DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of group I (claims 1, 5, 7, 9, 19, 23, 28, 32, 35, 40, 41, 43, 66, 85, 95, 113, 116, 117, 147 and 148 and species (SEQ ID NO: 13) in the reply filed on 8/15/25 is acknowledged.
Claims 129 and 134 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8/15/25.
Upon further consideration, SEQ ID NOs: 10 and 15 in claim 5 are rejoined with the elected species and examined. SEQ ID NO: 15 appears to be identical to SEQ ID NO: 13, the only difference is that there are T’s in place of U’s or vice versa at some nucleotides.
SEQ ID NOs: 1-9, 11, 12, 14 and 16-21 in Claim 5 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/15/25.
Information Disclosure Statement
The U.S. applications in the information disclosure statements filed 11/28/22; 3/30/23; 6/1/23; 8/8/23; 3/14/23; and 8/15/25 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because they are not considered U.S. Patent documents having a publication date. “If a U.S. application being listed in an IDS has been issued as a patent or has been published, the applicant should list the patent or application publication in the IDS instead of the application.” “Pending U.S. applications that are being cited can be listed under the non-patent literature section or in a new section appropriately labeled.” See MPEP 609.04(a) Applicant could cite the pre-grant U.S. publication for these applications under the U.S. Patent documents section or lists the U.S. patent applications under the NPL documents or a new section. The IDS citing these applications have been placed in the application file, but the applications referred to therein has not been considered as to the merits. 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 Objections
Claim 1 is objected to because of the following informalities: suggest adding the term “microtubule-associated protein tau” before the abbreviation MAPT to understand the abbreviation.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 117 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of making the oligonucleotide of clam 1 comprising the following process steps: reacting a molecule comprising a guanidine moiety which bonds to a linkage phosphorous atom through its =N-, a chiral auxiliary agent and a nucleoside comprising a 5’-OH moiety to form an intermediate and converting the intermediate to the nucleic acid comprising a chiral guanidine moiety and repeating the steps (NOTE: this scope of enablement does not indicate that there is written support in the specification for this scope) resulting in the oligonucleotide of claim 1, does not reasonably provide enablement for method of making the oligonucleotide of claim 1 using a chiral auxiliary. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Page 149 of the specification discloses methods taught in the prior art for preparing oligonucleotide compositions (both stereorandom and chirally controlled). One of skill in the art would possess the knowledge that a chiral auxiliary is a temporary chiral group used in organic synthesis to control the stereochemical outcome of a reaction enabling the production of one enantiomer over another. A typical process involving a chiral auxiliary includes three steps: 1) covalent coupling: auxiliary is attached to the substrate, 2) stereoselective transformation: the compound undergoes one or more diastereoselective reactions; 3) removal of the auxiliary, the auxiliary is removed under conditions that do not racemize the oligonucleotide.
Instant claim 117 is very broad and only requires using a chiral auxiliary in the method of making the oligonucleotide of claim 1.
The skilled artisan would understand that additional steps and sometimes multiple cycles, which are missing from the claim, are required to complete the pre-amble of the claimed method.
On pages 152-160, the specification teaches making oligonucleotides using a chiral auxiliary.
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In addition, to the steps on these pages, the method would have to involve producing an oligonucleotide that has at least 15 contiguous bases of a base sequence that is identical with or complementary to a sequence of a MAPT gene or a transcript thereof. These methods steps are missing from claim 117.
Thus, without these additional method steps, the pre-amble of the claimed method is not completed using a chiral auxiliary.
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 35, 40, 41, and 43 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 35 recites the limitation "the pattern of backbone chiral centers…[(Rp)n(Sp)m]y" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claims 40, 41 and 43 are also rejected because they depend on claim 35.
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.
