DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 57, 60-65, 80, 107-110, and 129-151 are pending.
Preliminary Amendment
Applicant’s preliminary amendment filed on 07/08/2024 is acknowledged. The claims were amended to (1) cancel 1-56, 58, 59, 66-79, 81-106, and 111-128; (2) amend 60, 62, 80, 107, 109, and 110; and (3) add 129-151.
Priority
This application is a 371 of PCT/US2022/014231 filed on 01/28/2022. Acknowledgement is made of Applicant’s claim for priority based on a provisional application filed as 63/143,686 on 01/29/2021.
All claims are given the priority date of 01/29/2021.
Information Disclosure Statement
The information disclosure statement filed 07/08/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. The document in question is CA 2,526,893, a Canadian publication, listed under the U.S. Patent Documents section as #1. CA 2,526,893 is a foreign document and should be cited under the FOREIGN PATENT DOCUMENTS section and added to the IDS.
Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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) 57, 60-65, 80, 107-110, and 129-151 are rejected under 35 U.S.C. 103 as being unpatentable over Hung et al (WO 2011/032045 A1, published March 17th, 2011) in view of Freier et al (WO 2020/106996 A1, published May 28th, 2020 – priority date of November 21st, 2018).
Hung et al teaches, “Provided herein are methods, compounds, and compositions for reducing expression of huntingtin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate Huntington's disease, or a symptom thereof.”, (Abstract).
Hung et al provides the following definitions for clarity:
“"Huntingtin nucleic acid" means any nucleic acid encoding huntingtin. For example, in certain embodiments, a huntingtin nucleic acid includes a DNA sequence encoding huntingtin, an RNA sequence transcribed from DNA encoding huntingtin (including genomic DNA comprising introns and exons), and an mRNA sequence encoding huntingtin. "Huntingtin mRNA" means an mRNA encoding a huntingtin protein.”, (Page 9, lines 10-14).
“"Antisense compound" means an oligomeric compound that is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding.”, (Page 7, lines 26-27)
“"Antisense inhibition" means reduction of target nucleic acid levels or target protein levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.”, (Page 7, lines 28-31).
“"Antisense oligonucleotide" means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.”, (Page 8, lines 1-3).
Regarding claim(s) 57, 63, and 65, Hung et al teaches targeting SEQ ID NO:2:
“Example 1: Antisense oligonucleotides targeted to human huntingtin gene sequences
About seventeen hundred newly designed antisense compounds of various lengths, motifs and backbone composition targeting the human huntingtin gene sequence were tested for their effect on human huntingtin mRNA in vitro in several cell types. These gapmers were further designed with internucleoside linkages that are either only phosphorothioate linkages (described in Table 1) or that are phosphorothioate and phosphodiester linkages (described in Table 5). A number of the newly designed oligos and two benchmark oligonucleotides (previously designed and disclosed) are provided in Tables 1 and 5.
Gapmers with fully phosphorothioate internucleoside linkages.
Certain of the compounds presented in Table 1 have a motif of 5-10-5 OE, 6-8-6 MOE, or 5-8-5 MOE. The 5-10-5 gapmers have twenty linked nucleosides, wherein the central gap segment has ten 2'-deoxynucleosides and is flanked on both sides (in the 5' and 3' directions) by wings having five nucleosides each. The 6-8-6 gapmer has twenty linked nucleosides, wherein the central gap segment has eight 2'-deoxynucleosides and is flanked on both sides (in the 5' and 3' directions) by wings having six nucleosides each. The 5-8-5 gapmers have eighteen linked nucleosides, wherein the central gap segment has eight 2'-deoxynucleosides and is flanked on both sides (in the 5' and 3' directions) by wings having five nucleosides each. For all gapmers listed in Table 1, each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has a 2' -MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P=S) internucleoside linkages. All cytosines throughout each gapmer are 5- methylcytosines. Each gapmer in Table 1 is targeted to SEQ ID NO: 1 (GENBANK Accession No. NM_002111.6) or SEQ ID NO: 2 (GENBANK Accession No. NT_006081.17 truncated from nucleotides 462000 to 634000)...”, (See page 50, lines 7-29).
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SEQ ID NO:2 contains a sequence 100% complementary to instant SEQ ID NO: 3619. See alignment below.
