DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on December 17 2025 is acknowledged. Claims 1-43 are pending in the application. Claims 2-25 and 30-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 17 2025. Accordingly, claims 1 and 26-29 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/EP2020/073187 (08/19/2020) which claims benefit of 62/888,748 (08/19/2019) and claims benefit of 63/064,114 (08/11/2020) as reflected in the filing receipt issued on May 20 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 18 2022 and December 17 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 26 is objected to because of the following informalities: the chemical structure for M3’ and M6’ should be in the claim. While the structures for M1’, M2’, M4’ and M5’ are set forth in previously presented claim 1. The structures for M3’ and M6’ are never recited in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 26-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 26 as currently written is vague and indefinite. Claim 26 is directed to a conjugate prepared by a process. Thus, the process is critical to understanding the scope of the conjugate. Step 1) recites providing at least one GalNAc monomer selected from the group consisting of M1’, M2’, M3’, M4’, M5’ and M6’ which is not indefinite. However, the claim also recites “optionally adding at least one spacer”. But the claim never states where the spacer is added. Looking to claim 1 which recites the structure of, for exampleM1’, this compound is a specific structure with either protecting groups or alkyl/aryl/alkenyl groups. In order for a spacer to be added, the structure of the M1’-M6’ would have to change in order to allow for a spacer to be added. The specification indicates that the GalNAc moiety comprises at least one spacer (may also be called a linker)….wherein the monomers are attached to each other or to the spacer via a bond. This section also seems to suggest that the spacer is added to the deprotected oligonucleotide (which would be different from the GalNAc monomer). Thus the claim is indefinite as it does not clearly indicate where the spacer is added to the compound which is fully protected (i.e. all reactive sites are protected). This is different than step 2). The oligonucleotide would not have such protecting groups therefore, the linker can be added at either the 3’-end, 5’-end or any other reasonable location of attachment on a oligonucleotide.
Claim 26 as currently written is vague and indefinite. Step 3) is specifically confusing. The step recites synthesizing the conjugate from the GalNAc monomer(s) in step 1) and the oligonucleotide(s) in step 2) which while broad is not indefinite. But the claim recites optionally removing the protecting groups. It is unclear how the removing the protecting groups can be optional. While not all protecting groups would need to be removed for synthesizing the conjugate, at least one protecting group would need to be removed in order for the synthesis of the conjugate to occur. As shown below, in M1’ for example, all the potential sites for reaction are protected (see arrows). While some are defined as alkyl/aryl/alkenyl (R1, R2, R3, R5, R6) others (specifically R4 and R7) are indicated as including a suitable protecting group. Thus they would prevent reaction until removed. But claim 26 indicates that these protecting groups are “optionally” removed. The broadest reasonable interpretation of the claim is that they are not required to be removed. But then if they are not removed it is not clear how the synthesis occurs.
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Claims 27-28 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Guzaev et al. (WO2018013999, cited on PTO Form 1449).
Applicant Claims
The instant application claims a conjugate prepared by a process comprising the steps of:1) providing at least one GalNAc monomer selected from the group consisting of M1’, M2’, M3’, M4’, M5’ and M6’; optionally adding at least one spacer; 2) providing at least one oligonucleotide; optionally adding at least one linker; and 3) synthesizing the conjugate from the GalNAc monomer(s) in step 1) and the oligonucleotide(s) in step 2), optionally removing the protecting groups.
A structure claimed is M3’:
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Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Guzaev et al. is directed to non-nucleosidic solid supports and phosphoramidite building blocks for oligonucleotide synthesis. Example 75 teaches compound 31i:
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which differs from the instant claim in that it contains a DMT protecting group instead of a TMT protecting group.
As shown in Fig. 2, R1 can be either DMT or TMT:
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Claimed is a synthesis of a compound of formula II (shown below) which is the reaction product of the above compounds with oligonucleotides.
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Example 135 discusses oligonucleotide synthesis, deprotection and analysis. Taught is coupling the phosphoramidites with oligonucleotides (see also paragraph 0073-0074).
