DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-5,8,12,13,15-18,23,24,26,27,29,30 and 33) in the reply filed on 12/15/2025 is acknowledged. While applicant stated “with traverse”, applicant did not distinctly and specifically point out the supposed errors in the restriction requirement. The requirement is still deemed proper and is therefore made FINAL.
Claims 34,36 and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. While applicant stated “with traverse”, applicant did not distinctly and specifically point out the supposed errors in the restriction requirement.
Applicant’s species election of an RNAi construct comprising the antisense sequence SEQ ID NO: 242 and sense sequence SEQ ID NO: 241 which corresponds to Duplex D-2040 in the reply filed on 12/15/2025 is acknowledged. Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement. The requirement is still deemed proper and is therefore made FINAL.
Upon further consideration, the species election has been expanded to include Duplex D-1040 of table 1 (page 57) comprising the sense sequence of SEQ ID NO: 81 and the antisense sequence of SEQ ID NO: 82 which are the unmodified sequences that correspond to the elected sequences (SEQ ID NOS: 241 and 242) with chemical modifications above.
Claims 1-5,8,12,13,15-18,23,24,26,27,29,30 and 33 are under examination.
Priority
This application is a 371 of PCT/US2020/035545, filed 06/01/2020 which claims benefit of 62/854,433, filed 05/30/2019 as reflected by the most recent filing receipt.
Drawings
The drawings are objected to because Figures 1 and 2 are not labeled correctly. See 37 CFR 1.84 Standards for Drawings, (u) Numbering of views. The first page says Figure 1 at the bottom and each view is labeled A-F, and Figure 2 is labeled at the bottom and each view labeled A-F. According to the requirements below, each view should be labeled for example as, FIG. 1A, FIG. 1B, etc.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: line 4 recites “SREBP”. For clarity, the full name of the protein should be recited, for example “sterol regulatory element binding protein (SREPB) cleavage-activating protein (SCAP)”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5,8,12,13,15-18,23,24,26,27,29,30 and 33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1,3,26 and 27 recite an RNAi construct and refer to sequences listed in Table 1 or Table 2, which are in the specification. Claims 2,4,5,8,12,13,15-18,23,24,29,30 and 33 depend from claim 1 and do not correct the issue and are therefore included in the rejection. Applicant must copy the table contents into the claim itself. There is no limit to the length of a claim. If the subject matter can be listed in the specification, that list can be copied and pasted into a claim.
Claim 4 recites “sufficiently complementary”. The term “sufficiently complementary” in claim 4 is a relative term which renders the claims indefinite. The term "sufficiently complementary” is not defined by the claim, the specification does not provide a clear definition for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, one in the art without a definition would not know where the metes and the bounds of the claims are. One in the art would not know, for example if 50% qualifies as, “sufficiently complementary”. One in the art could assert that 80% is sufficient and one could argue that 30% is sufficient. Without a clear definition, one in the art would be required to make assumptions of the metes and bounds of the claim based on their opinion of what “sufficiently complementary” would mean in the context of the instant claims.
Claims 5 and 8 depend from claim 4 and do not correct the issue and are therefore included in the rejection.
Additionally, claim 3 recites “wherein the sense strand comprises a region having at least 15 contiguous nucleotides differing by no more than 3 nucleotides from an antisense sequence listed in Table 1 or 2”. This is indefinite, as the claim recites the “sense strand” comprises a region…..from an “antisense sequence”, and a sense sequence and antisense sequence would not have a similar sequence as they are complementary. It is believed that claim 3 should recite “wherein the sense strand comprises a region having at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a sense sequence…”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5,8,13,15,29,30 and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Soutschek et al. (US 20090093426, Published 9 April 2009).
Regarding claims 1 and 2, Soutschek et al. teach double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a SCAP gene, the dsRNA comprising a sense strand comprising a first sequence and an antisense strand comprising a second sequence, and the antisense strand comprises a nucleotide sequence that is substantially complementary to at least part of an mRNA encoding a SCAP gene (paragraphs 0012-0014). Soutschek et al. teach an antisense strand sequence of the RNAi agent which is SEQ ID NO: 10 (Table 1, page 2), see below.
