisense strand to reduce target gene expression when the double stranded nucleic acid is introduced into a mammal or a mammalian cell; and wherein the RNA tetraloop consists of a GAAA sequence (claim 102). The reference application claims recites a method for reducing expression of a target gene in a cell comprising contacting the cell with the recited dsNA to reduce expression of a target gene (claim 108), and further recites pharmaceutical compositions comprising the recited dsNA and a pharmaceutically acceptable carrier (claim 109)
The reference application recites the same nucleic acid structure with the same conjugation linker structure at the 2’ position, but does not recite a Ligand group in the instant claims.
The independent teachings of Brown and Nair are as described above.
It would have been prima facie obvious before the effective filing date of the claimed to have substituted the 4-carbon alkyl chain and sugar unit to the right of the amide bond at the 2’s position of the dsNA recited in the reference application with lipophilic moieties such as C10 or C16 as disclosed in Nair and further use the conjugation linking chemistries as well as nucleotide modifications of Brown as described above to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to use lipophilic moieties because Nair discloses that increasing the hydrophobicity of gene silencing nucleic acids led to increased effectiveness of the gene silencing activity. One of ordinary skill in the art would have a reasonable expectation of success because both Brown and Nair disclose gene silencing nucleic acid conjugates where a sugar unit at the 2’ position is conjugated with similar amide linkers to link either a sugar or lipophilic moiety.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because Nair discloses that their lipophilic moieties can be saturated C4-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
Lastly, one of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries at the same 2’ position as well as nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/103,843 (‘843) in view of Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite a double-stranded oligonucleotide comprising an antisense strand of 15-30 nucleotides in length and a sense strand of about 9-50 nucleotides in length, wherein (i) the antisense and sense strands form a duplex region of about 9-26 base pairs, (ii) the antisense strand comprises an orientation of 5′ to 3′, (iii) the antisense strand comprises a 3′ overhang of at least four nucleotides, (iv) the antisense strand comprises a region of complementarity to an mRNA target sequence in a target mRNA, (v) the 3′ overhang comprises a sequence motif that reduces inhibition of the target mRNA by the double-stranded oligonucleotide in a cell of the liver, and (vi) the sequence motif comprises at least one 2′-F modified nucleotide, provided the at least one 2′-F modified nucleotide is not one of the two 3′terminal nucleotides of the antisense strand (claim 1). The reference application claims recite wherein inhibition of the target mRNA is reduced compared to inhibition of the target mRNA by a double-stranded oligonucleotide not having the sequence motif (claim 2). The reference application claims recite several lipid moieties that can be selected such as shown:
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The reference application claims recite the same GAAA tetraloop and sequence features (claims 42-46).
The reference application recites several of the same nucleic acid structures/features with the same lipophilic moieties but does not recite conjugation chemistry structures as well as all of the recited nucleotide / sequence modifications in the instant claims.
The teachings of Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by including the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety as well as the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/654,127 (‘127) in view of Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite a double-stranded oligonucleotide comprising an antisense strand of about 20-22 nucleotides in length and a sense strand of about 18-20 nucleotides in length, wherein the antisense and sense strands form a duplex region of about 18-20 base pairs, wherein the antisense strand comprises an orientation of 5′ to 3′, wherein the antisense strand comprises a 3′ overhang of at least one nucleotide, wherein the antisense strand comprises a region of complementarity to a mRNA target sequence, and wherein the sense strand comprises at least one lipid moiety conjugated to a nucleotide on the sense strand (claim 382). The reference application claims recite several lipid moieties that can be selected such as shown:
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The reference application claims recite a method of reducing expression of a target mRNA comprising administering a recited oligonucleotide (claim 399).
The reference application recites several of the same nucleic acid structures/features with the same lipophilic moieties but does not recite conjugation chemistry structures as well as all of the recited nucleotide / sequence modifications in the instant claims.
The teachings of Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by including the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety as well as the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/290,211 (‘211) in view of Nair et al. (WO2019217459A1 in PTO-892) and Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite a double-stranded oligonucleotide comprising an antisense strand of 15-30 nucleotides in length and a sense strand of 15-50 nucleotides in length, wherein the antisense and sense strands form a duplex region of 15-30 base pairs, wherein the antisense strand comprises a region of complementarity to a neuronal mRNA target sequence, and wherein the sense strand comprises at least one lipid moiety, wherein the lipid moiety is a C16 hydrocarbon chain conjugated to the 2′ carbon of the ribose ring of the 5′ terminal nucleotide of the sense strand (claim 96) . The reference application claims recite the C16 hydrocarbon chain has the following structure shown below:
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The reference application claims recite a method of reducing expression of a neuronal mRNA in a cell comprising administering the double-stranded oligonucleotide (claim 115).
