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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/11/2025 has been entered.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 09/11/2025 is acknowledged. Claims 20-24 and 26-31 were/stand cancelled. Claims 1,8,17 and 32 were amended. Claims 1-19 and 32-34 are pending and under examination.
Response to Arguments
Applicant’s arguments and amendments, see page 6, filed 09/11/2025, with respect to objection to the specification have been fully considered and are persuasive due to the amendment to the specification removing hyperlinks. The objection to the specification has been withdrawn.
Applicant’s arguments and amendments, see page 6, filed 09/11/2025, with respect to the 35 U.S.C. 112(b) rejection of claims 8,17,32 and 33 have been fully considered and are persuasive due to the amendments to claims 8,17 and 32 correcting the issues of indefiniteness and antecedent basis. The 35 U.S.C. 112(b) rejection of claims 8,17,32 and 33 has been withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities: line 10 of claim 1 has a typo as there is a dash between “the” and “modified. Appropriate correction is required.
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.
Claims 1-19 and 32-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-19 and 32-34 introduce new matter as claim 1 recites the limitation: “wherein the nucleotides of the 5’ domain are unmodified ribonucleotides, modified ribonucleotides, or combinations thereof, provided that the 5’ domain comprises at least 4 modified ribonucleotides, wherein the modified ribonucleotides of the 5’ domain need not be consecutive”. Claims 2-19 and 32-34 are included in the rejection as they depend from claim 1 and do not correct the issue.
The examiner is unable to find support in the specification for the limitation above and was not described in the specification as filed, and a person skilled in the art would not recognize in the applicant' s disclosure a description of the invention as presently claimed. This limitation was caused by the amendment removing “comprises” which allowed the 5’ domain to also comprise deoxyribonucleotides, however as amended the nucleotides of the 5’ domain are either unmodified ribonucleotides, modified ribonucleotides or combinations thereof, and therefore cannot be deoxyribonucleotides.
The specification discloses an antisense oligonucleotide wherein the 5’ domain comprises unmodified deoxyribonucleotides, unmodified ribonucleotides, modified deoxyribonucleotides, modified ribonucleotides, or combinations thereof, provided that the 5’ domain comprises at least 1 modified deoxyribonucleotide or modified ribonucleotide comprising a modified sugar and/or backbone (page 3, lines 18-22; page 11, lines 26-29) but does not describe the instantly claimed limitation which requires only ribonucleotides whether modified or unmodified in the 5’ domain and not containing deoxyribonucleotides in the 5’ domain. This is further supported by the sequences in Table 1 on page 31 of the instant specification. Not a single sequence is provided that meets the instant claim limitations.
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SEQ ID NOs 1,2,7 and 8 have no modifications and therefore do not have at least 4 modified ribonucleotides in the 5’ domain and also contain deoxyribonucleotides in the 5’ domain.
Regarding SEQ ID NOs: 3,5,9 and 10, if the 3’ domain is 10 nucleotides in length, then there is a deoxyribonucleotide (T) in the 5’ domain, while if there are 12 nucleotides in the 3’ domain, then the 5’ domain contains only ribonucleotides. However, in this case when the 3’ domain contains 12 nucleotides, then the 5’ domain only contains 3 modified ribonucleotides and the instant claims require at least 4 modified ribonucleotides in the 5’ domain.
SEQ ID NOs: 4,6 and 11-15 have a deoxyribonucleotide (T) in the 5’ domain and do not meet the instant claims.
MPEP 2163.06 states: “Applicant should therefore specifically point out the support for any amendments made to the disclosure.” While Applicant stated on page 6 of the remarks under “Status of the Claims” that no new matter is added, Applicant has not directed the Examiner to the support in the specification for the amendments. Therefore, it is the Examiner' s position that the disclosure does not reasonably convey that the inventor had possession of the subject matter of the amendment at the time of filing of the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5,8-14,16-19,32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over WO 9402498, hereinafter ‘498, Published 03 March 1994, cited on an IDS dated 02/05/2024.