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Nucleotides 1-19 of the antisense strand of SEQ ID NO: 10 of Soutschek et al. has 100% identity to nucleotides 1-19 of instant antisense sequence of instant SEQ ID NO: 82. See the alignment below, wherein Qy is instant SEQ ID NO: 82 and Db is SEQ ID NO: 10 of Soutschek et al. Therefore, Soutschek et al. teach the limitations of instant claim 1 in which the antisense strand comprises a region having at least 15 contiguous nucleotides differing by no more than 3 nucleotides from an antisense sequence of instant SEQ ID NO: 82
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Regarding claim 3, Soutschek et al. teach the corresponding sense strand sequence of SEQ ID NO: 9, shown above. Nucleotides 1-18 of the sense sequence of SEQ ID NO: 9 of Soutschek et al. (Db) have 100% identity to nucleotides 3-20 of instant SEQ ID NO: 81 (Qy).
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Regarding claim 4, Soutschek et al. teach the dsRNA comprises two RNA strands that are sufficiently complementary to hybridize to form a duplex structure. One strand of the dsRNA (the antisense strand) comprises a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence, derived from the sequence of an mRNA formed during the expression of a SCAP gene, the other strand (the sense strand) comprises a region which is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. Generally, the duplex structure is between 15 and 30 base pairs in length (paragraph 0060).
Regarding claim 5, Soutschek et al. teach the duplex structure may also be between 18 and 25 base pairs in length (paragraph 0060).
Regarding claim 8, Soutschek et al. teach the sense sequence of SEQ ID NO: 9 which is 21 nucleotides in length, and the antisense sequence of SEQ ID NO: 10, which is 21 nucleotides in length (Table 1, page 2).
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Regarding claims 13 and 15, as Soutschek et al. teach the above sequences of SEQ ID NO: 9 and 10 as each having ‘TT’ overhang at the 3’ end (see above), and therefore teach at least one nucleotide overhang of 1-4 unpaired nucleotides (claim 13), and a nucleotide overhang at the 3’ end of both the sense strand and the antisense strand (claim 15).
Regarding claims 29-30, the wherein clause is a functional limitation that would be carried out by structure of the recited RNAi construct. Nevertheless, Soutschek et al. teach the dsRNAs molecules upon contacting with a cell expressing the SCAP gene, inhibits the expression of the SCAP gene by at least 20%, or at least 25%, 30%, 35%, 40%, 45%, 50%, 55% 60%, 65%, 70%, 85%, 90% or 95%, e.g. in primary hamster hepatocytes (paragraph 0013).
Regarding claim 33, Soutschek et al. teach a pharmaceutical composition comprising one or more dsRNA of the invention and a pharmaceutically acceptable carrier or delivery vehicle, and preferably the dsRNA is chosen from ….AD-9494… (paragraph 0023). See AD-9494 below for reference.
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Duplex AD-9494 is made of the sense strand of SEQ ID NO: 9 and the antisense strand of SEQ ID NO: 10 (See Table 1, page 2) which meets the structural limitations of instant claim 1 regarding the antisense sequence of instant SEQ ID NO: 82 as discussed above. Therefore, as Soutschek et al. specifically discloses a pharmaceutical composition comprising AD-9494 and a pharmaceutically acceptable carrier or delivery vehicle, Soutschek et al. anticipates claim 33.
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.
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 Interpretation
Table 2, page 63 shows the elected sequences of Duplex D-2040 contain modifications, and page 61 defines the modifications.
Sense sequence 5’-3’ Antisense sequence 5’-3’
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The above chemical modification motifs can be summarized as below:
Sense strand: positions 1-8,10,15-20 2’-OMe; positions 9,11-14 2’-F; phosphorothioate linkage between positions 20 and 21; position 21 inverted abasic residue.
Antisense strand: positions 1,3-6,8-11,13,15-23 2’-OMe; positions 2,7,12,14 2’-F; phosphorothioate linkage between positions 1 and 2, 2 and 3, 21 and 22, and 22 and 23.
In addition, as claims 1-5,8,12,13,15-18,23,24,29,30 and 33 do not require the entire sequence of instant SEQ ID NOs: 241 and 242, but rather 15 contiguous nucleotides differing by no more than 3 nucleotides from the sense sequence (SEQ ID NO: 241) and antisense sequence (SEQ ID NO: 242), the rejection of those claims will include only the chemical modifications at the positions for the sequence match required by the claims and not for the entire sequence (as later required by claims 26 and 27). The rejection of claims 26 and 27 will address all of the chemical modifications.