The reference application recites several of the same nucleic acid structures/features with the same lipophilic moieties but does not recite a lipophilic moiety structure as well as conjugation chemistry structures and all of the recited nucleotide / sequence modifications in the instant claims.
The independent teachings of Nair and Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by substituting the lipophilic moiety in the reference application with a lipophilic moiety in Nair and further include the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety as well as the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (lipophilic moiety) for another (lipophilic moiety) to obtain predictable results because both lipophilic moiety structures are suitable to use in lipid-modified nucleic acid conjugates.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because Nair discloses that their lipophilic moieties can be saturated C4-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/274,826 (‘826) in view of Nair et al. (WO2019217459A1 in PTO-892) and Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite an oligonucleotide-ligand conjugate for reducing expression of a target mRNA in the central nervous system (CNS) comprising (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length and a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand and the sense strand each comprise a 5′ end and a 3′ end, wherein the antisense strand and the sense strand form a duplex region, wherein the antisense strand has a region of complementarity to a target sequence in the target mRNA in the CNS, wherein the region of complementarity is at least 15 contiguous nucleotides in length, wherein the oligonucleotide comprises a stem-loop; and (ii) one or more lipid moieties conjugated to the stem-loop (claim 1). The reference application recites the same GAAA tetraloop and sequencing structures (claims 2-9). The reference application recites a method of reducing expression of a target mRNA in a subject by administering the recited oligonucleotide-ligand conjugate (claim 43).
The reference application recites several of the same nucleic acid structures/features with lipophilic moieties but does not recite a recited lipophilic moiety structure as well as conjugation chemistry structures and all of the recited nucleotide / sequence modifications in the instant claims.
The independent teachings of Nair and Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by including a lipophilic moiety structure disclosed in Nair as well as include the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety and the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for including a lipophilic moiety structure in Nair because both the reference application and Nair recite gene silencing oligonucleotides that are both conjugated to lipophilic moieties.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/383,237 (‘237) in view of Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite an RNAi oligonucleotide for reducing MAPT gene expression. The recited oligonucleotide contains several of the same features as the instant oligonucleotide such as the GAAA tetraloop and nucleotide sequence structure and length (claims 1-16). Furthermore, the reference application claims recite the oligonucleotide is conjugated to a lipid moiety such as C8-C30 hydrocarbon (claim 59).
The reference application recites several of the same nucleic acid structures/features with the same lipophilic moieties but does not recite conjugation chemistry structures as well as all of the recited nucleotide / sequence modifications in the instant claims.
The teachings of Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by including the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety as well as the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because the reference application recites their lipophilic moieties can be C8-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/316,529 (‘529) in view of Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite an RNAi oligonucleotide for reducing MAPT gene expression. The recited oligonucleotide contains several of the same features as the instant oligonucleotide such as the GAAA tetraloop and nucleotide sequence structure and length (claims 1-16). Furthermore, the reference application claims recite the oligonucleotide is conjugated to a lipid moiety such as C8-C30 hydrocarbon (claim 56).
The reference application recites several of the same nucleic acid structures/features with the same lipophilic moieties but does not recite conjugation chemistry structures as well as all of the recited nucleotide / sequence modifications in the instant claims.
The teachings of Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by including the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety as well as the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because the reference application recites their lipophilic moieties can be C8-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6, 9-10, 12-14, 16, 20-22, 28, 31, 33, 36-37, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/316,561 (‘561) in view of Brown et al. (US20170305956A1 in PTO-892).
The reference application claims recite an RNAi oligonucleotide for reducing SNCA gene expression. The recited oligonucleotide contains several of the same features as the instant oligonucleotide such as the GAAA tetraloop and nucleotide sequence structure and length (claims 1-16). Furthermore, the reference application claims recite the oligonucleotide is conjugated to a lipid moiety such as C8-C30 hydrocarbon (claim 56).
The reference application recites several of the same nucleic acid structures/features with the same lipophilic moieties but does not recite conjugation chemistry structures as well as all of the recited nucleotide / sequence modifications in the instant claims.
The teachings of Brown are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the nucleic acid recited in the reference application by including the conjugation linker chemistries as disclosed in Brown described above to link the lipophilic moiety as well as the nucleotide / sequence modifications as disclosed in Brown described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results for incorporating a recited conjugation linking chemistries as well as a recited nucleotide/sequence modifications in the instant claims because Brown provides guidance of these conjugation linking chemistries as well as the nucleotide modifications for the same gene silencing nucleic acid conjugates as described above.
Furthermore, the recited C1-50 hydrocarbon structures are also rendered obvious because the reference application recites their lipophilic moieties can be C8-C30 hydrocarbon chains, which overlaps in the number of carbons shown for the first four hydrocarbon structures. See MPEP 2144.05 I.
Additionally, MPEP 2144.09 II states that “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
This is a provisional nonstatutory double patenting rejection
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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