Claims 5 and 113 are 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 5 depends on claim 1 that requires the base sequence of the oligonucleotides has at least 15 contiguous of a base sequence that is identical to a base sequence of a MAPT1 gene, however, claim 5 indicates that the base sequence of the oligonucleotide has at least 10 contiguous bases of SEQ ID NO: 14. Claim 5 has to have at least 15 contiguous bases of SEQ ID NO: 14 to further limit claim 1. 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 113 depends on claim 85 that requires the oligonucleotides of the plurality share a common base sequence, however, claim 113 indicates that 40-100% of all oligonucleotides share the common base sequence are oligonucleotides of the plurality. 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, 5, 7, 9, 19, 23, 28, 32, 35, 40, 41, 43, 66, 85, 95, 113, and 116 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015010135 (ISIS PHARMACEUTICALS, cited on an IDS) taken with Dyudeeva et al. (Russian Journal of Bioorganic Chemistry, 2019, Vol. 45, pp. 709-718, of record).
ISIS discloses an oligonucleotide (page 3, lines 12-15), wherein the base sequence of the oligonucleotide comprises at least 15 contiguous bases of a base sequence that is identical with or complementary to a base sequence of a MAPT gene or a transcript thereof (antisense oligonucleotides 18-20 nucleosides in length targeting a sequence in the Tau (MAPT) gene sequence, complementary to the target sequence to at least 9-20 nucleobase portions; page 17, lines 33-34; page 33, line 23 to page 34, line 2; page 52, lines 29-33; page 81, lines 5-26), wherein the oligonucleotide comprises one or more modified sugars, one or more modified nucleobases, and/or one or more modified internucleotide linkages (a modified oligonucleotide comprising a modified internucleoside linkage, a modified nucleobase, or a modified sugar; page 5, lines 6-31. ISIS teaches an antisense oligonucleotide (gapmer) decreases tau mRNA expression that has at least (10)15 contiguous nucleotide of instant SEQ ID NO: 10 (Qy). See table 31, page 105; SEQ ID NO: 1602 (Db) which has a high percentage of inhibition which would make it a lead candidate to further study.
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ISIS does not specifically teach the oligonucleotide comprising a guanidine moiety which bonds to a linkage phosphorous atom through =N-.
However, Dyudeeva et al. teach making oligonucleotides having a guanidine moiety exhibit nuclease resistance.
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These oligonucleotides are highly promising for use in molecular biology, nucleic acid diagnostics and biotechnology (abstract). Table 1 discloses oligonucleotides with phosphoryl groups.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ISIS taken with Dyudeeva to make the oligonucleotides targeting MAPT have the guanidine moiety to study the bioavailability of the oligonucleotides, namely to arrive at the claimed invention. See also MPEP 2143(I)B or C. ISIS teaches an antisense oligonucleotide that would read on an oligonucleotide having at least 10(15) contiguous nucleotide of instant SEQ ID NO: 10. SEQ ID NO: 1602 one of the highest percentage of tau mRNA inhibition and would be lead candidate for future therapeutic studies. One of ordinary skill in the art would have been motivated to combine the teaching to make a gapmer comprising a 5’-wing-core-wing-3’ structure, wherein the 5’-wing and 3’-wing each independently have two or more modified sugars. ISIS disclose a gapmer and teaches the core of the gapmer has a natural DNA sequence (pages 5-7, 18, 28-30 and 157-160). ISIS teaches using 2’-MOE or 2’-OMe modified sugars at either wing of the gapmer (pages 28-30 and 158). Instant claim 32 reads on a natural DNA sugar. See Paragraph 21 of the as-filed specification discloses: In some embodiments, a core sugar is a natural DNA sugar which comprises no substitution at the 2’ position (two -H at 2’-carbon). Pages 28-30 and 52 of ISIS teach using a natural DNA in the core of the gapmer. With respect to the structure in claims 35, 40, 41 and 43, the claims do not define the variables. In view of the broadest reasonable interpretation of the structure, the instant structure could read on any gapmer having a backbone motif taught by ISIS (pages 28-30 and 158). ISIS teaches making an oligomer in a pharmaceutically acceptable salt (page 44). ISIS teaches using phosphorothioate internucleotide linkages in the 5’ and 3’ wings to increase the stability of the oligomer (page 35). Since a composition requires more than one oligonucleotide to inhibiting MAPT gene in a cell, it would have been obvious to make a composition comprising a plurality of the oligonucleotides for delivery to a cell or a subject. It would have been obvious to one of ordinary skill in the art to make a composition comprising the oligonucleotide and a pharmaceutically acceptable carrier to deliver the oligonucleotide to a cell or a subject.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 1, 5, 7, 9, 19, 23, 28, 32, 35, 40, 41, 43, 66, 85, 95, 113, 116, and 117 are rejected under 35 U.S.C. 103 as being unpatentable over Wave Life Sciences (WO 2018/223056, published 12/16/18) taken with WO 2015010135 (ISIS PHARMACEUTICALS), both cited on an IDS.
