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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 04/14/2026 is acknowledged. Claims 1 and 33 were amended. Claims 35-49 are new. Claims 1-19 and 32-49 are pending and under examination.
Declaration Under 37 CFR 1.132
The Declaration under 37 CFR 1.132 filed 04/14/2026 is insufficient to overcome the rejection of claims 1-19 and 32-34 based upon 35 U.S.C. 103 as set forth in the last Office action because: It refer(s) only to the system described in the above referenced application and not to the individual claims of the application. Thus, there is no showing that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
The Declaration of 02/26/2025 shows specific sequences directed to specific target mRNA (PNPLA3, MAPT and SOD1), while no specific cellular target mRNA is recited in the instant claims and therefore the unexpected results are not commensurate in scope with the claims. In addition, the antisense oligonucleotides 3, 5 and 7 shown on pages 3-5 of the Declaration do not show that there would be an unexpected result of these antisense oligonucleotides because the ASOs in the Declaration contain deoxyribonucleotide(s) in the 5’ domain and therefore are not commensurate in scope with the claims that require only ribonucleotides in the 5’ domain. The Declaration on pages 3-5 says Orange G/A/C/T is 2’-substituted ribonucleotide, however the Examiner is unable to tell which nucleotides this pertains to in the sequences. Fig. 1 on page 3 of the Declaration is the only figure showing that ASO3 has a lower target mRNA level than ASO1 or ASO2. It is also noted that in Fig. 2 on page 4 of the Declaration, and Fig. 3 on page 5, it does not appear that the same unexpected effect happens, because over time the end result is the same/similar amount of target mRNA remaining at the same concentrations between ASO4 and ASO5 in Fig. 2, and ASO6 and ASO7 in Fig. 3. In Fig. 2, while the ASO4 and ASO 5 have different IC50 values, both ASOs achieve the same or similar effect as the concentration of the ASO increases. This is a difference in degree, not kind. The same is true for Fig. 3 where both ASO6 and ASO7 achieve a similar effect as the concentration of the ASO increases. The instant claims to do not require any concentrations or any particular effect. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02. Therefore, the data provided in the Declaration does not always support the unexpected effect Applicant is claiming.
Withdrawn Objections/Rejections
Applicant’s arguments and amendments, see page 8, filed 04/14/2026, with respect to objection to claim 1 have been fully considered and are persuasive due to the amendment to claim 1 removing the dash in line 10 The objection has been withdrawn.
Applicant’s arguments, see pages 24-28, filed 04/14/2026, with respect to the 35 U.S.C. 112(a) rejection of claims 1-19 and 32-34 for new matter have been fully considered and are persuasive due to Applicant’s argument regarding the amendment being a narrowing claim amendment of a Markush grouping. The 35 U.S.C. 112(a) rejection of claims 1-19 and 32-34 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.
Rejections Necessitated by Amendment
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 35 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 35 depends on claim 1, and recites “wherein the 5’ terminal nucleotide is a ribonucleotide (RNA)”. Claim 1 already requires that the nucleotides of the 5 domain be unmodified ribonucleotides, modified ribonucleotides or combinations thereof, and therefore already requires the 5’ terminal nucleotide to be a ribonucleotide. Therefore, claim 35 does not further limit claim 1. Claims 36-38 are not included in the rejection because they further limit the 5’ terminal ribonucleotide with a modification that is further limiting than 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 Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-5,8-14,16-19,32,33 and 35-49 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 1,3 and 39-49, ‘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 claim 1 requires the 5’ domain nucleotides are ribonucleotides, and does not teach the 5’ terminal nucleotide is a ribonucleotide.
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 2,4,14 and 35-37, ‘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 2,4,14,35-37,39-43,45,46,48 and 49.
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 32,33,38,44 and 47, ‘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 and to modify the sequence so that the sequence binds to a portion of a cellular target RNA sequence 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. One of ordinary skill in the art would have been motivated to provide an antisense oligonucleotide that is complementary to a portion of a cellular target RNA sequence because ‘498 also taught that 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).
Accordingly, the limitations of claims 1,3,5,8-13,16-19,32-33 and 49 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, or wherein the 5’ terminal nucleotide is an RNA, 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 claims 14 and 35-48.