Further, Hung et al teaches, “In certain embodiments, a target region is a structurally defined region of the target nucleic acid. For example, a target region may encompass a 3' UTR, a 5' UTR, an exon, an intron, an exon/intron junction, a coding region, a translation initiation region, translation termination region, or other defined nucleic acid region… In certain embodiments, the desired effect is a reduction in mRNA target nucleic acid levels. In certain embodiments, the desired effect is reduction of levels of protein encoded by the target nucleic acid or a phenotypic change associated with the target nucleic acid.”, (Page 27 and 28, lines 23-26 and 2-5, respectively).
Moreover, Hung et al teaches, “Modifications to antisense compounds encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense compounds are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity. Chemically modified nucleosides may also be employed to increase the binding affinity of a
shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense compounds that have such chemically modified nucleosides.”, (Pages 32 and 33, lines 25-32 and 1-2, respectively).
Lastly, Hung et al teaches, “Antisense compound targeted to a huntingtin nucleic acid can be utilized in pharmaceutical compositions by combining the antisense compound with a suitable pharmaceutically acceptable diluent or carrier. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS). PBS is a diluent suitable for use in compositions to be delivered parenterally. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising an antisense compound targeted to a huntingtin nucleic acid and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is PBS. In certain embodiments, the antisense compound is an antisense oligonucleotide. Pharmaceutical compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.”, (Pages 36 and 37, lines 27-30 and 1-13, respectively).
In summary, Hung et al teaches (1) about 1,700 antisense compounds targeting htt (SEQ ID NOs:1 or 2; of which instant SEQ ID NO: 3619 has 100% complementary to SEQ ID NO: 2) to reduce htt mRNA (antisense compounds reading on oligomeric compounds), in which the targeting region may encompass an intron; (2) single-strandedness; (3) 20 nucleotide antisense gapmers; (4) gapmers of mixed backbone (PS and PO linkage) and nucleobase modifications; (5) that each cystine in the gapmer is a 5-methylcytosine; (6) pharmaceutical compositions comprising the oligomeric compound and a pharmaceutically acceptable diluent; (7) a diluent of PBS; and (8) pharmaceutically acceptable salts such as sodium.
Hung et al does not teach that the targeting nucleic acid is (1) a 6-10-4 gapmer, with the modification pattern of “sooooossssssssssoss” for internucleoside linkage (wherein s = phosphorothioate and o= phosphodiester bonds), or “eeeeeeddddddddddeeee” for modified sugars (wherein e = 2’MOE and d=2’deoxyribose); (2) “population” in regard to the chirality of the modified oligonucleotides; or (3) artificial cerebrospinal fluid (aCSF) as a diluent.
Freier et al teaches “…compounds, methods, and pharmaceutical compositions for reducing the amount of prion RNA (PRNP RNA) in a cell or animal, and in certain instances reducing the amount of prion protein (PrP protein) in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease...”, (see page 1, Field section). “…Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif provides reasonable support for additional oligonucleotides having the same or similar motif…”, (see page 71, lines 21-24).
Regarding claim(s) 57, 60-62, 63-65, Freier et al teaches “Embodiment 52”, “Embodiment 53”, “Embodiment 62”, “Embodiment 90”, “Embodiment 91”, and “Embodiment 101”, which are (1) The oligomeric compound “of embodiment 39”, wherein the oligonucleotide has the following linkage motifs…;(2) The oligomeric compound of any of embodiments 1-52, consisting of a modified oligonucleotide; (3) The oligomeric compound of any of embodiments 1-62 wherein the oligomeric compound is a single-stranded oligomeric compound; (4) A modified oligonucleotide, or salt thereof; (5) A modified oligonucleotide; and (6) A compound comprising a modified oligonucleotide according to the following chemical notation: Ges, mCeo, Teo, Teo, Aeo, Teo, Tds, Ads, Tds, Tds, mCds, Ads, Tds, Gds, Tds, Tds, mCeo, Tes, mCes, mCe (SEQ ID NO: 1939), wherein, A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE modified sugar, d = a 2’-D deoxyribosyl sugar, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage, respectively. Embodiment 52 gives the following linkage motifs: “soossssssssssooooss, sooossssssssssoooss, sooosssssssssssooss, sooooossssssssssoss, ssooooossssssssssos, soooossssssssssoos, soooosssssssssooss, soosssssssssooss, sooosssssssssooss, or soosssssssssoos wherein“s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage.” Embodiment(s) 90, 91 and 101 are or comprise 6-10-4 gapmers (20 nucleotides), with the modification pattern of “sooooossssssssssoss” for internucleoside linkages, “eeeeeeddddddddddeeee” for modified sugars, and all cytosines are 5-methylcyotsines, with the only difference between embodiments is that 91 has sodium salt ions as well. See embodiments 90 and 91 below. (Embodiments 52 and 53 are on page 14, Embodiment 62 is on page 15, Embodiment 90 is on page 21, Embodiment 91 is on page 22, and Embodiment 101 is on page 29).