In addition, claim 3 is being interpreted as “wherein the sense strand comprises a region having at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a sense sequence…” rather than an “antisense” sequence as instantly recited.
The following 103 rejection is based on the elected sequences of SEQ ID NOs: 241 and 242 of D-2040 that include chemical modifications.
Claims 1-5,8,12,13,15-18,23,24,29,30 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Soutschek et al. (US 20090093426, Published 9 April 2009), in view of Maier et al. (US 20170275626, Published 28 Sept 2017).
The elected sequences and chemical modification pattern are shown again below.
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Regarding claims 1 and 2, Soutschek et al. teach double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a SCAP gene, the dsRNA comprising a sense strand comprising a first sequence and an antisense strand comprising a second sequence, and the antisense strand comprises a nucleotide sequence that is substantially complementary to at least part of an mRNA encoding a SCAP gene (paragraphs 0012-0014). Soutschek et al. teach an antisense strand sequence of the RNAi agent which is SEQ ID NO: 10 (Table 1, page 2), see below.
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Nucleotides 1-19 of the antisense strand of SEQ ID NO: 10 of Soutschek et al. has 100% identity to nucleotides 1-19 of instant antisense sequence of SEQ ID NO: 242. See the alignment below, wherein Qy is instant SEQ ID NO: 242 and Db is SEQ ID NO: 10 of Soutschek et al. Therefore, Soutschek et al. teach the limitations of instant claim 1 in which the antisense strand comprises a region having at least 15 contiguous nucleotides differing by no more than 3 nucleotides from an antisense sequence of SEQ ID NO: 242.
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Soutschek et al. teach the dsRNA molecules of the invention can be comprised of at least one modified nucleotide such as a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative. Alternatively, the modified nucleotide may be chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide (paragraph 0014).
Soutschek et al. does not teach the specific chemical modification pattern of nucleotides 1-19 of instant SEQ ID NO: 242 as shown above in the claim interpretation section.
Before the effective filing date, Maier et al. taught RNAi duplex agents having particular motifs that are advantageous for inhibition of target gene expression (paragraph 0002). Maier et al. taught dsRNA comprising a sense strand and antisense strand with various motifs, and taught an antisense strand having a length of 23 nucleotides, 2’-OMe modifications at positions 1,3,7,9,11,13,15,17,19-23 and 2’-F modifications at positions 2,4-6,8,10,12,14,16 and 18; phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraphs 0155-0158). Maier et al. also taught dsRNA agents comprising an antisense strand comprising 2’-F modifications at positions 2,6,9,14 and 16, and 2’-OMe modifications at positions 1,3-5,7,8,10-13,15 and 17-23 (paragraph 0202) and phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraph 0203).
Maier et al. taught the inventors found that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity, and that by introducing chemical modifications at the 2’-position or equivalent positions in a non-ribose, acyclic, or backbone that provide less steric bulk than a 2’-OME modification at certain positions in antisense and/or sense strand, the dsRNA agents were able to regain the gene silencing activity (paragraph 0261).
Therefore, it was known in the prior art to provide a dsRNA wherein the antisense strand has mixture of 2'-O-methyl and 2'-F at various positions, including many of the instant recited positions, and it was known in the art that 2’OMe modifications at positions 2 and 14 from the 5’ end of the antisense strand dampened gene activity and providing other chemical modifications at these positions that provide less steric bulk (Maier et al. taught 2’-F modifications at positions 2 and 14), and was known in the art to provide phosphorothioate internucleotide linkages at the recited positions in the antisense sequences.
Regarding claim 3, Soutschek et al. teach the corresponding sense strand sequence (SEQ ID NO: 9) to the antisense sequence of SEQ ID NO: 10 (Table 1, page 2). Nucleotides 1-18 of the sense sequence of SEQ ID NO: 9 of Soutschek et al. (Db) have 100% identity to nucleotides 3-20 of instant SEQ ID NO: 241 (Qy).
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Soutschek et al. does not teach the specific chemical modification pattern for nucleotides 3-20 of instant SEQ ID NO: 241 as shown above.