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 8-23, filed 04/14/2026, with respect to the rejection(s) of claims 1-5,8-14,16-19,32 and 33 under 35 U.S.C. 103 as unpatentable over ‘498 have been fully considered but are not persuasive.
Applicant provides an explanation of the state of the art regarding antisense oligonucleotides and gapmers on pages 8-9, an explanation of the instant invention on pages 9-10, and an explanation of WO 1994/02498 (‘498) on pages 10-11. Applicant states the legal standard for obviousness and MPEP 2142. Applicant argues on pages 12-13 that the Examiner has not established a prima facie case of obviousness as the basis for maintaining this rejection improperly relies on a teaching of the instant application and requires a person of ordinary skill in the art to ignore the teachings of ‘498 and the past 30 years of antisense oligonucleotide design where the gapmer structure dominated, and even if a prima facie case of obviousness has been made, the evidence of record rebuts the rejection. Applicant argues that regarding Oligo E of ‘498 as the starting point for chemical modification, one skilled in the art would not and did not look to Oligo E as a starting point for further modification based on the teachings of ‘498, and the starting point for a POSITA was Oligo C, a gapmer. 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. 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 75% 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. In Example 4 of ‘498 Oligo F did not activate RNase H at all. Applicant cites Procter & Gamble Co. v. Teva Pharm. USA, Inc., regarding selecting a starting point for chemical modification, and therefore as the critical objective of ‘498 was to improve the antisense activity of oligonucleotide phosphorothioates, one of skill in the art would not look to, nor select Oligo E as it was less active than Oligo A, and because it lacked 2’-O-methyloligoribonucleotides at the 3’ end, it did not have increased stability. Applicant argues one skilled in the art would and did look to Oligos C and D which have RNA at the 5’ and 3’ ends, and refers to the Agrawal Declaration. In addition, the attached Declaration by Dr. Agrawal, gapmer Oligos C and D became the structural design for antisense oligonucleotides, and therefore, one skilled in the art based on ‘498 would not have selected Oligo E nor modified this compound with a reasonable expectation of success for improving properties of ASOs.
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.). In addition, the rejection is made under 103 and does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. In addition, the Examiner did not solely rely on just Table II and the results thereof, but also relied on and cited more general teachings and broader disclosure in the 103 rejection for providing motivation based on the teachings of ‘498 which teaches 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), and that 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). The Examiner stated in the 103 rejection that ‘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).
Applicant argues on page 16, even if one of skill in the art would select Oligo E, ‘498 would not motivate one to modify the 5’ A, and instead one would be motivated to make a gapmer and add RNAs to the 3’ end. Applicant argues the sole motivation for selecting is the structural similarity of Oligo E to the instant claimed compounds and the motivation to select Oligo F to make the modification of the 5’ most nucleotide is because Oligo F has a 5’ RNA, and that this is hindsight. Applicant argues on page 17, that the Examiner stating the predictable result is increased resistance to phosphodiesterase is factually incorrect and mischaracterizes the teaching of ‘498. Applicant argues the Examiner ignores that essentially all of the 3’ domain is also 2’-OMe ribonucleotides, whereas the instant claims require that the 3’ domain be DNA, and there is no teaching or suggestion in ‘198 that the stability of oligonucleotide F was a result of the 5’ terminal DNA nucleotide (A) being substituted with 2’-OME modified A nucleotide. The only oligonucleotides that had increased resistance were those that had RNA at the 3’ end (Oligos B,C,D and F). Therefore, one skilled in the art would not have singled out the 5’ terminal nucleotide as suggested by the examiner. Applicant argues in addition, Oligo F did not activate RNase H which is a critical property. The Examiner has provide no evidence that substituting the 5’A with a 2’-OMe ribonucleoside while ignoring the additional 10 nucleotides of Oligo F that are modified, especially at the 3’ end would have any effect on the properties of Oligo E, and the allegation of the expected results being improved stability is speculation.