Regarding claims 1 and 3, ‘498 teaches synthetic oligonucleotides useful for studying gene expression and in the antisense oligonucleotide therapeutic approach, including improved qualities resulting from modifications in the sugar phosphate backbone (Field of Invention, page 1), and particularly hybrid oligonucleotides that resist nucleolytic degradation, form stable duplexes with RNA or DNA, and activate RNase H when hybridized with RNA by having phosphorothioate and/or phosphorodithioate internucleotide linkages and segments of oligodeoxyribonucleotides, as well as segments of either oligoribonucleotides or 2’-substitued oligoribonucleotides (page 5, lines 1-10).
‘498 teaches the oligonucleotides of the invention range from 2-50 nucleotides in length, most preferably 6-50 nucleotides in length (page 10, lines 19-23), and that oligonucleotides of the invention contain four or more deoxyribonucleotides in a contiguous block to provide an activating segment for RNase H and such segments may be present at any location within the oligonucleotide (page 10, lines 31-36) and range from 1-49 deoxyribonucleosides (page 11, lines 8-9). ‘498 also teaches the oligonucleotides of the invention contain ribonucleosides, 2’-substituted ribonucleosides or combinations thereof (page 11, lines 10-13), preferably 6 or more ribonucleotides and/or 2’-substituted ribonucleotides to enhance duplex stability, and can be present singly, in pairs or in larger contiguous segments at any position within the oligonucleotide (page 11, lines 23-29). ‘498 teaches the ability to vary the numbers and positions of deoxyribonucleosides and ribonucleosides or 2’-substituted ribonucleosides allows the investigator to examine how each of these variables affects parameters of nuclease resistance, duplex stability and Rnase H activation, and that each possible embodiment is useful in such studies (page 12, lines 3-14).
‘498 teaches oligo E in Table II, page 20, which comprises a 3’ domain 11 deoxyribonucleotides in length at positions 1-11 from the 3’-end, and comprises 8 contiguous 2’-OMe modified ribonucleosides in the 5’ domain, with an overall length of the oligonucleotide being 20 nucleotides. Table II teaches the underlined sequences contain 2’-OMe ribonucleoside. Oligo E contains “A” as the 5’-most nucleotide and which is not underlined and based on the synthesis thereof on page 19 is a deoxyribonucleotide.
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Figure 2 shows the complementarity to the target RNA sequence for oligo E and that there are 20 contiguous nucleobases complementary to an equal length portion of the target RNA sequence.
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Oligo E of ‘498 does not teach wherein the nucleotides of the 5’ domain are unmodified ribonucleotides, modified ribonucleotides, or combinations thereof, as there is one deoxynucleotide present in the 5’ domain which is the “A” at the 5’ most nucleotide and the instant claims require the 5’ domain nucleotides are ribonucleotides.
However, ‘498 also teaches Oligo F in which the 5’ domain contains all 2’-OMe ribonucleosides as seen in Table II above and the 5’ most nucleotide is a 2’-OMe ribonucleoside. ‘498 teaches testing the oligonucleotides for nuclease resistance and that Oligonucleotide F was very resistant to phosphodiesterase, whereas Oligonucleotide A was digested almost to completion and Oligonucleotide C was digested to 50% (page 20, lines 24-27). ‘498 teaches the results indicate that the presence of 2’-OMe ribonucleosides in an oligonucleotide phosphorothioate enhances resistance to exonucleolytic digestion and this enhanced resistance increased when a larger proportion of 2’-OMe ribonucleotides are used (page 21, lines 3-7). In addition, when testing duplex stability, the presence of 2’-OMe ribonucleotides enhances duplex stability and this enhancement increases with increased proportions of 2’-OMe ribonucleosides and these results should be similarly applicable to hybrid oligonucleotide phosphorothioates and/or phosphorodithioates containing ribonucleotides, 2’-substituted ribonucleotides or mixtures of ribonucleotides and 2’-substituted ribonucleotides, and thus the hybrid oligonucleotide phosphorothioates and/or phosphorodithioates according to the invention should bind viral RNA or virus, pathogenic organism or cellular mRNA with greater affinity than ordinary oligodeoxynucleotide phosphorothioates (page 23, lines 1-14).