However, Maier et al. taught dsRNA comprising a sense strand and antisense strand with various motifs including, the sense strand having a length of 21 nucleotides, 2’-OMe modifications at positions 1-6,8,10,12-21, 2’F modifications at position 7 and 9 (paragraphs 0150-0158) and a dsRNA agent comprising a sense strand comprising 2’-F modifications at positions 10 and 11 (paragraph 0171) and a sense strand comprising 2’-F modifications at positions 9-11 and 2’-OMe modifications at positions 1-6,8 and 12-21 (paragraph 0198). Maier et al. taught phosphorothioate internucleotide linkages at the 5’ end of the sense strand (sense strand comprising phosphorothioate internucleotide linkages between nucleotide positions 1 and 2 and between 2 and 3 counting from the 5’ end (paragraphs 0158,0163,0172,0181,0190,0199).
Therefore, it was known in the prior art to provide a dsRNA wherein the sense strand has mixture of 2'-O-methyl and 2'-F at various positions, including many of the instant recited positions and phosphorothioate linkages at the recited positions.
Regarding claim 4, Soutschek et al. teach the dsRNA comprises two RNA strands that are sufficiently complementary to hybridize to form a duplex structure. One strand of the dsRNA (the antisense strand) comprises a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence, derived from the sequence of an mRNA formed during the expression of a SCAP gene, the other strand (the sense strand) comprises a region which is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. Generally, the duplex structure is between 15 and 30 base pairs in length (paragraph 0060).
Regarding claim 5, Soutschek et al. teach the duplex structure may also be between 18 and 25 base pairs in length (paragraph 0060).
Regarding claim 8, Soutschek et al. teach the sense sequence of SEQ ID NO: 9 which is 21 nucleotides in length, and the antisense sequence of SEQ ID NO: 10, which is 21 nucleotides in length (Table 1, page 2).
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Regarding claim 12, Soutschek et al. teach “blunt end” means that there are no unpaired nucleotides at that end of the dsRNA, i.e., no nucleotide overhang. A “blunt ended” dsRNA is a dsRNA that has no nucleotide overhang at either end of the molecule (paragraph 0047), and the dsRNA may also have a blunt end, generally located at the 5′-end of the antisense strand. Such dsRNAs have improved stability and inhibitory activity, thus allowing administration at low dosages, i.e., less than 5 mg/kg body weight of the recipient per day (paragraph 0066).
Regarding claim 13, Soutschek et al. teach embodiments where one end of the dsRNA has a single-stranded nucleotide overhang of 1-4, and that dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties than their blunt-ended counterparts, and that the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA without affecting its overall stability, and is particularly stable and effective in vivo as well as in a variety of cells (paragraph 0066).
Regarding claim 15, Soutschek et al. teach generally the single-stranded overhang is located at the 3’-terminal end of the antisense strand or at the 3’-terminal of the sense strand (paragraph 0066).
Regarding claim 16, Soutschek et al. teach each of the sequences of SEQ ID NOs: 9 and 10 cited above have TT at the end of each sequence as shown below.
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Regarding claims 17,18 and 23, Soutschek et al. teach the dsRNA molecules of the invention can be comprised of at least one modified nucleotide such as a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative. Alternatively, the modified nucleotide may be chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide (paragraph 0014). In addition, as the elected sequences require chemical modifications at specific positions, the teachings of Maier et al. have been described above pertaining to claims 1-3.
Regarding claim 24, the teachings of Maier et al. have been described above and taught antisense strand sequences with two consecutive phosphorothioate internucleotide linkages at the 3’ end of the antisense strand phosphorothioate (internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraphs 0158,0167,0176,0185,0194,0203). Maier et al. also taught two consecutive phosphorothioate internucleotide linkages at the 5’ end of the sense strand (sense strand comprising phosphorothioate internucleotide linkages between nucleotide positions 1 and 2 and between 2 and 3 counting from the 5’ end (paragraphs 0158,0163,0172,0181,0190,0199).
Regarding claims 29-30, the wherein clause is a functional limitation that would be carried out by structure of the recited RNAi construct. Nevertheless, Soutschek et al. teach the dsRNAs molecules upon contacting with a cell expressing the SCAP gene, inhibits the expression of the SCAP gene by at least 20%, or at least 25%, 30%, 35%, 40%, 45%, 50%, 55% 60%, 65%, 70%, 85%, 90% or 95%, e.g. in primary hamster hepatocytes (paragraph 0013).
