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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 11, 2026 has been entered.
Application Status
Applicant’s remarks and the listing of the claims filed September 11, 2026 are acknowledged. No claim amendments were made. Claims 1-6, 9-11, 13, and 16-18 are pending and under examination herein.
Priority
Acknowledgement is made of Applicant’s claim for priority to Application No. EP21211372.4. The certified copy of Application No. EP21211372.4 has been received. Claims 1-6, 9-11, 13, and 16-18 find support in Application No. EP21211372.4, and therefore, the effective filing date of the claims under examination is November 30, 2021.
Withdrawn Rejections
Applicant’s remarks 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, and e) and phosphodiester linkages (b and c) 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, neither the teachings of Merkle nor Boudet, 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 (i.e., d and e in claim 1, and f, in claim 3) adjacent to the target adenosine, which are, therefore, within the ADAR contact region. Based on the prior art, the skilled artisan would have likely exchanged at least these linkages of a phosphorothioated prior art chemically modified oligonucleotide (e.g., “v117.25” of Merkle) for phosphodiester linkages. The § 103 rejections raised in the previous action over Merkle and Boudet are withdrawn, accordingly.
With respect to the non-statutory double patenting rejections raised over co-pending Application Nos. 17/256,092, 18/565,733, and 18/565,415, in view deficiencies of the prior art described above, the co-pending claims cannot render obvious the instant claims. With respect to the non-statutory double patenting rejections raised over co-pending Application No. 19/223,597, the co-pending claims recite several of the phosphorothioate linkages recited in the instant claims (i.e., “wherein a, d, e, and f are phosphorothioate (PS) linkages”), but are generic with respect to the linkages which are phosphate linkages (“at least 2 of internucleoside linkages b, c, g, and j are phosphate (PO) linkages, and internucleoside linkage h is a PO linkage”), the structure of the Nu +1 nucleotide, and the remaining phosphorothioate and phosphodiester linkages required of the instant claims. In view of the deficiencies of the prior art described above, the co-pending claims of Application No. 19/223,597 also cannot render obvious the instant claims.
Applicant’s remarks and amendments have been thoroughly considered. The response is not sufficient to place the claims in condition for allowance for the reasons that follow. Any objection or rejection not reiterated hereinafter 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 1-6, 9-11, 13, and 16-18 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 1 recites a chemically modified oligonucleotide for site-directed A-to-I editing of a target RNA inside a cell with endogenous ADAR that has a length of 30-60 nucleosides, and is capable of binding to a target sequence in the target RNA. The oligonucleotide comprises a CBT of 3 nucleotides (5’-Nu-1 Nu0 Nu+1-3’), wherein Nu0 is directly opposite to a target adenosine to be edited to an inosine. The oligonucleotide comprises a core sequence with Formula I which comprises the CBT, wherein Nu+1 comprises hypoxanthine or 2’-deoxy-inosine, at least linkages a, d, and e are phosphorothioate linkages, and at least linkages b and c are phosphate linkages (“PO”), which is understood to refer to a phosphodiester linkage. The CBT is flanked at the 5’ end by a 5’ flanking sequence at least 19 nucleotides in length, and flanked at the 3’ end by a 3’ flanking sequence at least 4 nucleotides in length, wherein the 5’ flanking sequence is longer than the 3’ flanking sequence.
Claim 2 recites that linkages h and i are also PO linkages. Claims 3-6, and 16-17 encompass further limitations of the phosphorothioate linkages of the oligonucleotide, wherein f, j, and/or g are additionally phosphorothioate linkages. Claims 9-10 encompass oligonucleotides with particular percentages of 2’-modified nucleosides outside of the CBT, oligonucleotides with particular percentages of 2’-fluoro, 2’-OMe, and 2’-H nucleosides throughout the core sequence, oligonucleotides with at least 2/3 CBT nucleotides comprising 2’-modifications, and oligonucleotides without continuous stretches of more than six 2’-OMe nucleosides. Claim 11 encompasses oligonucleotides comprising 2’-H at each nucleotide of the CBT. Claim 13 encompasses oligonucleotides wherein N0 comprises a cytosine. Claim 18 encompasses oligonucleotides which “do[] not comprise stereopure phosphorothioate linkages,” 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.
Accordingly, claims 1-6, 9-11, 13, and 16-18 encompass a genus of chemically modified oligonucleotides which comprise 30 or more nucleotides (“has a length of 30 to 60 nucleotides”), and vary in 2’- and linkage chemistry and content. The oligonucleotides may comprise essentially any sequence, with any number of bulges/mismatches/wobble bases/etc. provided the sequence is “capable of binding to a target sequence,” which is interpreted as having some level of complementarity to a target sequence, and comprises either a hypoxanthine or 2’-deoxy-inosine at position Nu+1. Only five linkages of the 30 or more nucleotides require specific linkage chemistry (i.e., linkages a, b, c, d, and e). The genus is chemically diverse, and includes many distinct species. The specification has not sufficiently described the genus of chemically modified oligonucleotides which can be used for editing of a target adenosine to an inosine in a target RNA inside a cell with an endogenous ADAR.
