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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 5, 2026 has been entered.
Application Status
Applicant’s remarks and amendments to the claims filed June 5, 2026 are acknowledged. Claim 45 was amended. Claims 45-64 are pending.
Restriction/Election
Claims 61-64 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 45-60 are under consideration hereinafter.
Priority
Applicant’s claim for priority based on Application No. PCT/EP2022/083943, filed November 30, 2022, and PCT/EP2023/083741, filed November 30, 2023 is acknowledged. It is noted that a copy of PCT/EP2022/083943 has not been retrieved by the Office, although Applicant has provided access to the application via the Priority Document Exchange (see filing receipt dated September 16, 2025). Nevertheless, Examiner has reviewed the contents of the as-filed applications in WIPO PatentScope. The claims under examination find support in PCT/EP2022/083943, and therefore, the effective filing date of the claims is November 30, 2022.
Withdrawn Rejections
Applicant’s remarks and amendments to the claims have been considered. Applicant’s remarks with respect to the amended claims, and specifically, with respect to the particular linkages in the “core sequence” which are required to be phosphorothioate linkages (a, d, e, and f), phosphodiester linkages (h), and which must be either phosphodiester or phosphorothioate linkages (at least 2 of b, c, g, and j, and up to 2 of b c, g, and j, respectively), are convincing to overcome the prior art rejections of record. While the prior art provides guidance to prepare chemically modified oligonucleotides with different linkage types, and suggests avoiding phosphorothioate linkages in particular regions of an oligonucleotide (i.e., in the vicinity of the ADAR contact region), which would motivate the skilled artisan to modify the linkages of prior art oligonucleotides, Examiner agrees with Applicant that neither the teachings of Moelhart Hoeg nor Merkle, nor the remaining prior art reviewed during the updated search, teach or suggest a chemically modified oligonucleotide with the specific linkages required of the recited oligonucleotide. The instantly claimed chemically modified oligonucleotide requires phosphorothioate linkages at several linkages (d, e, and f) adjacent to the target adenosine, which are, therefore, within the ADAR contact region. Based on the prior art, Examiner agrees that the skilled artisan would have likely exchanged at least these linkages of a phosphorothioated prior art chemically modified oligonucleotide (e.g., CMP 26_8 of Moelhart Hoeg) for phosphodiester linkages. The prior art rejections raised in the previous action, as well as the non-statutory double patenting rejections raised over co-pending Application Nos. 18/565,415 and 18/565,733 in view of the prior art, are withdrawn, accordingly.
Applicant’s remarks and amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. Any rejection or objection not reiterated herein has been overcome by amendment.
Claim Rejections - 35 USC § 112(a) – Written Description
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 45-60 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. The rejections that follow are new.
MPEP 2163.II.A3.(a).(i) states the following:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Species Encompassed
Claim 45 recites a chemically modified oligonucleotide that is 23-38 nucleosides in length, and comprises a sequence complementary to a target sequence in SERPINA1 mRNA. Each nucleotide of the oligonucleotide is selected from 2’-OMe modified nucleoside, 2’-MOE modified nucleoside, 2’-F modified nucleoside, and 2’-deoxyribonucleoside. At least 50% of the linkages in the oligonucleotide are phosphorothioate, and the oligonucleotide “does not comprise a stereopure PS linkage,” which is interpreted as encompassing oligonucleotides in which the stereochemistry of phosphorothioate linkages is not controlled. This limitation, therefore, reads on oligonucleotides in which each phosphorothioate linkage may have an Rp or Sp configuration.
The oligonucleotide comprises a CBT of 3 nucleosides (5’-N-1 N0 N+1-3’), wherein N0 is directly opposite to a target adenosine to be edited to an inosine, wherein the target adenosine is the result of a G to A mutation in SERPINA1 gene that results in a E342K substitution in the A1AT protein. The oligonucleotide comprises at least 4 nucleosides 3’ of the CBT, and at least 16 nucleosides 5’ of the CBT. The oligonucleotide comprises a core sequence with the formula in claim 45 which comprises the CBT, wherein N0 is a deoxycytidine, N+2 is a 2’-OMe modified nucleoside, and N+3 is a 2’-F modified nucleoside, and at least 2/3 nucleotides of the CBT are modified at the 2’ position or are deoxyribonucleosides, or a combination thereof (e.g., N0 is deoxycytidine and N+1 is 2’ modified, or both N0 and N+1 are deoxyribonucleosides). Linkages a, d, e, and f are phosphorothioate linkages, linkage h is a phosphate linkage (“PO”), which is understood to refer to a phosphodiester linkage, and up to 2 linkages from b, c, g, and j are phosphorothioate linkages, and at least 2 linkages from b, c, g, and j are phosphodiester linkages.
