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 .
Claim Status
Claims 1, 4-5, 8, 13-16, 18, 25, 31, 35-36, 40, 44-45, 47-48, 50, 55-58, 62-69, 74 are cancelled.
Claims 6-7, 9, 11, 17, 19-22, 24, 26, 28-30, 33-34, 37-39, 41-43, 46, 49, 51-54, 59, 61, 70-71, 73 are amended.
Claims 2-3, 6-7, 9-12, 17, 19-22, 24, 26-30, 32-34, 37-39, 41-43, 46, 49, 51-54, 59-61, 70-73 are examined on the merits.
Election/Restrictions
Applicant’s election without traverse of SEQ ID NO: 345, in the reply filed on 07/10/2026 is acknowledged.
Upon further consideration the requirement for Election of species is withdrawn.
Priority
Applicant’s claim for the benefit of a Provisional Application No 63086576 filed 10/01/2020 is acknowledged.
Claim Objections
Claim 19 is objected to because of the following informalities: The recitation of “6, 7, 8, 9, 10” and “6-10” is redundant.
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 41-43, 46, 49 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.
Claim 41 recites “The oligomeric compound of claim 1, wherein the
oligomeric compound comprises a conjugate group, and wherein the conjugate group comprises a conjugate moiety and a conjugate linker”.
However, claim 1 has been cancelled. Because claim 41 expressly depends from claim 1, claim 41 lacks the proper antecedent claim and does not clearly define the scope of the claimed subject matter. It is therefore unclear what limitations of claim 1 are incorporated into claim 41 and what oligomeric compound is encompassed by claim 41.
Claim 42 depends from claim 41, and claim 41 itself depends from cancelled claim 1, claim 42 likewise lacks a proper antecedent basis and does not clearly define the scope of the claimed oligomeric compound.
Claim 43 depends from claim 41, and claim 41 itself depends from cancelled claim 1, claim 43 likewise lacks a proper antecedent basis and does not clearly define the scope of the claimed oligomeric compound.
Claim 46 depends from claim 41, and claim 41 itself depends from cancelled claim 1, claim 46 likewise lacks a proper antecedent basis and does not clearly define the scope of the claimed oligomeric compound.
Claim 49 depends from claim 41, and claim 41 itself depends from cancelled claim 1, claim 49 likewise lacks a proper antecedent basis and does not clearly define the scope of the claimed oligomeric compound.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 2-3, 6-7, 33, 37-39, 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Blume et al. (“Blume”, US 2005/0244851 A1), as evidenced by GenBank Accession No. BC019110.1.
Regarding claims 2-3, 7, 33, 37-39, Blume teaches nucleic acid sequences which are complementary, in one embodiment, to a wide variety of human exons (e.g., abstract). Blume teaches that antisense probes that are derived from the opposite strand of the gene may also be included (e.g., paragraph 0065). Blume teaches that the backbone of the polynucleotide can comprise sugars and phosphate groups, as may typically be found in RNA or DNA, or modified or substituted sugar or phosphate groups. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides (It reads on modified nucleobase) and nucleotide analog (e.g., paragraph 0045). Blume teaches SEQ ID NO 4848545 with 100% identity to SEQ ID NO 14 of the instant claims (see alignment below) (It reads on a contiguous 20 nucleobases).
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230
529
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Regarding claim 6, Blume teaches SEQ ID NO 4848545 with 100% identity to nucleotides 1685-1704 of SEQ ID NO 2 (see alignment below) (It reads on complementary to nucleotides 1685-1704 of SEQ ID NO 2).
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199
569
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SEQ ID NO 4848545 aligns with CHMP7 mRNA (see alignment below).
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265
820
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Regarding claim 51, Blume teaches the term "complementary" as used herein refers to the hybridization or base pairing between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer binding site on a single stranded nucleic acid (e.g., paragraph 0038).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 9-12, 17, 19-22, 24, 26-30, 34, 41-42, 46, 49, 52-54, 70-73 are rejected under 35 U.S.C. 103 as being unpatentable over Vietri et al. (“Vietri”, Nature, 2015) in view of Blume et al. (“Blume”, US 2005/0244851 A1), Dean et al. (“Dean”, US 2019/0323013 A1) and Wan et al. (“Wan”, J. Med. Chem. 2016).
BRI: For purpose of examination claim 41 is interpreted as dependent of claim 2.