The examiner does not agree that there is not motivation or a reasonable expectation of success to provide additional ribonucleotides, particularly 2’-OMe ribonucleotides in the 5’ region, including the 5’ terminal ribonucleotide, as ‘498 taught enhanced resistance to exonucleolytic digestion was increased when a larger proportion of 2’-OMe ribonucleotides are used. In addition, regarding the argument about the Examiner ignoring that essentially all of the 3’ domain is also 2’-OMe ribonucleotides, whereas the instant claims require that the 3’ domain be DNA, the Examiner did not state in the rejection that Compound E was being modified in the 3’ domain with 2’-OMe ribonucleotides, but rather “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”. It seems based on the general teachings of ‘498 that increasing 2’-OMe ribonucleotides in the hybrid oligonucleotide is associated with increased stability (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). It seems equally obvious for the 5’ terminal nucleotide to also be RNA, including 2’-OMe ribonucleotides. In addition, it is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV). The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Applicant argues on page 18 that although the Examiner correctly characterizes the general teachings of ‘498, the Examiner improperly concludes that the ability to examine how each of these variables affects the parameters is the same as predictability and obviousness, and cites Takeda Chemical Industries Ltd v. Alphapharm Pty. Ltd, and the issue is not whether one can simply swap a DNA nucleotide for an RNA nucleotide. The mere fact that a compound could be modified in a particular way does not establish that one of skill in the art would be motivated to make that modification and a myriad of other modifications can also be envisioned. Applicant cites MPEP 2143, Example 9, Eisai Co. Ltd. V. D. Reddy’s Labs, Ltd.
In which the Federal Circuit affirmed the district court’s summary judgement of nonobviousness, stating that no reason had been advanced to modify the prior art compound in a way that would destroy an advantageous property. One would not look to Oligo F which has no RNaseH activation activity to modify Oligo E with an expectation of successfully acquiring an active ASO.
This is not found persuasive because the Examiner has stated the motivation to modify Oligo E (specifically to substitute the 5’-most nucleotide of Oligo E which is a deoxyribonucleotide with a 2’-OMe ribonucleoside as in Oligo F) is that ‘498 teaches that 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) and therefore the motivation is to enhance stability. As stated above, the motivation to modify may be for a different purpose or to solve a different problem.
Applicant argues on page 19 the claims have been amended to require cellular targets, as Oligo E targets a viral sequence, not a cellular sequence, and the claimed compounds now require at least two significant structural modifications over Oligo E.
This is not found persuasive. It is noted that the non-final rejection cited ‘498 as teaching “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 9-14 of ‘198, and page 10 of the Office Action mailed 12/16/2025). Therefore, the amendment does not overcome the rejection, as ‘498 was already cited for teaching that the hybrid oligonucleotides of the invention should bind cellular mRNA with greater affinity than ordinary oligodeoxynucleotide phosphorothioates, and already provides a case of obviousness for this limitation.
Applicant argues on pages 20-21 that as shown previously and demonstrated by the Vathipediekal Declaration, the splitmer antisense oligonucleotides of the claims have an increase in antisense potency of 2-fold to 33-fold as compared to unmodified, control antisense oligonucleotide (similar to Oligo A of ‘498) and gapmer antisense oligonucleotides (similar to Oligo C of ‘498). It was unexpected that instant antisense oligonucleotides would be so potent. Applicant notes that the Examiner did not find the previous Declaration to be persuasive because the Examiner stated in order to show an unexpected effect, applicants must first show the expected effect and the ASOs in the Declaration contains deoxyribonucleotides in the 5’ domain and therefore are not commensurate in scope with the claims, and Applicant disagrees, as the Examiner has not cited any case law or explain the point regarding how one might show what the expected property might be, and it is not true that the burden is on the Applicant to “show the expected result” of a modification in order to establish an unexpected result, and the burden of proof rests with the Office in making a prima facie case of obviousness. Applicant disagrees that the expected results would be improved stability as suggested by the Examiner, as the fact that Oligo F may be more stable (as well as inactive) with 11 structural changes as compared to Oligo E does not logically support the argument that any one of those structural changes alone with result in improved stability (with or without activity). Applicant has shown that splitmers according to the claimed invention markedly have improved potency over prior art gapmers, and there is nothing in the record that shows improved potency is the expected result, as Oligo E does not have improved potency over Oligo A or C, and Oligo F (the oligo the examiner has chosen to rely on) was not more potent. Applicant believes that this is beyond dispute that improved potency was unexpected and cites In re Chupp. Additionally, the Vathipadiekal Declaration provided additional data demonstrating that splitmer ASOs directed to PNPLA3 (ASO3), MAPT(ASO5) and SOD1 (ASO7) were superior to both unmodified phosphorothioate antisense oligonucleotides and gapmer oligonucleotides, and Applicant provide the ASO3 splitmer having 10 nucleotides in the 3’ domain, the ASO5 splitmer having 11 nucleotides in the 3’ domain and the ASO7 spitmer having 12 nucleotides in the 3’ domain. Additionally, the data demonstrated that PNPLA3 unnmodified control ASO1 and gapmer ASO2 were inactive, only the claimed splitmer ASO3 showed potent inhibition of the target; MAPT splitmer (ASO5) was 33 fold more potent than gapmer (ASO4) and SOD1 splitmer (ASO7) was 2.5 fold more potent than gapmer (ASO6). Given the compounds in the declaration are structurally diverse and show activity against multiple targets, the evidence of the Declaration is commensurate in scope with the claims. The fact that three different splitmers were more potent against three different targets was unexpected and cites MPEP Sec. 2145.