‘498 teaches oligonucleotides with preferably 6 or more ribonucleotides and/or 2’-substituted ribonucleotides to enhance duplex stability and which can be present singly, in pairs or in larger contiguous segments at any position within the oligonucleotide (page 11, lines 23-29), and the ability to vary the numbers and positions of phosphorothioate and/or phosphorodithioate internucleotide linkages, deoxyribonucleosides, and ribonucleosides or 2’-substituted ribonucleosides allows the investigator to examine how each of these variables affects parameters of nuclease resistance, duplex stability and Rnase H activation, and that each possible embodiment is useful in such studies (page 12, lines 3-14).
Regarding claims 2,4 and 14, ‘498 teaches the length of the oligonucleotide as 2-50 nucleotides in length, most preferably 6-50 nucleotides in length, and in the preferred embodiment would have 1-49 phosphorothioate and/or phosphorodithioate internucleotide linkages (page 10, lines 19-26), that oligonucleotides of the invention contain four or more deoxyribonucleotides in a contiguous block to provide an activating segment for RNase H and such segments may be present at any location within the oligonucleotide (page 10, lines 31-36), and can range from 1-49 deoxyribonucleosides (page 11, lines 8-9), the oligonucleotides of the invention contain ribonucleosides, 2’-substituted ribonucleosides or combinations thereof (page 11, lines 10-13), preferably 6 or more ribonucleotides and/or 2’-substituted ribonucleotides to enhance duplex stability, and can be present singly, in pairs or in larger contiguous segments at any position within the oligonucleotide (page 11, lines 23-29).
‘498 does not explicitly teach the limitations as recited in claims 2,4 and 14.
However, ‘498 teaches the ability to vary the numbers and positions of phosphorothioate and/or phosphorodithioate internucleotide linkages, deoxyribonucleosides, and ribonucleosides or 2’-substituted ribonucleosides allows the investigator to examine how each of these variables affects parameters of nuclease resistance, duplex stability and Rnase H activation, and that each possible embodiment is useful in such studies (page 12, lines 3-14). ‘498 also teaches Oligo F in which the 5’ domain contains all 2’-OMe ribonucleosides as seen in Table II above and that Oligonucleotide F was very resistant to phosphodiesterase (page 20, lines 24-27) and that the presence of 2’-OMe ribonucleosides in an oligonucleotide phosphorothioate enhances resistance to exonucleolytic digestion and this enhanced resistance increased when a larger proportion of 2’-OMe ribonucleotides are used (page 21, lines 3-7). When testing duplex stability, the presence of 2’-OMe ribonucleotides enhances duplex stability and this enhancement increases with increased proportions of 2’-OMe ribonucleosides and these results should be similarly applicable to hybrid oligonucleotide phosphorothioates and/or phosphorodithioates containing ribonucleotides, 2’-substituted ribonucleotides or mixtures of ribonucleotides and 2’-substituted ribonucleotides (page 23, lines 1-14).
Regarding claim 5, ‘498 teaches the nucleotides of the 3’ domain comprise unmodified nucleobases (See Table II above, Oligo E).
Regarding claims 8-10, ‘498 teaches all internucleotide linkages are phosphorothioate linkages (See Table II above).
Regarding claim 11, ‘498 teaches the antisense oligonucleotide is single- stranded (See Figure 2, Oligo E above).
Regarding claims 12 and 13, ‘498 teaches the modified ribonucleotides of the 5’ domain comprises a modified sugar which is 2’-OMe and that all internucleotide linkages are phosphorothioate linkages (See Table II above).
Regarding claim 16, ‘498 teaches an antisense oligonucleotide that is 100% complementary over its entire length to a portion of the target RNA (See Figure 2 above).
Regarding claims 17 and 18, ‘498 teaches the hybrid oligonucleotide phosphorothioates of the invention bind viral RNA or virus, pathogenic organism or cellular mRNA with greater affinity than ordinary oligodeoxynucleotide phosphorothioates (Example 3, page 23).
Regarding claim 19, ‘498 teaches a pharmaceutical composition of oligonucleotides in a pharmaceutically acceptable carrier (page 16, lines 14-22).
Regarding claims 32 and 33, ‘498 teaches 2’-OMe modified ribonucleosides in the 5’-domain (See Table II above Oligo E).