It is taught that those skilled in the art will appreciate the utility of oligonucleotides derivatized with non-nucleosidic modifiers. Said compounds combine the natural ability of oligonucleotides to form duplexes with complementary DNA or RNA with useful physical and chemical properties added by modifiers (paragraph 029).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Guzaev et al. suggests reacting the phosphoramidite building block with an oligonucleotide, Guzaev et al. does not expressly teach a compound of 31i where DMT is replaced with TMT.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a compound corresponding to instantly claimed M3’ in the formation of an oligonucleotide conjugate. One skilled in the art would have been motivated to replace DMT of 31i with TMT as both are taught as suitable protecting groups at that position (see Fig. 2) in Guzaev et al. This amounts to simple substitution of one known protecting group with another. MPEP 2143.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a compound corresponding to instantly claimed M3’ in the synthesis of an oligonucleotide. One skilled in the art would have been motivated to utilize this phosphoramidite building block and form an oligonucleotide conjugate as Guzaev et al. teaches this is the use for these compounds. One skilled in the art would have been motivated to utilize these phosphoramidite building blocks in order to provide advantages to the oligonucleotide as taught by Guzaev et al., namely useful physical and chemical properties (see paragraph 0029).
Claims 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Guzaev et al. as applied to claim 26 above and in view of Saetrom (USPGPUB No. 20160298113).
Applicant Claims
The instant application claims the oligonucleotide is an saRNA (claim 27) or siRNA (claim 29). A specific saRNA claimed is XD-03302 which corresponds to an sense strand (SEQ ID No: 2) and antisense strand (SEQ ID NO: 3) as set forth in Table 2.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Guzaev et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Guzaev et al. teaches conjugation with an oligonucleotide, Guzaev et al. does not expressly teach a saRNA, siRNA or XD-03302. However, these deficiencies are cured by Saetrom.
Saetrom is directed to C/ebp alpha short activating rna compositions and methods of use. Taught are compositions of short activating RNA (saRNA) molecules that modulate C/EBPalpha gene expression and/or function (paragraph 0009). It is taught that in one embodiment formulations may be constructed or composition altered such that they passively or actively are directed to different cell types. Selective targeting through expression or different ligands on their surface include GalNAc (paragraph 0204). Small activating RNA or saRNA means a single stranded or double stranded RNA typically with less than 50 nucleotides (paragraph 0098). Preferably the saRNA is double stranded (paragraph 0123). Example 23 shows saRNA sequences which include sense strand (SEQ ID No. 280) and antisense strand (SEQ ID No: 318).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Guzaev et al. and Saetrom and utilize the phosphoramidite building block of Guzaev et al. with the saRNA of Saetrom. One skilled in the art would have been motivated to utilize this building block as it contains GalNAc. Since Guzaev et al. teaches the advantages of incorporating the building block into oligonucleotides and Saetrom teaches the use of GalNAc for selective targeting, there is a reasonable expectation of success.
Regarding claim 28, XD-03302 contains sense strand (SEQ ID No: 2) and antisense strand (SEQ ID NO: 3). As shown below sense strand (SEQ ID No. 280) and antisense strand (SEQ ID No: 318) has 100% identity to instantly claimed SEQ ID No: 2 and 3. Since Saetrom teaches that double stranded strands are preferable and that these strands (280 and 318) were prescreened for cross reactivity and minimization of potential off-target effects, one skilled in the art would have been motivated to select these sequences.
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Regarding claim 29, as claimed the composition comprising a saRNA can further comprise a siRNA (claim 59). Small interfering RNA (siRNA) is a double stranded RNA involved in the RNAi pathway. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Guzaev et al. and Saetrom and utilize the phosphoramidite building block of Guzaev et al. with any oligonucleotide. One skilled in the art would have been motivated to utilize the phosphoramidite building block of Guzaev et al. for the advantages taught by Guzaev et al. Furthermore, since the GalNAc provides for targeting to specific cells as taught by Saetrom this provides further motivation to utilize the phosphoramidite building block.
Allowable Subject Matter
Claim 1 is allowed. The prior art does not teach or suggest the instantly claimed GalNAc monomer, specifically, the linker connecting the GalNac to the sugar at the 2’ position. The examiner notes that the recitation “wherein R1, R2 and R3 are independent selected from alkyl, aryl and alkenyl group” are interpreted in the alternative. The claim makes it clear that R1, R2 and R3 can be the same or different and are independent selected from an alkyl, aryl and alkenyl. Therefore, while the claim utilizes the word “and”, the claim when read as a whole clearly makes it clear that the listing is in the alternative. MPEP 2173.01; 2173.05(h). The recitation C1-6 is interpreted as corresponding to C1-C6 (aka methyl, ethyl, etc.). Finally, the examiner notes that they did reach out to Applicants representative to indicate that claim 1 would be indicated as allowable. However, the examiner was unable to speak with the representative. If Applicants have any questions, they are encouraged to reach out to the examiner.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636