Claim 46 recites that the oligonucleotide comprises one or more mismatches, wobble bases, and/or bulges with respect to the target sequence. Claims 47-54 recite further limitations to the nature of the 2’-modifications, and encompass oligonucleotides with particular percentages of 2’-F, and 2’-OMe modified nucleosides, and oligonucleotides without continuous stretches of more than four 2’-OMe nucleosides, and/or more than seven 2’-MOE nucleosides. Claim 55 encompasses oligonucleotides with one or more 3’-phosphoroamidate linkages. Claim 56 encompasses oligonucleotides which do not comprise “a loop-hairpin structured ADAR recruitment motif,” which is interpreted as excluding oligonucleotides which form an intramolecular hairpin or stem-loop structure ([0012]).
Accordingly, claims 45-56 encompass a genus of chemically modified oligonucleotides which vary in length (between 23-38 nucleosides), linkage chemistry and content beyond the five linkages with specific linkage chemistry (i.e., linkages a, d, e, f, and h), and 2’ chemistry and content beyond the three nucleosides with specific 2’ chemistry (i.e., nucleosides N0, N+2, and N3). The oligonucleotides may comprise essentially any sequence, with any number of bulges/mismatches/wobble bases/etc. provided the sequence is “complementary” to a SERPINA1 target sequence, and comprises a deoxycytidine at position N0. The genus is chemically diverse, and includes many distinct species. The specification has not sufficiently described the genus of chemically modified oligonucleotides which facilitate editing of a target adenosine to an inosine, wherein the target adenosine is the result of a G to A mutation in SERPINA1 gene that results in a E342K substitution in the A1AT protein.
Species Described in the Specification
The specification describes several specific species in the genus which facilitate editing of a target adenosine to an inosine, wherein the target adenosine is the result of a G to A mutation in SERPINA1 gene that results in a E342K substitution in the A1AT protein. The species are set forth in Tables 9-10, and 21. Specifically, the species corresponding to SEQ ID NOs: 64, 66-74, 77-82, and 136-138, which are between 31 and 38 nucleosides in length, and comprise a minimum of 23 nucleosides 5’ of the CBT, and 5 nucleosides 3’ of the CBT. With respect to linkages b, c, g, and j, the SEQ ID NOs comprise PO linkages at linkages b, c, and g, and a PS linkage at linkage j. SEQ ID NOs: 73-74 and 77-82 also comprise an additional PS linkage at linkage i. The species have specific sequences and appear to be fully complementary to SERPINA1 mRNA, barring the presence of “dI” at nucleoside N+1. The species have specific linkage chemistry and content, and 2’ chemistry and content.
In addition to the particular species within the genus, the specification provides general guidance applicable to the design of oligonucleotides, which is gleaned from data generated using the species in editing experiments. The specification provides that “blocks of continuous sugar modifications should be avoided, and certain levels of 2’-F and 2’-OMe modifications included to obtain efficient editing yields, as all embodiments contain uniform 2’-modification blocks that do not exceed 6 nt, or even 3 nt” ([0222]). The speciifcation provides that “shortening of the 3’ terminus is tolerated to a length of about 5 nts 3’ of the CBT,” and that “5’ terminus shortening strongly decreases the overall editing efficacy of the oligonucleotides” ([0222]). The specification provides that the claimed ASOs “might benefit from a reduced amount of DNA nucleosides (≤ 6 nt) outside the CBT,” and that “a higher 2’-F content (ranging between 40.6-57.6%...) is well tolerated and even preferable” ([0225]). The specification concludes that “effective editing efficacy [of] ASOs with a length of 30 nt (or “sweet spot” of around 33/32 nt)… are dependent on certain modification rules” ([0226]). The specification, while alluding to the existence of such rules, does not appear to establish such rules, or reference prior art which establishes such rules.
