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 .
DETAILED ACTION
Applicant's preliminary amendment filed on June 8, 2023 is acknowledged. Claims 5-8, 10-12, 14, 16, 17, 20-22, 26, 27, 29-31, 36-48, 51, and 53-80 have been canceled. Claims 23, 24, 25, and 28 were amended. Claims 1-4, 9, 13, 15, 18, 19, 23-25, 28, 32-35, 49, 50, and 52 are pending.
It is noted that the amendment to the claims filed on June 8, 2023 indicate that claims 29-31 are canceled and also indicate that claims 30-31 are canceled.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-4, 9, 13, 15, 18, 19, 23-25, and 28) in the reply filed on December 1, 2025 is acknowledged.
Claims 32-35, 49, 50, and 52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 1, 2025.
Claims 1-4, 9, 13, 15, 18, 19, 23-25, and 28 are examined on the merits herein.
Priority
PNG
media_image1.png
44
462
media_image1.png
Greyscale
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 8, 2023 and December 8, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on June 8, 2023.
The drawings are objected to because Figures 1B and 6 are blurry. 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.
Specification
The substitute specification filed on June 8, 2023 has been entered.
Claim Objections
Claim 19 is objected to because of the following informality:
Claim 19 recites in part “wherein the gapmers are conjugated to a lipid”. Claim 19 depends on claim 1 and claim 1 recites “A gapmer or pharmaceutically acceptable salt of the gapmer”. It would be remedial to amend claim 19 to recite “wherein the gapmer is conjugated to a lipid” (emphasis added).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 28 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 28 recites a pharmaceutical composition comprising the gapmer or pharmaceutically acceptable salt of the gapmer of claim 1. Claim 28 does not add anything additional to the product of claim 1; therefore, claim 28 fails to further limit the claim which it depends on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) in view of Summerton et al. (US 5,506,337).
Regarding claims 1, 2, and 28, Crooke teaches in Example 15 the following:
PNG
media_image2.png
290
478
media_image2.png
Greyscale
[column 45].
However, Crooke does not teach that the morpholino monomers are linked to each other by phosphorodiamidate bonds.
Summerton et al. teaches a combinatorial library of non-biological oligomers formed predominantly of morpholino subunit structures of the form:
PNG
media_image3.png
120
132
media_image3.png
Greyscale
where (i) the structures are linked together by linkages "L" one to four atoms long joining the morpholino nitrogen of one subunit structure to the 4' cyclic carbon of an adjacent subunit structure. One preferred linkage is a 3-atom phosphorodiamidate linkage [column 4, lines 28-29].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke wherein the morpholino monomers are linked to each other by phosphorodiamidate bonds because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Crooke taught the synthesis and use of oligomeric compounds including oligoribonucleotides useful for strand cleavage of target RNA strands in addition to therapeutics and diagnostics [column 1, first paragraph] and Summerton et al. taught that a 3-atom phosphorodiamidate linkage is a preferred linkage between morpholino subunit structures.
Claims 3 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) and Summerton et al. (US 5,506,337) as applied to claims 1, 2, and 28 above, and further in view of Kordasiewicz et al. (US 2016/0145617).
Regarding claims 3 and 19, the teachings of Crooke and Summerton et al. are discussed above.
However, Crooke and Summerton et al. do not teach the structure of the gapmer as recited in claim 3. Crooke and Summerton et al. also do not teach the gapmer conjugated to a lipid.
Kordasiewicz et al. defines a “gapmer” as a chimeric antisense compound in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions [0127]. Kordasiewicz et al. teaches SEQ ID NO: 1700 which is a 5-8-5 MOE gapmer oligomer for modulating Tau expression [page 89]. Kordasiewicz et al. also teaches that antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides. Typical conjugate groups include cholesterol moieties and lipid moieties [0388].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein the gapmer is a 5-8-5 gapmer because it would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kordasiewicz et al. taught a 5-8-5 gapmer oligomer for modulating gene expression.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein the gapmer is conjugated to a lipid because it would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kordasiewicz et al. taught that antisense compounds covalently linked to one or more moieties or conjugates (e.g., cholesterol moieties and lipid moieties) enhances the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotide.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) and Summerton et al. (US 5,506,337) as applied to claims 1, 2, and 28 above, and further in view of Butler et al. (WO 2017/062862).
Regarding claim 4, the teachings of Crooke and Summerton et al. are discussed above.
However, Crooke and Summerton et al. do not teach that the phosphorothioate and phosphorodiamidate bonds each possess a phosphorus that is independently in an R or S configuration and wherein each configuration is at least 90% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein the phosphorothioate and phosphorodiamidate bonds each possess a phosphorus that is independently in an R or S configuration and wherein each configuration is at least 90% pure because it would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) and Summerton et al. (US 5,506,337) as applied to claims 1, 2, and 28 above, and further in view of Butler et al. (WO 2017/062862) and Iwamoto et al. (Nature Biotechnology 2017).