Therefore, it would have been obvious at the time of the effective filing date to substitute the 5’-most nucleotide of Oligo E which is a deoxyribonucleotide with a 2’-OMe ribonucleoside as in Oligo F with a reasonable expectation of success as the would amount to simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because ‘498 teaches Oligo F which has all 2’-OMe ribonucleosides in the 5’ domain is very resistant to phosphodiesterase and results indicate that the presence of 2’-OMe ribonucleosides in an oligonucleotide phosphorothioate enhances resistance to exonucleolytic digestion and this enhanced resistance increased when a larger proportion of 2’-OMe ribonucleotides are used (page 21, lines 3-7), and the presence of 2’-OMe ribonucleotides enhances duplex stability and this enhancement increases with increased proportions of 2’-OMe ribonucleosides and these results should be similarly applicable to hybrid oligonucleotide phosphorothioates and/or phosphorodithioates containing ribonucleotides, 2’-substituted ribonucleotides or mixtures of ribonucleotides and 2’-substituted ribonucleotides (page 20, lines 24-27; page 21, lines 3-7; page 23, lines 1-14). In addition ‘498 teaches oligonucleotides with preferably 6 or more ribonucleotides and/or 2’-substituted ribonucleotides to enhance duplex stability and which can be present singly, in pairs or in larger contiguous segments at any position within the oligonucleotide (page 11, lines 23-29), and the ability to vary the numbers and positions of phosphorothioate and/or phosphorodithioate internucleotide linkages, deoxyribonucleosides, and ribonucleosides or 2’-substituted ribonucleosides allows the investigator to examine how each of these variables affects parameters of nuclease resistance, duplex stability and Rnase H activation.
Accordingly, the limitations of claims 1,3,5,8-13,16-19,32 and 33 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious at the time of the effective filing date to modify the length of the 3’-domain to comprise 10 or 12 deoxyribonucleotides, which also modifies the positions of the nucleotides from the 3’-end in order to try different lengths of the 3’-domain to investigate how the length and positions of the deoxyribonucleotides in the 3’-domain affect nuclease resistance, duplex stability and Rnase H activation. One of ordinary skill in the art would be motivated to do so based on the teachings of ‘498 that the ability vary the numbers and positions of deoxyribonucleosides, and ribonucleosides or 2’-substituted ribonucleosides allows the investigator to examine how each of these variables affects parameters of nuclease resistance, duplex stability and Rnase H activation, and that each possible embodiment is useful in such studies (page 12, lines 3-14), and would make obvious the limitations of claims 2 and 4.
It would have been obvious at the time of the effective filing date, to provide all nucleotides of the 5’ domain as modified ribonucleotides in order to provide an antisense oligonucleotide that can be studied for how the number and types of modifications affect different properties of the antisense oligonucleotide. One of ordinary skill in the art would be motivated to do so based on the teachings of ‘498 that the ability to vary the numbers and positions of deoxyribonucleosides and ribonucleosides or 2’-substituted ribonucleosides allows the investigator to examine how each of these variables affects parameters of nuclease resistance, duplex stability and Rnase H activation, and that each possible embodiment is useful in such studies (page 12, lines 3-14), and would make obvious the limitations of claim 14.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant’s arguments and amendments, see pages 6-7, filed 09/11/2025, with respect to the rejection(s) of claim(s) 1,3,5,8-13,16-19,32 and 33 under 35 U.S.C. 102(a)(1) as anticipated by WO 94702498 have been fully considered and are persuasive due to the amendment to claim 1 reciting “the nucleotides of the 5’ domain are unmodified ribonucleotides, modified ribonucleotides, or combinations thereof...” and removing “comprises”, and therefore ‘498 no longer anticipates. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 1 regarding a case of obviousness.