Species Described in the Specification
The specification describes several specific species in the genus which facilitate editing of a target adenosine to an inosine in a target RNA based on the examples in the disclosure. The species are set forth in Tables 1, 5, and 7. Specifically, the species corresponding to SEQ ID NOs: 5, 7-10, 21-23, and 27 which are each 59 nucleosides in length, and comprise at least 19 nucleosides 5’ of the CBT, at least 4 nucleosides 3’ of the CBT, and comprise a 2’-deoxy-iosine at Nu+1. With respect to linkages, the SEQ ID NOs comprise PO linkages at least at linkages b and c, and optionally h, and/or i, and PS linkages at least at linkages a, d, e, and optionally f, g, and/or j. The species have specific sequences and appear to be fully complementary to their target RNAs, barring the presence of “dI” at nucleoside Nu+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 the prior art and data generated using the species in editing experiments. For example, the specification states that “[i]f the chemical modification of the oligonucleotide is too extensive, the efficacy of the editing is reduced to an unacceptable level” (pg. 6). The specification does not appear to provide sufficient guidance to determine which of the many known modifications, and in what content, would be “too extensive.” The specification cautions against “uniform and block-wise 2’-O-methyl modification,” but does not appear to provide guidance as to unacceptable block length (pg. 7). The specification provides that “many chemical modifications… have an influence on the properties of the oligonucleotides” (pg. 8); however, the specification describes the influence of only a few of the recited modifications with respect to the oligonucleotides of the instant invention. The specification states that “[t]he phosphorothioate pattern in the core sequence of formula I is of utmost importance,” and explicitly warns against full modification of linkages a-j, and placing phosphorothioate linkages at positions h and i (pg. 11; pg. 18). However, the specification does not appear to describe the function of sufficient combinations of phosphorothioate/phosphate linkages, e.g., across longer or shorter oligonucleotides, or asymmetric oligonucleotides, or less than fully complementary oligonucleotides, to provide the skilled artisan with guidance to determine which oligonucleotides in the genus will function.
The specification provides that “[b]est results with the chemically modified nucleic acids according to the invention can be achieved when preferably, several, at least two and more preferred at least three of the following features are realized in the oligonucleotide… up to 4 to 6 of the linkages a-j are phosphate linkages whereas the remainder are phosphorothioate linkages; at least one DNA sugar nucleoside in the Central Base Triplet opposite to the adenosine to be deaminated; stabilization of pyrimidine bases outside the Central Base Triplet by 2’-F or 2’-OMe modifications… in roughly equal stoichiometry… avoids blocks of 2’-OMe… stabilization of both termini by blocks of three nucleotides which have a double modification…” (pg. 12). It is noted that many members of the instantly claimed genus do not meet the guidance for “best results” described in the specification. For example, the instantly claimed genus need only have 2 phosphate linkages, does not require any DNA sugar nucleoside in the CBT, and does not require any particular 2’- modification(s) or content. The speciifcation provides that “asymmetric design can enhance editing yields in short sequences of the nucleic acid, e.g., 45 nt… provided that the nucleic acid is shortened at the correct terminus” (pg. 10). However, the specification does not appear to provide any guidance as to which terminus is the “correct” terminus, and how short is too short for oligonucleotide function.
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 a target RNA, specific linkage chemistry and content across the entire oligonucleotide, specific lengths, 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. For example, species which comprise different sequences than those particularly described, and comprise any number of mismatches relative to a target RNA, species which comprise particular 2’ groups at particular locations, or in continuous stretches, or in overall contents which may be unsuitable for ADAR editing, species which comprise particular linkages at particular locations, or in overall contents which may be unsuitable for ADAR editing, or species which are incorrectly shortened. 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 could actually be used to edit a target adenosine to an inosine in a target RNA inside a cell with an endogenous ADAR.
Guidance in the Prior Art
The prior art describes chemically modified oligonucleotides which are used for editing of a target adenosine to an inosine in a target RNA inside a cell with an endogenous ADAR. See disclosures of Boudet (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).
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 edit a target adenosine to an inosine in a target RNA inside a cell with an endogenous ADAR. Indeed, based on Merkle and Boudet (see at least the teachings described in [0027]-[0028] of the prior action), it would appear that in order to arrive at such an oligonucleotide the skilled artisan would essentially need to vary each parameter (e.g., sequence, length, symmetry, 2’- and linkage content and chemistry), for each combination of target sequence, oligonucleotide sequence, and ADAR, and test to see which oligonucleotides function as intended.
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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JENNIFER A DUNSTON can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