Regarding claim 9, the teachings of Crooke and Summerton et al. are discussed above.
However, Crooke and Summerton et al. do not teach that all the phosphorodiamidate bonds of the wing regions possess a phosphorus atom having an S configuration wherein each S configuration is at least 90% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
Iwamoto et al. demonstrated that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. Further, Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein all the phosphorodiamidate bonds have an S configuration that is at least 90% pure because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Iwamoto et al. taught that Sp-configured linkages are stabilized relative to Rp configurations. In addition, Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031), Summerton et al. (US 5,506,337), and Kordasiewicz et al. (US 2016/0145617) as applied to claims 1, 2, 3, 19, and 28 above, and further in view of Butler et al. (WO 2017/062862) and Iwamoto et al. (Nature Biotechnology 2017).
Regarding claim 23, the teachings of Crooke, Summerton et al., and Kordasiewicz et al. are discussed above.
However, Crooke, Summerton et al., and Kordasiewicz et al. do not teach that all the phosphorodiamidate bonds of the wing regions possess a phosphorus atom having an S configuration wherein each S configuration is at least 90% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
Iwamoto et al. demonstrated that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. Further, Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke, Summerton et al., and Kordasiewicz et al. wherein all the phosphorodiamidate bonds have an S configuration that is at least 90% pure because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Iwamoto et al. taught that Sp-configured linkages are stabilized relative to Rp configurations. In addition, Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) and Summerton et al. (US 5,506,337) as applied to claims 1, 2, and 28 above, and further in view of Butler et al. (WO 2017/062862) and Iwamoto et al. (Nature Biotechnology 2017).
Regarding claim 13, the teachings of Crooke and Summerton et al. are discussed above.
However, Crooke and Summerton et al. do not teach that all the phosphorothioate bonds in the gap region possess a phosphorus atom having an S configuration wherein each S configuration is at least 95% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
Iwamoto et al. demonstrated that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. Further, Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein all the phosphorothioate bonds have an S configuration that is at least 95% pure because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Iwamoto et al. taught that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs, specifically Sp-configured PS linkages are stabilized relative to Rp configurations. In addition, Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031), Summerton et al. (US 5,506,337), and Kordasiewicz et al. (US 2016/0145617) as applied to claims 1, 2, 3, 19, and 28 above, and further in view of Butler et al. (WO 2017/062862) and Iwamoto et al. (Nature Biotechnology 2017).
Regarding claim 24, the teachings of Crooke, Summerton et al., and Kordasiewicz et al. are discussed above.
However, Crooke, Summerton et al., and Kordasiewicz et al. do not teach that all the phosphorothioate bonds in the gap region possess a phosphorus atom having an S configuration wherein each S configuration is at least 90% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
Iwamoto et al. demonstrated that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. Further, Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke, Summerton et al., and Kordasiewicz et al. wherein all the phosphorothioate bonds have an S configuration that is at least 90% pure because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Iwamoto et al. taught that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs, specifically Sp-configured PS linkages are stabilized relative to Rp configurations. In addition, Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) and Summerton et al. (US 5,506,337) as applied to claims 1, 2, and 28 above, and further in view of Butler et al. (WO 2017/062862) and Wan et al. (Nucleic Acids Research 2014).
Regarding claim 15, the teachings of Crooke and Summerton et al. are discussed above.
However, Crooke and Summerton et al. do not teach that the phosphorothioate bonds in the gap region have a mix of R and S phosphorus configurations wherein each R and S configuration is at least 90% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
Wan et al. teaches that bicyclic oxazaphospholidine monomers were used to prepare a series of phosphorothioate (PS) modified gapmer antisense oligonucleotides (ASOs) with control of the chirality of each of the PS linkages within the 10-base gap. The stereoselectivity was determined to be 98% for each coupling. Wan et al. studied how PS chirality influences biophysical and biological properties of the ASO including binding affinity (Tm), nuclease stability, activity in vitro and in vivo, RNase H activation and cleavage patterns in a gapmer context. Compounds that had nine or more Sp linkages in the gap were found to be poorly active in vitro, while compounds with uniform Rp-gaps exhibited activity very similar to that of the stereo-random parent ASOs. Conversely, when tested in vivo, the full Rp-gap compound was found to be quickly metabolized resulting in low activity. A total of 31 ASOs were prepared with control of the PS chirally of each linkage within the gap in an attempt to identify favorable Rp/Sp positions. Wan et al. demonstrated that a mix of Rp and Sp is required to achieve a balance between good activity and nuclease stability.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein the phosphorothioate bonds in the gap region have a mix of R and S phosphorus configurations wherein each R and S configuration is at least 90% pure because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Wan et al. taught that a mix of Rp and Sp in the gap is required to achieve a balance between good activity and nuclease stability. In addition, Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031), Summerton et al. (US 5,506,337), and Kordasiewicz et al. (US 2016/0145617) as applied to claims 1, 2, 3, 19, and 28 above, and further in view of Butler et al. (WO 2017/062862) and Wan et al. (Nucleic Acids Research 2014).