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Moreover, Freier et al teaches that Embodiment 90 corresponds to the compound No. 1373022. Freier describes that there are six compounds that are more efficacious than the comparator compounds in vivo. Those compound numbers are 1238994, 1373021, 1373022, 1373023, 1373057, and 1411016. Three of these six compounds are 6-10-4 MOE gapmers (1373021, 1373022, 1373023) with the modification pattern of “sooooossssssssssoss” for internucleoside linkages, “eeeeeeddddddddddeeee” for modified sugars, and all cytosines are 5-methylcyotsines. Compounds 1238994 and 1411016 are 5-10-5 MOE gapmers, and 1373057 is a 5-9-5 MOE gapmer.
Data described by Freier et al from page 63-64. [6-10-4] and boldness added for emphasis:
Average PRNP expression levels in the spinal cord of mice study:
“For example, as provided in Example 5, Compound No. 1238994, Compound No. 1373021[6-10-4], Compound No. 1373022[6-10-4], Compound No. 1373023[6-10-4], Compound No. 1373057, and Compound No. 1411016 achieve an average expression level (% control) of 27% (tables 65 and 75), 25% (tables 66 and 75), 30% (tables 66 and 75), 18% (tables 66 and 75), 25% (tables 66 and 75), and 24% (tables 71 and 72), respectively, in the spinal cord of transgenic mice, whereas comparator compounds Compound No. 169746, Compound No. 169750, and Compound No. 169764 achieve an average expression level (% control) of 52% (table 62), 61% (table 62), and 61% (table 62), respectively, in the spinal cord of transgenic mice. Therefore, certain compounds described herein are more efficacious than comparator compounds, Compound No. 169746, Compound No. 169750, and Compound No. 169764 in this assay.”
Average PRNP expression levels in the cortex of mice study:
“For example, as provided in Example 5, Compound No. 1238994, Compound No. 1373021[6-10-4], Compound No. 1373022[6-10-4], Compound No. 1373023[6-10-4], Compound No. 1373057, and Compound No. 1411016 achieve an average expression level (% control ) of 44% (tables 65 and 75), 33% (tables 66 and 75), 35% (tables 66 and 75), 28% (tables 66 and 75), 52% (tables 66 and 75), and 36% (tables 71 and 72), respectively, in the cortex of transgenic mice, whereas comparator compounds Compound No. 169746, Compound No. 169750, and Compound No. 169764 achieve an average expression level (% control) of 67% (table 62), 73% (table 62), and 77% (table 62), respectively, in the cortex of transgenic mice. Therefore, certain compounds described herein are more efficacious than comparator compounds, Compound No. 169746, Compound No. 169750, and Compound No. 169764 in this assay.”
Mouse tolerability study:
“For example, as described herein, certain compounds Compound No. 1238994, Compound No. 1373021[6-10-4], Compound No. 1373022[6-10-4], Compound No. 1373023[6-10-4], Compound No. 1373057, and Compound No. 1411016 achieved average 3-hour FOB scores in mice of 0 (table 83), 2.5 (table 84), 1.8 (table 84), 0 (table 84), 0 (table 85), and 1.8 (table 94), respectively, at a dose of 700 pg. Compound No. 169753 achieved a 3-hour FOB scores in mouse of 4.2 (table 83). Therefore Compound No. 1238994, Compound No. 1373021, Compound No. 1373022, Compound No. 1373023, Compound No. 1373057, and Compound No. 1411016 described herein are more tolerable than comparator compound Compound No. 169753 in this assay.”
Rat tolerability study:
“For example, as described herein, certain compounds Compound No. 1238994, Compound No. 1373021[6-10-4], Compound No. 1373022[6-10-4], Compound No. 1373023[6-10-4], Compound No. 1373057, and Compound No. 1411016 achieved average 3-hour FOB scores in rat of 1.0 (table 107), 3.0 (table 97), 1.5 (table 97), 1.3 (table 97), 0.8 (table 98) and 3.3 (table 108), respectively, at a dose of 3mg. Compound No. 169753 achieved a 3-hour FOB score in rat of 5.5 (table 106). Therefore Compound No. 1238994, Compound No. 1373021, Compound No. 1373022, Compound No. 1373023, Compound No. 1373057, and Compound No. 1411016 described herein are more tolerable than comparator compound Compound No. 169753 in this assay.”