Regarding claim 33, Soutschek et al. teach a pharmaceutical composition comprising one or more dsRNA of the invention and a pharmaceutically acceptable carrier or delivery vehicle, and preferably the dsRNA is chosen from ….AD-9494… (paragraph 0023). See AD-9494 below for reference.
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Duplex AD-9494 is made of the sense strand of SEQ ID NO: 9 and the antisense strand of SEQ ID NO: 10 (See Table 1, page 2)
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to provide a dsRNA agent that inhibits SCAP expression as taught by Soutschek et al. and use the teachings of Maier et al. regarding RNAi duplex agents having particular motifs that are advantageous for inhibition of target gene expression with chemical modifications at certain positions of the antisense and sense strands, and arrive at the claimed invention with a reasonable expectation of success. There would be a reasonable expectation of success because both Soutschek et al. and Maier et al. pertain to dsRNA for inhibiting expression of a target gene, and Soutschek et al. suggests the same chemical modifications as Maier et al. One of ordinary skill in the art would have been motivated to design and provide a dsRNA agent that targets SCAP as taught by Soutschek et al. and to arrive at the specific modification pattern of the antisense sequence and sense sequence based on the teachings of Maier et al. teaching the RNAi duplex agents having particular motifs that are advantageous for inhibition of target gene expression including phosphorothioate internucleotide linkages, 2’-O-Me,and 2’-F at specific positions and varying the positions of these modifications, and that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261).
Although the cited art does not specifically teach the exact modification pattern, it would have been obvious for one ordinarily skilled in the art to perform routine optimization of the pattern to achieve improved results. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
In the instant case, the focus is in the change of form, or substitution of equivalents over the prior art. Substitution of equivalents in terms of identifying optimal locations, both in terms of potency and reduced toxic effects, for 2’F and 2’-OMe modifications in dsRNA, since varying 2’-F and 2’-OMe positions in a double stranded nucleic acid for optimal or better results in known in the prior art.
Accordingly, the limitations of claims 1-5,8,12,13,15-18,23,24,29,30 and 33 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Soutschek et al. and Maier et al. as applied to claims 1-5,8,12,13,15-18,23,24,29,30 and 33 above, and further in view of NCBI Reference NM_012235.1 (24 Oct 2002), Li et al. (US 20180195069, Published 12 July 2018) cited above, and Ma et al. (Nature 20 May 2004; 429(6989): 318-322).
The elected sequences and chemical modification pattern are shown again below.
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The teachings of Soutschek et al. and Maier et al. as applicable to claims 1-5,8,12,13,15-18,23,24,29,30 and 33 have been described above.
Soutschek et al. also teach design of siRNAs to identify siRNAs targeting hamster, mouse and human SCAP using the mRNA sequences of SCAP which were examined by computer analysis to identify homologous sequences of 19 nucleotides that yielded RNAi agents (paragraph 0180).
Maier et al. also taught the dsRNA agent can comprise a phosphorus-containing group at the 5’ end of the sense strand or antisense strand and can be a 5’-end phosphate (paragraph 0052). Maier et al. taught 5’-phosphorylation of dsRNA is desirable for loading of siRNAs into the RISC complex resulting in RNAi-mediated gene silencing, and that metabolically stable 5’ phosphate mimics can lead to higher stability, increased RISC loading and more potent gene silencing (paragraph 0745). Maier et al. taught a 5’-phosphate and benefits of 5’-phosphorylation of dsRNA is desirable for loading of siRNAs into the RISC complex resulting in RNAi-mediated gene silencing, and that metabolically stable 5’ phosphate mimics can lead to higher stability, increased RISC loading and more potent gene silencing (paragraph 0745).
Soutschek et al. and Maier et al. do not teach the antisense strand comprises a sequence and all the modifications of the antisense sequence of SEQ ID NO: 242 and do not teach a sense strand comprises a sequence and all the modifications of SEQ ID NO:241.
A blast search of the sense sequence of instant SEQ ID NO: 241 shows that nucleotides 1-20 of SEQ ID NO:241 aligns with nucleotides 1818-1837 of NM_012235.4 Homo sapiens SREBF chaperone (SCAP) transcript variant 1, mRNA.