Applicant argues on page 10 it would not be obvious to modify Oligo E to produce a product of the claims, and ‘498 already provides modifications to control Oligo A to determine how each of these variables affects the antisense oligonucleotide. Applicant argues as shown by ‘498 and as supported by Metelev, oligo 5 (Oligo E of ‘498) showed less anti-HIV activity than the unmodified, control oligonucleotide oligo 1 (Oligo A of ‘498) as evaluated by levels of p24 and syncytia. Applicant argues that data in Fig. 5 of Metelev showed that while Oligo E showed inhibition of p24, Oligo E was less active than the unmodified control Oligo A. In addition, inhibition of syncytia was examined which is used to demonstrate the virus’s infectivity and refers to Exhibit A: Chowdhury MI, et al. Applicant argues that while p24 was shown to be inhibited, the infectivity indicated by syncytia remains crucial for assessing inhibition, and as seen in Fig. 5, Oligo E had marginal anti-HIV activity based on syncytia where 5% of the cells contacted with Oligo E formed syncytia, in contrast 25-50% of cell contacted with the control Oligo A form syncytia, and 0-25% of cells contacted with Oligo C form syncytia. Applicant argues based on the promising data for Oligo C in ‘498 and Metelev, one skilled in the art would and did look to Oligo C for guidance on improving potentency of antisense oligonucleotides, as Oligo C, the so-called gapmer structure, has been the go-to format for antisense oligonucleotides (See Exhibit B: P. P. Seth and E.E. Swazye).
This is not found persuasive, because page 2932 of Metelev et al. teaches that all of the oligonucleotides inhibited virus replication in the acute HIV-1 infection assay. While oligonucleotides 3 and 4 were more potent, this does not mean that oligonucleotide 5 (Compound E) didn’t work at all, as it still inhibited virus replication, including significant inhibition compared to the control, and is therefore a suitable option, and does not cause ‘498 to teach away from the claimed invention. In addition, oligonucleotide 6 (Compound F of ‘498), which contains all modified ribonucleotides in the 5’ domain, was more resistant to nucleases and had greater affinity for the complementary RNA (pg 2932 of Metelev et al.).
Applicant argues on page 9 that as argued previously and demonstrated by the Vathipediekal Declaration, the product of the claims have a several-fold greater activity as compared to unmodified, control antisense oligonucleotide (similar to Oligo A/1 of ‘498/Metelev) and gapmer antisense oligonucleotides (similar to Oligo C/3 of ‘498/Metelev). It was unexpected that instant antisense oligonucleotides would be so potent and therefore, a person skilled in the art based on the teachings of the ‘498 publication would not be motivated to further modify Oligo E so that the 5’ domain was completely RNA and have a reasonable expectation of success that this modification would not only result in an oligonucleotide that was now more potent that unmodified, control Oligo A, but also more potent than Oligo C of ‘498.
This is not found persuasive because in order to show an unexpected effect, applicants must first show the expected effect. The target mRNA in the Declaration, PCSK9, and compounds 4 and 12-14 were found to have an over 2-fold greater activity at 25nM compared to compound 1 which is the unmodified phosphorothioate oligonucleotide similar to Compound A/1 of ‘498 and was unexpected that this would be so potent as explained in the Declaration. However, the target mRNA is not recited in the claims and therefore the unexpected results are not commensurate in scope with the claims, as no specific mRNA target and no sequences are recited. In addition, compounds 4 and 12-14 are found in the table on pages 49-50 of the instant specification. Based on the amended claims, these compounds do not fall within the scope of the claims. These sequences contain “T”, a deoxyribonucleotide, in the 5’ domain and do not comprise at least 4 modified ribonucleotides in the 5’ domain as required by the instant claims. If the 3’ domain is 12 deoxyribonucleotides in length, then compounds 4 and 12-14 do not contain the “at least 4 modified ribonucleotides” as required by the instant claims in the 5’ domain. Pages 49-50 do not explain or describe what the underlined nucleotides and lower case letters stand for in the table on pages 49-50. However, Table 1 on page 31 indicates that underlined = 2’-O-methyl phosphorothioate, and underlined and lowercase = 2’-O-methyl phosphodiester, so this is how the examiner is interpreting the table on pages 49-50. Therefore, the compounds with the best activity cited in the Declaration and instant specification do not fall within the current claim scope. Below are Compounds 4 and 12-14 found on pages 49-50 of the specification for reference.
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Regarding claim 14, wherein all of the nucleotides of the 5’ domain are modified ribonucleotides, no antisense oligonucleotides are shown in the results with this limitation on pages 49-50.