Regarding claim 25, the teachings of Crooke, Summerton et al., and Kordasiewicz et al. are discussed above.
However, Crooke, Summerton et al., and Kordasiewicz et al. do not teach that the phosphorothioate bonds in the gap region have a mix of R and S phosphorus configurations wherein each R and S configuration is at least 90% pure.
Butler et al. teaches that properties such as activity, toxicity, distribution, and pharmacokinetics of an oligonucleotide can be adjusted by optimizing its pattern of backbone chiral centers in combination with adjustment/optimization of chemical modifications, patterns of modifications such as linkage pattern and nucleoside modification pattern. Further, Butler et al. demonstrated that modifications of sugars, bases, and/or internucleotidic linkages are combined with stereochemistry patterns to provide oligonucleotides and compositions with enhanced properties such as low toxicity and better protein binding [0013]. Butler et al. teaches that purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100% [00463], and the provided chirally controlled (and/or stereochemically pure) preparations are of a stereochemical purity of greater than 90% and up to greater than 99% [00475]. Butler et al. also teaches that the chirally controlled oligonucleotides and chirally controlled oligonucleotide compositions are of high crude purity and of high diastereomeric purity [00619].
Wan et al. teaches that bicyclic oxazaphospholidine monomers were used to prepare a series of phosphorothioate (PS) modified gapmer antisense oligonucleotides (ASOs) with control of the chirality of each of the PS linkages within the 10-base gap. The stereoselectivity was determined to be 98% for each coupling. Wan et al. studied how PS chirality influences biophysical and biological properties of the ASO including binding affinity (Tm), nuclease stability, activity in vitro and in vivo, RNase H activation and cleavage patterns in a gapmer context. Compounds that had nine or more Sp linkages in the gap were found to be poorly active in vitro, while compounds with uniform Rp-gaps exhibited activity very similar to that of the stereo-random parent ASOs. Conversely, when tested in vivo, the full Rp-gap compound was found to be quickly metabolized resulting in low activity. A total of 31 ASOs were prepared with control of the PS chirally of each linkage within the gap in an attempt to identify favorable Rp/Sp positions. Wan et al. demonstrated that a mix of Rp and Sp is required to achieve a balance between good activity and nuclease stability.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke, Summerton et al., and Kordasiewicz et al. wherein the phosphorothioate bonds in the gap region have a mix of R and S phosphorus configurations wherein each R and S configuration is at least 90% pure because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Wan et al. taught that a mix of Rp and Sp in the gap is required to achieve a balance between good activity and nuclease stability. In addition, Butler et al. taught that structural elements including stereochemistry can have a significant impact on oligonucleotide properties and also taught that the purity of a chirally controlled oligonucleotide composition can be controlled by stereoselectivity of each coupling step in its preparation process and teaches a new internucleotidic linkage formed may have stereoselectivity of at least 90% up to virtually 100%.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Crooke (US 5,898,031) and Summerton et al. (US 5,506,337) as applied to claims 1, 2, and 28 above, and further in view of Østergaard et al. (Nucleic Acids Research 2020).
Regarding claim 18, the teachings of Crooke and Summerton et al. are discussed above.
However, Crooke and Summerton et al. do not teach that the phosphorothioate and phosphorodiamidate bonds all possess phosphorus atoms that are stereorandom.
Østergaard et al. teaches that ASOs with stereorandom phosphorothioate linkages in the DNA gap region offer the optimal balance of activity and metabolic stability and that ASO sequence and design are the primary drivers which determine the pharmacological and toxicological properties of gapmer ASOs [page 1699, left column, last paragraph bridging to right column]. Østergaard et al. also teaches that the added cost and complexity of controlling phosphorothioate chirality makes it a less attractive strategy relative to the gap modification approach using 2’ and backbone modifications for improving therapeutic profile [page 1699, left column, first paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gapmer of Crooke and Summerton et al. wherein the phosphorothioate and phosphorodiamidate bonds all possess phosphorus atoms that are stereorandom because it would have amounted to combining prior art elements according to known methods to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Østergaard et al. taught that stereorandom phosphorothioate linkages in the DNA gap region offer the optimal balance of activity and metabolic stability. Although Østergaard et al. did not explicitly teach stereorandom chemistry of the wing regions or stereorandom phosphorodiamidate bonds, Østergaard et al. taught that controlling chirality is complex and costly and thus one of ordinary skill in the art would have been motivated to form a stereorandom gapmer because it is easier and cheaper.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637