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Likewise, a blast search of the antisense sequence of instant SEQ ID NO: 242 shows nucleotides 1-21 of SEQ ID NO:242 aligns with nucleotides 1838-1818 of NM_012235.4 Homo sapiens SREBF chaperone (SCAP) transcript variant 1, mRNA.
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The mRNA sequence of Homo sapiens SCAP transcript variant 1 of NM_012235.1 was publicly available (24 Oct 2002) before the effective filing date and the mRNA sequence is shown below.
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Regarding the inverted abasic residue on the 3’ end of the sense strand, Li et al. taught RNA interference agents for inhibiting alpha-1 antitrypsin gene expression (paragraph 0002), that have antisense strands and sense strands, and taught RNAi agents comprising sense strand sequences with chemical modifications including 2’-O-methyl, 2’-fluoro, phosphorothioate linkages at specific positions, as well as an inverted abasic deoxyribose (invAb) at the last position at the 3’ end of the sense strand (paragraphs 0096-0099), and that in some embodiments the 3’ end of the sense strand may include additional abasic residues including UUAb, UAb or Ab added to the 3’ end of the sense strand, and in some embodiments the abasic residues are inverted (invAb) (paragraph 0153). Li et al. taught that inclusion of one or more inverted abasic residues or abasic sites at or near the terminal end or ends of the sense strand of an RNAi agent allows for enhanced activity or other desired properties of an RNAi agent (paragraph 0153).
Regarding the UU overhang on the 3’ end of the antisense strand, Ma et al. taught siRNAs and that the PAZ domain is an RNA-binding module found in Argonaute and some Dicer proteins, and that PAZ anchors the 2-nucleotide 3’ overhang of the siRNA-like duplex within a highly conserved binding pocket (Abstract). Ma et al. taught siRNAs that are 19-23 base-paired duplex with a 2-nucleotide 3’ overhangs at both ends and that the PAZ domain requires the 2-nt 3’ overhang for efficient complex formation (page 1). Ma et al. taught that RNAs containing UU and AG 3’ overhangs bind PAZ with the highest affinities, and that the overhang contributes critically to the binding, and in which the PAZ domain optimally fits the duplex end with the 2-nt 3’-overhang in a sequence-independent manner (page 3 bottom to page 4 top).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to provide a dsRNA agent that inhibits SCAP expression as taught by Soutschek et al. and use the teachings of Soutschek et al. regarding the length of the RNAi duplex region being 15-30 base pairs in length, as well as the teachings of Maier et al. regarding chemical modification motifs and benefits of specific chemical modifications at specific positions, the teachings of Li et al. regarding the position and benefits of the inverted abasic residue on the sense strand and the teachings of Ma et al. regarding the UU overhang on the 3’ end of the antisense strand, in view of the NCBI Reference Sequence Accession number NM_012235.1 of the SCAP mRNA sequence, to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to design and provide a dsRNA agent that targets SCAP and to use the known mRNA sequence of NCBI Reference Sequence Accession number NM_012235.1 and the design method and dsRNA sequences of Soutschek et al. and arrive at the instant sequences of SEQ ID NOs: 241 and 242 and the chemical modifications at specific positions based on the teachings of Maier et al., Li et al. and Ma et al. to provide a dsRNA with enhanced RNAi activity. In addition, because the mRNA sequence of SCAP (NCBI Reference Sequence Accession number NM_012235.1) was publicly available, and nucleotides 1-20 of SEQ ID NO:241 aligns with nucleotides 1818-1837 of NM_012235 and nucleotides 1-21 of SEQ ID NO:242 aligns with nucleotides 1838-1818 of NM_012235, an ordinary artisan could have used the teachings of Soutschek et al., Maier et al., Li et al. and Ma et al. to arrive at the instant sense and antisense sequences with a reasonable expectation of success based on a 21-mer and 23-mer and the known chemical motif patterns and modifications known in the art.