In addition, while the antisense oligonucleotides 3, 5 and 7 shown on pages 3-5 of the Declaration may have better activity than unmodified phosphorothioate ASOs and gapmer ASOs, this does not show that there would be an unexpected result of these antisense oligonucleotides because the ASOs in the Declaration contain deoxyribonucleotides in the 5’ domain and therefore are not commensurate in scope with the claims as the amended claims require only ribonucleotides in the 5’ domain. Also, none of the instant claims require that the 5’-most nucleotide be a modified ribonucleotide, as shown in the ASOs of the Declaration. Therefore the ASOs of the Declaration are not commensurate in scope with the claims for the reasons above.
Neither the specification, nor the Declaration filed 02/26/2025 show a single antisense oligonucleotide with the limitations of the as amended claims. Therefore, there can be no case for unexpected results as applicant has not provided any evidence of antisense oligonucleotides falling within the instant claim limitations.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over ‘498 as applied to claims 1-5,8-14,16-19,32 and 33 above, and further in view of Le et al. (RSC Adv., Vol. 7, 2017, 54542-54545), cited on an IDS dated 11/30/2021.
The teachings of ‘498 as applicable to claims 1-5,8-14,16-19,32 and 33 are described above.
While ‘498 teaches the nucleotides at the 9th,10th and 11th positions from the 3’ end comprise an unmodified nucleobase, ‘498 does not teach that at least one of the nucleotides of the 3’ domain comprises a modified nucleobase.
However, before the effective filing date, Le et al. teach that chemically-modified nucleotides is paramount to improve pharmacokinetics of AO-based therapeutic molecules (Introduction, page 54542), and teach the design and synthesis of 5’(phenyltriazol)-2’-deoxyuridine/2’-O-Me mixmer RNA AO’s and the evaluation of efficacy to induce exon-skipping in vitro (Introduction, page 54542). Le et al. teach a 20-mer antisense oligonucleotide containing two 5-(phenyltriazol)-2’-deoxyuridine nucleotides at positions 10 and 16 (ON1), and the other antisense oligonucleotide (ON2) containing two consecutive 5-(phenyltriazol)-2’-deoxyuridine nucleotides at positions 15 and 16 (See table 1, page 54543).
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Le et al. teach the benefit of incorporating nucleobase modified nucleotides such as 5-(phenyltriazol)-2’-deoxyuridine in reducing the cytotoxic effect of the 2’-O-MePS AO, and that the 5-(phenyltriazol)-2’-deoxyuridine building block is one of the nucleobase modifications that has demonstrated the most positive effects on the thermal duplex stability, but requires at least two of these modifications are placed consecutively (page 54544).
Therefore, it would have been obvious at the time of the effective filing date, to further modify Oligo E that has the 5’-most nucleotide as 2’-OMe ribonucleoside as in Oligo F of ‘498 with the nucleobase modifications in the 3’ domain as taught by Le et al., for the purpose of improving thermal duplex stability. One of ordinary skill in the art would have been motivated to provide 2 consecutive nucleotides of the 3’ domain at positions 15 and 16 of the antisense oligonucleotide with a modified nucleobase based on the teachings of Le et al. that incorporating nucleobase modified nucleotides such as 5-(phenyltriazol)-2’-deoxyuridine reduces the cytotoxic effect of the 2’-O-MePS AO, and that at least two of these modifications placed consecutively improves thermal duplex stability, and would make obvious the limitations of claims 6 and 7.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 09/11/2025 have been fully considered but they are not persuasive. Applicant argues on page 10 that as discussed above claim 1 is patentable over ‘498 and the secondary references fail to teach or suggested that the claimed products would possess the unexpected properties over the prior art.
This is not found persuasive because as the examiner responded above, amended claim 1 is obvious over ‘498 for the reasons above, and as Le et al. provides the teachings regarding the limitations of claims 6 and 7, the examiner is maintaining the obviousness rejection over claims 6 and 7.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over ‘498 as applied to claims 1-5,8-14,16-19,32 and 33 above, and further in view of Benizri et al. (Bioconjug Chem. 20 February 2019; 30(2): 366-383).