Pages 10-20, 143-232 and 1307-1316 of ‘056 disclose a composition comprising an oligonucleotide that is complementary to a RNA sequence, has a length of about 15 to 49 nucleotides and has at least one non-natural bases, sugar, and/or internucleotidic linkage. The oligonucleotide comprises a guanidine moiety which bonds to a linkage phosphorous atom through its =N- (pages 10-20). Pages 156-232 disclose using at least one non-negatively (neutral) charged internucleotidic linkage, including the structure in instant claim 28. The oligonucleotide can comprise DNA and RNA nucleotides and 2’-modifications, including 2’-F, LNA, and 2’-OMe modifications. The oligonucleotide can be capable of directing RNase H-mediated knockdown of a target gene and can be a gapmer (pages 10-20 and 143-153). ISIS contemplates chirally controlled oligonucleotide compositions having a plurality of oligonucleotides having improved properties and/or activity (pages 13-14). The plurality of oligonucleotides share a common base sequence, a common pattern of backbone linkages and common stereochemistry independently at least 1-50 chiral internucleotidic linkages (chirally controlled internucleotidic linkages). Pages 29-32 discloses a pattern that could read on the pattern recited in instant claim 35. Page 62 discloses that the oligonucleotide can be in a composition comprising a pharmaceutical acceptable carrier or can be a pharmaceutically acceptable salt.
‘056 does not teach making an oligonucleotide targeting a MAPT gene or a transcript thereof, wherein the oligonucleotide has the guanidine moiety which bonds to a linkage phosphorous atom through its =N-.
However, ISIS discloses an oligonucleotide (page 3, lines 12-15), wherein the base sequence of the oligonucleotide comprises at least 15 contiguous bases of a base sequence that is identical with or complementary to a base sequence of a MAPT gene or a transcript thereof (antisense oligonucleotides 18-20 nucleosides in length targeting a sequence in a MAPT gene sequence), complementary to the target sequence to at least 9-20 nucleobase portions (page 17; pages 33-34, page 52 and page 81), wherein the oligonucleotide comprises one or more modified sugars, one or more modified nucleobases, and/or one or more modified internucleotide linkages (a modified oligonucleotide comprising a modified internucleoside linkage, a modified nucleobase, or a modified sugar; page 5. ISIS teaches an antisense oligonucleotide (gapmer, 2’-MOE wing) decreases tau expression that has at least (10)15 contiguous nucleotide of instant SEQ ID NOs: 10 (Qy) and 13 (12 contiguous nucleotides of SEQ ID NO: 13). See table 31, page 105; SEQ ID NO: 1602 (Db) which has a high percentage of inhibition of tau mRNA which would make it a lead candidate to further study for potential therapeutic usage.