This is not found persuasive. Firstly, the Declaration of 02/26/2025 shows specific sequences directed to specific target mRNA (PNPLA3, MAPT and SOD1), while no specific cellular target mRNA is recited in the instant claims and therefore the unexpected results are not commensurate in scope with the claims. In addition, the antisense oligonucleotides 3, 5 and 7 shown on pages 3-5 of the Declaration do not show that there would be an unexpected result of these antisense oligonucleotides because the ASOs in the Declaration contain deoxyribonucleotide(s) in the 5’ domain and therefore are not commensurate in scope with the claims that require only ribonucleotides in the 5’ domain. The Declaration on pages 3-5 says Orange G/A/C/T is 2’-substituted ribonucleotide, however the Examiner is unable to tell which nucleotides this pertains to in the sequences. Fig. 1 on page 3 of the Declaration is the only figure showing that ASO3 has a lower target mRNA level than ASO1 or ASO2. It is also noted that in Fig. 2 on page 4 of the Declaration, and Fig. 3 on page 5, it does not appear that the same unexpected effect happens, because over time the end result is the same/similar amount of target mRNA remaining at the same concentrations between ASO4 and ASO5 in Fig. 2, and ASO6 and ASO7 in Fig. 3. In Fig. 2, while the ASO4 and ASO 5 have different IC50 values, both ASOs achieve the same or similar effect as the concentration of the ASO increases. This is a difference in degree, not kind. The same is true for Fig. 3 where both ASO6 and ASO7 achieve a similar effect as the concentration of the ASO increases. The instant claims to do not require any concentrations or any particular effect. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02. Therefore, the data provided in the Declaration does not always support the unexpected effect Applicant is claiming.
Applicant concedes that they do not compare its splitmers with an oligo that differs from the claimed invention solely in the 5’ most nucleotide, and one possibility is that the ‘498 data is incorrect and Oligo E is more potent than Oligo A and C, and a second possibility is that there is something about the assay that renders Oligo E inferior. It is impossible to retest Oligo E to see if in fact the reference is just wrong or there is another technical reason for Oligo E’s inferiority because the HIV assays are no longer available and cannot be safely recreated.
The Examiner acknowledges that Applicant admits that no comparison to its splitmers with an oligo that differs from the claimed invention solely in the 5’ most nucleotide has been done, and that there are potential incorrect data in ‘498, however without this information, it is not possible to determine if the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art. The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Note: MPEP 716.02(d).
In summary, neither the specification, nor the Declaration filed 02/26/2025 or 04/14/2026 show an 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 1-5,8-14,16-19,32,33 and 35-49 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 1-5,8-14,16-19,32,33 and 35-49 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 04/14/2026 have been fully considered but they are not persuasive. Applicant argues on page 23 that above claim 1 is patentable over ‘498 and the secondary references fail to teach or suggest anything 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 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 1-5,8-14,16-19,32,33 and 35-49 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 1-5,8-14,16-19,32,33 and 35-49 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 04/14/2026 have been fully considered but they are not persuasive.
Applicant argues on page 24 that claim 1 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 1-5,8-14,16-19,32,33 and 35-49 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 1-5,8-14,16-19,32,33 and 35-49 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 04/14/2026 have been fully considered but they are not persuasive.
Applicant argues on page 24 that claim 1 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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