Claim Interpretation: The instant specification states that 5’-end blocking agent refers to a modification or motif linked to the 5’ end of the antisense oligonucleotide. Without wishing to be bound to a particular theory, the presence of a 5’ end blocking agent may prevent excision of the bound antisense oligonucleotide by RNase H beyond the 11th nucleotide from the 3’ end and for example target the RNA molecule between the 17th, and 18th positions from the 3’ end. Such 5’ end blocking agents may promote specificity, increased potency, in vivo stability and less off-target activity. 5’ end blocking agents include, but are not limited to, a non-ionic backbone modification, non-complementary overhanging nucleotides, 2’-substitued ribonucleotides, locked nucleic acid (LNA) nucleotides, acyclic nucleotides, inverted deoxyabasic moieties, a conjugate, a non-nucleotide moiety (page 27, lines 8-17).
The teachings of ‘498 as applicable to claims 1-5,8-14,16-19,32 and 33 are described above.
‘498 does not teach an antisense oligonucleotide comprising a 5’ blocking agent.
However, before the effective filing date, Benizri et al. teach antisense oligonucleotides and bioconjugated oligonucleotides which provide means to enhance tissue targeting, cell internalization, endosomal escape, target binding specificity, and resistance to nucleases (Abstract). Benizri et al. teach a GalNAc modification facilitates cell internalization and enables the oligonucleotide to escape the endosome, and can be positioned at the 3’ or 5’ extremities (pages 6-7).
Therefore, it would have been obvious at the time of the effective filing date, to modify the synthetic oligonucleotide of ‘498 according to the teachings of Benizri et al. to form a conjugate of the antisense oligonucleotide at the 5’ end with GalNAc in order to improve the cell internalization of the oligonucleotide. One of ordinary skill in the art would have been motivated to provide GalNAc conjugated to the 5’ end of the antisense oligonucleotide based on the teachings of Benizri et al. that a GalNAc modification facilitates cell internalization and enables the oligonucleotide to escape the endosome, and can be positioned at the 3’ or 5’ extremities (pages 6-7).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 09/11/2025 have been fully considered but they are not persuasive.
Applicant argues on page 10 that claim 1 as amended is patentable over ‘498 and that Benizri does not provide any teachings that ‘498 lacks.
This is not found persuasive because as the examiner responded above, amended claim 1 is obvious over ‘498 for the reasons above, and Benizri provides the teachings regarding the limitations of claim 15. Therefore, the examiner is maintaining the obviousness rejection over claim 15.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over ‘498 as applied to claims 1-5,8-14,16-19,32 and 33 above, and further in view of Morvan et al. (J. Am. Chem. Soc., 1996, 118, pages 255-256).
Claim Interpretation: Page 25, lines 24-27 of the instant specification discuss that representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino, thiodiester, thionocarbamate; siloxane; and N,N’-dimethylhydrazine. Therefore, the examiner is interpreting these linkages as examples of non-phosphorus containing internucleoside linking groups that are non-limiting.
The teachings of ‘498 as applicable to claims 1-5,8-14,16-19,32 and 33 are described above.
‘498 does not teach an antisense oligonucleotide containing a nonphosphorus-based modified backbone.
However, before the effective filing date, Morvan et al. teach the replacement of natural phosphodiester backbone with synthetic linkages in antisense oligonucleotides, and advanced studies on methylene (methylimino) (MMI) as a linkage for incorporation into AOs. (page 255, left column). Morvan et al. teach the MMI linkage is achiral and neutral, stable, readily incorporated into AOs, and that AO’s containing MMI linkages hybridize to complementary RNA with high affinity and base-pair specificity (page 255, left column).
Therefore, it would have been obvious at the time of the effective filing date, to modify the synthetic oligonucleotide of ‘498 with a non-phosphorus based backbone which is methylene (methylimino) for the purpose testing to see the improvement in hybridization of the antisense oligonucleotide to complementary RNA. One of ordinary skill in the art would have been motivated to provide an antisense oligonucleotide with a methylene (methylimino) backbone linkage in order to improve hybridization of the AO with complementary RNA with high affinity and base pair specificity.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 09/11/2025 have been fully considered but they are not persuasive.
Applicant argues on page 10 that claim 1 as amended is patentable over ‘498 and that Morvan does not provide any teachings that ‘498 lacks.
This is not found persuasive because as the examiner responded above, amended claim 1 is obvious over ‘498 for the reasons above, and Morvan provides the teachings regarding the limitations of claim 34. Therefore, the examiner is maintaining the obviousness rejection over claim 34.
Conclusion
No claims are allowed.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636