Taken together, the specification provides specific species in the genus, which do not represent the full scope of the claimed genus, because unlike the claimed genus, they possess a specific nucleobase sequence and therefore, level of complementarity to the SERPINA1 mRNA, specific linkage chemistry and content across the entire oligonucleotide, lengths between 31-38 nucleosides, and specific 2’ chemistry and content across the entire oligonucleotide. The claimed genus is comparably unlimited, and, based on the specification encompasses many species which may not facilitate editing of a target adenosine to an inosine, wherein the target adenosine is the result of a G to A mutation in SERPINA1 gene that results in a E342K substitution in the A1AT protein. For example, species which comprise different sequences than those particularly described, and comprise any number of mismatches relative to the SERPINA1 mRNA, species which comprise particular 2’ groups at particular locations, or in continuous stretches, or in overall contents which unsuitable for ADAR editing, species which comprise particular linkages at particular locations, or in overall contents which are unsuitable for ADAR editing, or species which are between 23-30 nucleosides in length, or which comprise only 4 nucleosides 3’ of the CBT or 16 nucleosides 5’ of the CBT, or which comprise 2’-MOE nucleosides, or which comprise phosphoramidate linkages for which the specification provides no guidance. While the skilled artisan could certainly prepare the oligonucleotides encompasses by the genus, the specification does not provide sufficient guidance to the skilled artisan to predict which of the many, chemically diverse species would actually function as a SERPINA1 editing oligonucleotide.
Guidance in the Prior Art
The prior art describes chemically modified oligonucleotides which facilitate editing of a target adenosine which results from a G to A mutation in SERPINA1 gene, and that results in a E342K substitution in the A1AT protein. See disclosures of Moelhart Hoeg (of record) and Merkle (of record), which were discussed in the previous actions. However, a search of the prior art failed to uncover any species in the instantly claimed genus.
The prior art provides general guidance regarding the length, 2’ chemistry and content, and linkage chemistry and content of chemically modified oligonucleotides. For example, with respect to length, the prior art teaches that “symmetry and length” are “very important” parameters of oligonucleotides (Merkle, pg. 45). The prior art would suggest to the skilled artisan that an oligonucleotide must comprise sufficient nucleosides for ADAR binding (Merkle, pgs. 45-46). The prior art suggests that certain oligonucleotides encompassed by the claims may not function, e.g., oligonucleotides comprising fewer than 20 nucleotides 5’ of the central nucleoside, when accompanied by fewer than 49 nucleotides 3’ of the central nucleoside (Merkle, Fig. 12; “10-1-49,” “15-1-15”). The prior art also teaches that an asymmetrical 24-1-10 oligonucleotide 35 nucleosides in length was not functional (pg. 52-53). Given that the specification describes functional oligonucleotides with similar lengths to the non-functional prior art oligonucleotide, this suggests that the function of shorter oligonucleotides is unpredictable, and may be dependent on the target (and therefore the oligonucleotide’s nucleobase sequence), or effect of length and/or symmetry with 2’ and/or linkage chemistry and content, etc.
With respect to linkage chemistry, the prior art suggests that PS linkages stabilize oligonucleotides, but may also impede ADAR binding in the vicinity of the target adenosine (see Merkle, pgs. 49-50). The prior art also suggests that PS linkages may be particularly important for shorter oligonucleotides (see Merkle, pg. 53). Beyond generic guidance, the prior art does not appear to provide linkage chemistry and content rules which are applicable to all chemically modified oligonucleotides, particularly with different sequences, lengths, and 2’ chemistry and content.
Finally, regarding 2’ chemistry and content, the prior art teaches that the three nucleosides opposite the target adenosine should be DNA nucleosides, because these nucleosides are “sensitive to 2’-OMe modifications” (Merkle, pg. 57). The prior art suggests that that 2’-MOE modified oligonucleotides are not functional (Merkle, pg. 57), and that oligonucleotides with high content of 2’-F and 2’-OMe nucleosides may function poorly (Merkle, pg. 56-57). The prior art teaches that 2’-OMe and 2’-MOE probably “severely interfere[] with dsRBD binding,” and that 2’-F, owing to its ability to “mimic[] closely the 2’-OH group in RNA,” is the most preferred modification (pg. 59). However, again, the prior art does not appear to provide 2’ chemistry and content rules which are applicable to all chemically modified oligonucleotides, particularly with different sequences, lengths, and linkage chemistry and content, etc.
Taken together, the prior art does not appear to provide any species within the claimed genus, and, beyond providing generic guidance as to the approximate length and symmetry, and 2’ and linkage content and chemistry, the prior art does not provide any means for the skilled artisan to reasonably predict which of the many, chemically diverse species within the genus will facilitate editing of a target adenosine to an inosine, wherein the target adenosine is the result of a G to A mutation in SERPINA1 gene that results in a E342K substitution in the A1AT protein.
Conclusion
Considering the large variation in the genus, the small percentage of species described in the specification, and the lack of predictability provided by the art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Dependent Claims
Claims 57-60 are rejected for depending from the claim(s) analyzed above and failing to remedy the lack of written description described above. The claims do not further limit the structure of the chemically modified oligonucleotide so as to resolve the reasons for insufficient written description described above.
Conclusion
No claims are allowed.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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