Vietri teaches that endosomal sorting complex required for transport (ESCRT)-III, previously found to promote membrane constriction and sealing during receptor sorting, virus budding, cytokinesis and plasma membrane repair, is transiently recruited to the reassembling nuclear envelope during late anaphase. ESCRT-III and its regulatory AAA (ATPase associated with diverse cellular activities) ATPase VPS4 are specifically recruited by the ESCRT-III-like protein CHMP7 to sites where the reforming nuclear envelope engulfs spindle microtubules (e.g., abstract). Vietri teaches CHMP7 as a novel and essential recruiter of endosomal sorting complex required for transport (ESCRT)-III in knockdown studies using short interfering RNA (CHMP7 1-3 antisense oligonucleotides) (e.g., paragraph 2nd, column right, page 231; Fig. 1e; Extended Data Fig. 2e; Methods [siRNA treatments, page 236]). Vietri teaches that together with the established function for ESCRT-III during cytokinetic abscission checkpoint signaling in the presence of pathological chromatin bridges, ESCRT-III is at center stage for safeguarding the genome through mitotic exit (e.g., paragraph 1st, column right, page 234).
Vietri does not teach the antisense oligonucleotide comprising at least 12 contiguous nucleobases of SEQ ID NO: 14. Vietri does not teach the modified oligonucleotide comprises at least a bicyclic sugar. Vietri does not teach a bicyclic sugar moiety having a 2' -4' bridge, wherein the 2' -4' bridge is selected from -O-CH2-; and -O-CH(CH3)-. Vietri does not teach a non-bicyclic modified sugar moiety comprising a 2'-MOE modified sugar moiety or a 2'-OMe modified sugar moiety. Vietri does not teach modified oligonucleotide comprises a deoxy region consisting of 5-12 linked 2' -deoxynucleosides. Vietri does not teach the deoxy region consists of 6, 7, 8, 9, 10, or 6-10 linked nucleosides. Vietri does not teach each nucleoside immediately adjacent to the deoxy region comprises a modified sugar moiety. Vietri does not teach the deoxy region is flanked on the 5'-side by a 5'-external region consisting of 1-6
linked 5' -external region nucleosides and on the 3 '-side by a 3 '-external region consisting of 1-6 linked 3 '-external region nucleosides. Vietri does not teach a 5'-region consisting of 1-7 linked 5'-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and
a 3'-region consisting of 1-7 linked 3'-region nucleosides; wherein
each of the 5' -region nucleosides and each of the 3 '-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2' β-D-deoxyfuranosyl sugar moiety. Vietri does not teach the modified oligonucleotide comprises at least one modified internucleoside linkage. Vietri does not teach each internucleoside
linkage of the modified oligonucleotide is a modified internucleoside linkage. Vietri does not teach that at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. Vietri does not teach the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage. Vietri does not teach each internucleoside linkage is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage. Vietri does not teach the modified nucleobase is a 5-methyl cytosine. Vietri does not teach the oligomeric compound comprises a conjugate group, and wherein the conjugate group comprises
a conjugate moiety and a conjugate linker. Vietri does not teach wherein the conjugate linker consists of a single bond or comprises 1-3 linker-nucleosides. Vietri does not teach the conjugate group is attached to the modified oligonucleotide at the 5'-end of the modified oligonucleotide or at the 3 '-end of the modified oligonucleotide. Vietri does not teach the conjugate group comprises a cell-targeting moiety. Vietri does not teach the modified oligonucleotide of the oligomeric compound is a pharmaceutically acceptable salt comprising one or more cations selected from sodium, potassium, calcium, and magnesium. Vietri does not teach an oligomeric duplex, comprising a first oligomeric compound and a second oligomeric compound comprising a second modified oligonucleotide, wherein the first oligomeric compound is an oligomeric compound of. Vietri does not teach a pharmaceutical composition comprising the oligomeric compound of claim 2 and a pharmaceutically acceptable diluent. Vietri does not teach the pharmaceutically acceptable diluent is artificial CSF (aCSF) or phosphate-buffered saline (PBS). Vietri does not teach the pharmaceutical composition consists essentially of the oligomeric compound and artificial CSF (aCSF) or phosphate-buffered saline (PBS). Vietri does not teach a population of oligomeric compounds wherein all of the phosphorothioate intemucleoside linkages of the modified oligonucleotide are stereorandom.
However, this is cured by Blume, Dean and Wan.
The teachings of Blume are described above and applied as before.