Long-term tolerability study:
“For example, as described herein, certain compounds Compound No. 1238994, Compound No. 1373021[6-10-4], Compound No. 1373022[6-10-4], Compound No. 1373023[6-10-4], Compound No. 1373057, and Compound No. 1411016, are more tolerable in a long-term study in rats than comparator Compound No. 169753. For example, as provided in Example 8, Compound No. 1238994, Compound No. 1373021[6-10-4], Compound No. 1373022[6-10-4], Compound No. 1373023[6-10-4], Compound No. 1373057, and Compound No. 1411016 had no onset of an adverse event during the course of the study. In contrast, each rat treated with Compound No. 169753 had adverse event onset by 5 weeks post-treatment. Therefore, certain compounds described herein are more tolerable than comparator compounds Compound No. 169753 in this assay.”
Regarding claim(s) 107-110, Freier teaches “Embodiment 66”, “Embodiment 67”, and “Embodiment 68”, which are (1) A pharmaceutical composition comprising an oligomeric compound of any of embodiments 1-63 or an oligomeric duplex of embodiment 64 and a pharmaceutically acceptable carrier or diluent; (2) The pharmaceutical composition of embodiment 66, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid; and (3) The pharmaceutical composition of embodiment 67, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid, respectively (Embodiments 66-68 are on page 15).
Regarding claim(s) 129-140, Freier teaches “Embodiment 114”, “Embodiment 115”, and “Embodiment 116”, which are, (1) A pharmaceutical composition of any of embodiments 86-105, and a pharmaceutically acceptable diluent or carrier; (2) The pharmaceutical composition of embodiment 114, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid; and (3) The pharmaceutical composition of embodiment 115, wherein the pharmaceutical
composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid, respectively (Embodiments 114-116 on page 31).
Regarding claim(s) 80, 141-144, 146, 148, and 150, Freier teaches “Embodiment 112” and “Embodiment 113”, which are (1) A population of modified oligonucleotides of any of embodiments 86-105, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom; and (2) A pharmaceutical composition comprising the population of modified oligonucleotides of any of embodiments 106-112 and a pharmaceutically acceptable carrier or diluent, respectively (Embodiment 112 is on page 30 and Embodiment 113 is on page 31).
Regarding claim(s) 145, 147, 149, and 151, Freier teaches, “As used herein,“chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.”, (see page 4, lines 28-34). Moreover, “In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and phosphate- buffered saline (PBS). In certain embodiments, the sterile PBS is pharmaceutical grade PBS. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade. In certain embodiments, a pharmaceutical composition comprises a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists essentially of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.”, (see page 48, lines 8-17).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the single-stranded 5-10-5 MOE gapmer containing mixed PS/PO internucleoside linkages and 5-methylcytosines targeting the htt mRNA, as taught by Hung et al, to a 6-10-4 MOE gapmer with the modification pattern of “sooooossssssssssoss” for internucleoside linkages, “eeeeeeddddddddddeeee” for modified sugars, and all cytosines are 5-methylcytosines as taught by Freier et al, to yield the predictable results of tolerability in mice and rats, no onset of an adverse event in a long-term study as demonstrated by six compounds in Freier et al, three of which were 6-10-4 MOE gapmers (1373021, 1373022, 1373023), and enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, and increased inhibitory activity, as taught by Hung et al. One would have motivated to do so because Freier et al suggests “where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif provides reasonable support for additional oligonucleotides having the same or similar motif.”
Moreover, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try instant SEQ ID NO: 3619 for targeting and reducing htt mRNA, as taught by Hung et al. More specifically, through generating a finite list of oligomeric compounds to target and reduce htt mRNA, through designing oligonucleotides to target SEQ ID NO: 2, as taught by Hung et al, it would have been possible to select instant SEQ ID NO: 3619 (alignment shown above). One would have recognized a problem in the art, which includes both a design need (as explained above) and a market pressure to solve the problem of: the most efficacious knockdown of htt mRNA with an oligomeric compound. With the HTT gene sequence readily available, SEQ ID NO:2 (also referred as GENBANK Accession No. NT_006081.17 truncated from nucleotides 462000 to 634000 in both Hung et al and the instant specification) one of ordinary skill in the art could have pursued the claimed invention with reasonable expectation of success through tiling the HTT gene (SEQ ID NO: 2) with complementary modified oligonucleotides, as taught by Hung et al.
Conclusion
No claims allowed.
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/L.M.T./ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637