Although the cited art does not specifically teach the exact modification pattern, it would have been obvious for one ordinarily skilled in the art to perform routine optimization of the pattern to achieve improved results. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
In the instant case, the focus is in the change of form, or substitution of equivalents over the prior art. Substitution of equivalents in terms of identifying optimal locations, both in terms of potency and reduced toxic effects, for 2’F and 2’-OMe modifications in dsRNA, since varying 2’-F and 2’-OMe positions in a double stranded nucleic acid for optimal or better results in known in the prior art.
Accordingly, the limitations of claims 26 and 27 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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 1-5,8,12,13,15-18,23,24,26,27,29,30 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of copending Application No. 18/867,536 (‘536) in view of Soutschek et al., Maier et al., and NCBI Reference NM_012235.1 (24 Oct 2002), cited above.
Claim 1 of ‘536 recites an RNAi construct comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region having at least 15 contiguous nucleotides differing by no more than 3 nucleotides from an antisense sequence listed in Table 1, and wherein the RNAi construct inhibits the expression of a SREBP Cleavage Activating Protein (SCAP) mRNA. Table 1 discloses many sense and antisense sequence with chemical modification patterns. Duplex No. 20 has the same chemical modification pattern as instant SEQ ID NOs: 241 and 242, other than a phosphate on the 5’ end of the sense strand.
Instant SEQ ID NOs 241 and 242:
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45
653
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Duplex 20 of ‘536:
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61
790
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Claims 2-9 of ‘536 recite the same or similar limitations to instant claims 4,5,8 regarding the length of the duplex region and length of the sense and antisense strands, claim 10 of ‘536 recites at least one blunt end as in instant claim 12, and claims 11-14 recite the same limitations of the overhangs as in instant claims 13,15 and 16. Claims 15-23 of ‘536 recite nucleotide modifications as do instant claims 17,18,23,24. Claims 24-26 recite the antisense sense strand comprises a sequence selected from the antisense sequences listed in Table 1, and the sense strand comprises a sequence selected from the sense sequences listed in Table 1, and wherein the RNAi construct is any one of the duplex compounds listed in Table 1. Claims 28-34 of ‘536 recite the same limitations as instant claims 29,30 regarding reducing the level of SCAP in liver cells; claim 35 of ‘536 recites a composition comprising the RNAi construct of any one of claims 1-34 and a pharmaceutically acceptable carrier, excipient or diluent, as does instant claim 33. Claims 36-42 of ‘536 recite methods or reducing expression of SCAP in a patient and uses thereof.
‘536 does not recite the same sequences as instant SEQ ID NOs: 241 and 242, or a phosphate on the 5’ end of the sense strand.
The teachings of Soutschek et al., Maier et al., and NCBI Reference NM_012235.1 have all been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the claims of ‘536 based on the teachings of Soutschek et al., Maier et al., and NCBI Reference NM_012235.1 to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success because Soutschek et al. pertains to dsRNA for inhibiting SCAP and Maier et al. pertain to dsRNA for inhibiting expression of a target gene. One of ordinary skill in the art would have been motivated to design and provide a dsRNA agent that targets SCAP and to use the known mRNA sequence of NCBI Reference Sequence Accession number NM_012235.1 and the design method of Soutschek et al. and arrive at the instant sequences of SEQ ID NOs: 241 and 242 based on the teachings of Soutschek et al. and the 5’ phosphate modifications on the sense strand based on the teachings of Maier et al. teaching RNAi duplex agents with a sense strand comprising a 5’-phosphate and benefits of 5’-phosphorylation of dsRNA is desirable for loading of siRNAs into the RISC complex resulting in RNAi-mediated gene silencing, and that metabolically stable 5’ phosphate mimics can lead to higher stability, increased RISC loading and more potent gene silencing, to provide a dsRNA with enhanced RNAi activity. In addition, because the mRNA sequence of SCAP (NCBI Reference Sequence Accession number NM_012235.1) was publicly available, and nucleotides 1-20 of SEQ ID NO:241 aligns with nucleotides 1818-1837 of NM_012235 and nucleotides 1-21 of SEQ ID NO:242 aligns with nucleotides 1838-1818 of NM_012235, an ordinary artisan could have used the teachings of Soutschek et al., Maier et al. to arrive at the instant sense and antisense sequences with a reasonable expectation of success based on a 21-mer and 23-mer and the known chemical motif patterns and modifications known in the art.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-5,8,12,13,15-18,23,24,26,27,29,30 and 33 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636