Regarding claim 9, Dean 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 (e.g., paragraph 0116). Dean teaches that the antisense oligonucleotide contains at least one and typically more than one modified sugar, wherein the sugar is a bicyclic sugar (e.g., paragraph 0113).
Claim 10, Dean teaches modified sugars include, bicyclic modified sugars (BNAs), having a 4'-(CH2)n-O-2' bridge, where n=1 or n=2 (e.g., paragraph 132).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to incorporate the bicyclic modified sugar disclosed by Dean into the CHMP7-targeting oligonucleotide taught by Vietri and represented by the modified sequence disclosed by Blume in order to obtain the known benefits associated with modified sugars, including enhance the binding affinity toward target RNA sequences while conferring resistance to nucleases.
Claim 11-12, Dean teaches modified sugars include, but are not limited to: substituted sugars, especially 2'-substituted sugars having a 2'-F, 2'-OCH2 (2'-OMe) or a 2'-O(CH2)2-OCH3 (2'-O-methoxyethyl or 2'-MOE) substituent group (e.g., paragraph 0132).
Wan teaches that 2’-MOE has been used to enhance stability of single and double-stranded siRNA from exonuclease mediated metabolism (e.g., paragraph 3rd, left column, page 9650; Fig. 9)
It would have been obvious to a person of ordinary skill in the art at the time of the invention to incorporate the 2’-MOE non-bicyclic modification as taught by Dean and Wan into the CHMP7-targeting oligonucleotide taught by Vietri and represented by the modified sequence disclosed by Blume, because Dean and Wan expressly teaches these modifications in antisense compounds to impart nuclease stability.
Regarding claims 17, 19-22, 24, Dean teaches a modified oligonucleotide comprised of (a) a gap segment consisting of linked deoxynucleosides, preferably consists of a thirteen linked modified deoxynucleosides; (b) a 5' wing segment consisting of linked modified nucleosides, preferably consists of two linked modified nucleosides; and (c) a 3' wing segment consisting of linked modified nucleosides, preferably consists of five linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, and wherein each modified nucleoside within each wing segment comprises a modified sugar, preferably comprises a 2'-Omethoxyethyl sugar (e.g., paragraph 0154). Blume teaches that the oligonucleotide of the invention can optionally contain one or more nucleotides having modified sugar moieties. Sugar modifications may impart nuclease stability, binding affinity or some other beneficial biological property to the antisense compounds. The furanosyl sugar ring of a nucleoside can be modified in a number of ways including but not limited to: addition of a substituent group, particularly at the 2' position (e.g., paragraph 0132).
Wand teaches that modifications to the furanose sugar moiety can enhance binding affinity and modulate nuclease stability and/or interactions with cellular proteins which can enhance ASO activity (e.g., paragraph 3rd, column left, page 9646).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to incorporate the gapmer arrangement parameters (5-12 central deoxynucleosides flanked with 1-6/1-7 modified wing nucleosides) taught by Dean into the CHMP7-targeting oligonucleotide taught by Vietri and represented by the modified sequence disclosed by Blume to achieve an optimal balance nuclease stability, binding affinity or some other beneficial biological property to the antisense compounds as taught by Dean and Wan.
Regarding claims 26-27, Dean teaches that antisense compounds
defined by a SEQ ID NO may comprise, independently, one or more modifications to an internucleoside linkage (e.g., paragraph 0057).
Regarding claims 28, 70, Dean teaches that the modified internucleoside linkages are phosphorothioate linkages (e.g., paragraph 0121).
Wan teaches that the phosphorothioate (PS) modification also confers a substantial pharmacokinetic benefit by increasing the binding to plasma proteins which prevents rapid renal excretion and facilitates binding to cell surface proteins such as stabilins, which facilitate ASO uptake into cells and tissues (e.g., paragraph 3rd, column left, page 9648). Wan teaches feature of the PS modifications is that the negative charge resides exclusively on the sulfur atom which introduces chirality at phosphorus. As a consequence, a uniformly PS modified 20-mer ASO will be comprised of a mixture of 219 stereoisomers (e.g., paragraph 4th, column left, page 9648).
Regarding claims 29-30, Dean teaches that the naturally occurring internucleoside linkage of RNA and DNA is a 3' to 5' phosphodiester linkage (e.g., paragraph 0122).