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It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘056 taken with ISIS to make the oligonucleotides targeting MAPT have the guanidine moiety to study the bioavailability of the oligonucleotides, namely to arrive at the claimed invention. See also MPEP 2143(I)B or C. ISIS teaches an antisense oligonucleotide that would read on an oligonucleotide having at least 10(15) contiguous nucleotide of instant SEQ ID NO: 10. SEQ ID NO: 1602 one of the highest percentage of tau mRNA inhibition and would be lead candidate for future therapeutic studies. One of ordinary skill in the art would have been motivated to combine the teaching to make a gapmer comprising a 5’-wing-core-wing-3’ structure, wherein the 5’-wing and 3’-wing each independently have two or more modified sugars. ISIS disclose a gapmer and teaches the core of the gapmer has a natural DNA sequence (pages 5-7, 18, 28-30 and 157-160). ISIS teaches using 2’-MOE or 2’-OMe modified sugars at either wing of the gapmer (pages 28-30 and 158). Instant claim 32 reads on a natural DNA sugar. See Paragraph 21 of the as-filed specification discloses: In some embodiments, a core sugar is a natural DNA sugar which comprises no substitution at the 2’ position (two -H at 2’-carbon). ‘056 teaches that the structure in instant claim 28 can be a non-negative charged internucleotidic linkage and it could be used in a wing of the gapmer. Pages 28-30 and 52 of ISIS teach using a natural DNA in the core of the gapmer. With respect to the structure in claims 35, 40, 41 and 43, the claims do not define the variables. In view of the broadest reasonable interpretation of the structure, the instant structure could read on any gapmer having a backbone motif taught by ISIS (pages 28-30 and 158) or ‘056 (pages 29-32). ISIS teaches making an oligomer in a pharmaceutically acceptable salt (page 44). ISIS teaches using phosphorothioate internucleotide linkages in the 5’ and 3’ wings to increase the stability of the oligomer (page 35). Since a composition requires more than one oligonucleotide to inhibiting MAPT gene in a cell, it would have been obvious to make a composition comprising a plurality of the oligonucleotides for delivery to a cell or a subject. It would have been obvious to one of ordinary skill in the art to make a composition comprising the oligonucleotide and a pharmaceutically acceptable carrier to deliver the oligonucleotide to a cell or a subject. Paragraph 634 of ‘056 teaches that making oligonucleotides using a chiral auxiliary is well known in the prior art. One of ordinary skill in the art could use an auxiliary chiral for stereoselective (chiral control) coupling of nucleotide monomers in preparation of the oligonucleotide targeting MAPT.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Allowable Subject Matter
Claims 147 and 148 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The prior at (US 11279929, SEQ ID NO: 2) teaches that the MAPT gene is known in the prior art. Instant SEQ ID NOs: 13 and 15 appear to be 100% complementary to the gene. However, the nucleotide sequence for the gene is over 130000 nucleotides in length. There is nothing in the prior art to lead the skilled artisan to this specific 20-mer region in the gene and make a 20-mer antisense oligonucleotide with a reasonable expectation. Antisense oligonucleotides can be 15-25 nucleotides in length (column 42 of ‘929). The prior art teaches that one of skill in the art has to empirically determine each antisense oligonucleotide to determine if it can reduce expression of a target sequence. See Kang et al. Nucleic Acids Research Vol. 53, W39-W44, 2025. Kang teaches, “….designing ASOs remains a challenging problem due to the vast number of possible combinations.” “For example, an ASO of length l has 4l sequence variations, as each nucleotide can be A, U/T, G, or C.” “In addition, various chemical modifications have been introduced to improve ASO stability and binding affinity, further increasing the complexity of the design process.” There is nothing in the prior art to suggest to one of ordinary skill in the art to pick 20 nucleotides as the length of the MAPT antisense oligonucleotide and the specific 20-mer region of the gene, then arrive at SEQ ID NO: 13 or 15. Not including antisense oligonucleotide having 15-25 nucleotides to this gene, there are at least 6,000 20-mer antisense oligonucleotides for a MAPT gene. Table 6 of ‘929 teaches the variability in inhibiting MAPT expression (including some antisense oligonucleotide that do not inhibit MAPT expression) based on the antisense oligonucleotide and/or chemical modification pattern. The prior art does not teach or suggest picking this specific oligonucleotide from thousands of potential MAPT antisense oligonucleotides and then add a specific chemical modification (guanidine moiety which bonds a linkage phosphate atom through its =N-) from thousands of possible chemical modifications. There is not a finite number of predictable and identifiable chemically modified antisense for one of ordinary skill in the art to try and make this claimed sequence with a reasonable expectation of success.
In addition, the prior art does not teach or suggest an oligonucleotide set forth in SEQ ID NO: 13 or 15 and having the specific chemical modification pattern as set forth in the claims 147 and 148 (SEQ ID NOs: 29 and 30). There are hundreds, if not thousands, of known chemical modifications and patterns known to one of ordinary skill in the art (see columns 45-53 of ‘929). This indicates to one of ordinary skill in the art that it was not obvious to try the specific chemical modification pattern with either SEQ ID NO: 29 or 30 because there is not a finite number and predictable chemical modification patterns.
Conclusion
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636