Wan teaches that modifications to the phosphodiester backbone can modulate nuclease stability and pharmacokinetic properties (e.g., paragraph 4th, column left, page 9646).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to incorporate the phosphorothioate and/or phosphodiester internucleoside linkage as disclosed by Dean and Wan into the CHMP7-targeting oligonucleotide taught by Vietri and represented by the modified sequence disclosed by Blume to increase the binding to plasma proteins which prevents rapid renal excretion and facilitates binding to cell surface proteins such as stabilins, which facilitate ASO uptake into cells and tissues as disclosed by Wan.
Regarding claim 34, Dean teaches that modified nucleobases include synthetic and natural nucleobases such as, for example, 5-methylcytosine (5-me-C). Certain nucleobase substitutions, including 5-methylcytosine substitutions, are particularly useful for increasing the binding affinity of an antisense compound for a target nucleic acid (e.g., paragraph 0148).
Regarding claims 41-42, 46, 49, Dean teaches another modification of the oligonucleotides of the invention involves chemical linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. The compounds of the invention can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers (e.g., paragraph 0166).
Wan teaches that conjugation of lipophilic groups which enhance hydrophobicity or other moieties which target ASOs to specific cell types has long been recognized as a strategy to enhance ASO activity in animals at 5’, and 3’ end (e.g., paragraph 2nd, column right, page 9657, Fig. 21). Wan teaches that cholesterol conjugated PS ASOs showed that this moiety enhances ASO accumulation in the liver. These observations were also reproduced using double-stranded siRNA as well as single-stranded micro RNA antagonist ASOs which showed enhanced activity in animals relative to their unconjugated counterparts (e.g., paragraph 3rd, column right, page 9657).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to provide the conjugate as a conjugate moiety attached through a linker as a conventional configuration to covalent attachment of functional groups to the oligonucleotides as disclosed by Dean and Wan into the CHMP7-targeting oligonucleotide taught by Vietri and represented by the modified sequence disclosed by Blume to increase potency and to target specific cell types as taught by Wan.
Regarding claim 52, Vietri teaches targeting CHMP7 using siRNA oligonucleotides (CHMP7 1-3) (e.g., paragraph 2nd, column right, page 231; Fig. 1e; Extended Data Fig. 2e; Methods [siRNA treatments, page 236]).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to use the substitute the CHMP7 siRNA oligonucleotides CHMP7 1-3 of Vietri for inhibition of CHMP7 RNA expression, with the CHMP7-targeting oligonucleotide sequence of Blume, because Blume teaches a modified oligonucleotide that targets CHMP7, Vietri teaches that knockdown of CHMP7 by siRNA affect recruitment of endosomal sorting complex required for transport (ESCRT)-III. A person of ordinary skill in the art would have been motivated to utilize a modified oligonucleotide sequence of Blume as siRNA to study the role of ESCRT-III at center stage for safeguarding the genome through mitotic exit as taught by Vietri. The combination therefore provides a reasonable expectation of success in obtaining an antisense oligonucleotide capable of inhibiting CHMP7 mRNA expression.
Regarding claim 53, 59-61, 71-73, Dean teaches the composition comprises a modified oligonucleotide comprising linked nucleosides, or a salt thereof, and a pharmaceutically acceptable carrier or diluent (e.g., paragraph 0170). Dean teaches that antisense compound targeted to a nucleic acid can be utilized in pharmaceutical compositions by combining the antisense compound with a suitable pharmaceutically acceptable diluent or carrier. Dean teaches a pharmaceutically acceptable diluent that includes phosphate-buffered saline (PBS). PBS is a diluent suitable for use in compositions to be delivered parenterally (e.g., paragraph 0176).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to provide the modified oligonucleotide in a pharmaceutical composition, because Vietri and Blume teach a CHMP7-targeting oligonucleotide and Dean teaches methods of inhibiting gene expression by contacting a cell or administering to a subject a pharmaceutical composition comprising a modified gapmer oligonucleotide. It would have been obvious to a person of ordinary skill in the art to utilize the CHMP7-targeting oligonucleotide of Vietri/Blume and the pharmaceutical composition of Dean in methods for inhibiting target gene expression, as Dean explicitly teaches that such modified oligonucleotide compounds effectively downregulate target RNA suitable for use in compositions to be delivered parenterally.
Regarding claim 54, Dean teaches chimeric antisense compounds of the invention may be formed as composite structures of two oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers (e.g., paragraph 0164).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to combine the CHMP7-targeting oligonucleotide of Vietri and Blume with a second modified oligonucleotide to form the claimed oligomeric duplex, because Vietri and Blume teach a CHMP7-targeting oligonucleotide and Dean teaches chimeric antisense compounds of two oligonucleotides for targeting the complementary nucleic acid sequence as taught by Dean.
Accordingly, Vietri teaches CHMP7-targeting antisense oligonucleotides, Blume teaches the claimed antisense oligonucleotide sequence and the general teaching of modified oligonucleotides, while Dean teaches the particular sugar modifications, gapmer architecture, internucleosides linkages, modified nucleobases, conjugates, duplex structure, pharmaceutically acceptable salts and pharmaceuticals formulations. Wan teaches most commonly used nucleobase, sugar and backbone modification, and conjugation strategies used in oligonucleotide
medicinal chemistry. The claimed modifications represent known alternatives and combination of oligonucleotides chemistries, and their application to the Blume oligonucleotide would have been within the ordinary skill in the art with a reasonable expectation of success.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Vietri et al. (“Vietri”, Nature, 2015), Blume et al. (“Blume”, US 2005/0244851 A1), Dean et al. (“Dean”, US 2019/0323013 A1) and Wan et al. (“Wan”, J. Med. Chem. 2016) as applied to claims 2-3, 6, 7, 9-12, 17, 19-22, 24, 26-30, 33-34, 37-39, 41-42, 46, 49, 51-54, 70-73 above, and further in view of Rigo et al. (“Rigo”, WO 2016/112132 A1).
Vietri, Blume, Dean and Wan do not teach an internucleoside linkage motif of soooossssssssssooss, as required by the instant claim. However, this is cured by Rigo.
Rigo teaches compositions and methods for modulating levels of C9ORF72 antisense transcript in cells, tissues, and animals (e.g., line 20, page 2). Rigo teaches oligomeric compounds include, but are not limited to, oligonucleotides, oligonucleosides, oligonucleotide analogs, oligonucleotide mimetics, antisense compounds, antisense oligonucleotides, and siRNAs (e.g., line 9, page 29). Rigo teaches the modified oligonucleotide comprises internucleoside linkages in any of the following patterns: soooossssssssssooss; s = a phosphorothioate linkage, and o = a phosphodiester linkage (e.g., line 3, page 29).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to incorporate the internucleoside phosphorothioate and phosphodiester pattern of Rigo for the Blume’s modified oligonucleotide. A person of ordinary skill in the art would have been motivated to utilize the internucleoside phosphorothioate and phosphodiester pattern of Rigo to the antisense modified oligonucleotide, to increase the binding to plasma proteins which prevents rapid renal excretion and facilitates binding to cell surface proteins such as stabilins, which facilitate ASO uptake into cells and tissues as disclosed by Wan.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Vietri et al. (“Vietri”, Nature, 2015), Blume et al. (“Blume”, US 2005/0244851 A1), Dean et al. (“Dean”, US 2019/0323013 A1) and Wan et al. (“Wan”, J. Med. Chem. 2016) as applied to claims 2-3, 6, 7, 9-12, 17, 19-22, 24, 26-30, 33-34, 37-39, 41-42, 46, 49, 51-54, 70-73 above, and further in view of Wada et al. (“Wada”, Journal of Controlled Release, 2016).
BRI: For purpose of examination, claim 41 from which claim 43 depends is interpreted as dependent from claim 2.
Vietri, Blume, Dean and Wan do not teach a cleavable linker as required by the instant claim. However, this is cured by Wada.
Wada teaches that cholesterol conjugation with a phosphodiester bond inserted between the linkage and the ASO notably improved the inhibitory effects of the ASO in vivo. Benefit of releasing the conjugated cholesterol from ASO on antisense inhibitory effect, a cleavable hexamethylene succinimide (HMS) linker was selected as a hydrophobic linker (e.g., 3rd, column left, page 61; Fig. 6).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to provide a cleavable linker to the modified oligonucleotide, because Vietri teaches a CHMP7-targeting antisense oligonucleotides, Blume teaches the claimed CHMP7-targeting modified oligonucleotide sequence, Dean teaches methods of inhibiting gene expression by contacting a cell and Wada teaches the benefit of releasing the ASO from the cleavable linker conjugate. A person of ordinary skill in the art would have been motivated to utilize a cleavable linker conjugated to the antisense modified oligonucleotide not only to deliver the ASO to the specific tissue (liver) but also to fully elicit their antisense inhibition as taught by Wada.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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