DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 10/21/2025, in which claim 58 is amended and claim 56 is canceled.
Claims 1-55 and 57-65 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/IB2020/051885, filed on 03/04/2020, which claims domestic benefit to 62/815,172 filed on 03/07/2019 and 62/862,456 filed on 06/17/2019.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 05/05/2025, with respect that claim 58 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ameliorating cancer or viral infections, does not reasonably provide enablement for preventing cancer or viral infections has been fully considered and is persuasive as claim 58 has been amended to remove the scope of preventing. This rejection has been withdrawn.
The following are maintained grounds of rejection and objection.
Claim Objections
Claims 22, 25, 29, 31, 37, and 41 objected to because of the following informalities: claims 22, 25, 29, 31, 37, and 41 are each missing some or all of the chemical structures indicated by the claim. This appears to be a computer or file error. For purposes of compact prosecution, the structures of claims 22, 25, 29, 31, 37, and 41 are being interpreted as the structures in the amended claims filed 08/31/2021. Appropriate correction is required.
Response to Arguments
Applicant's arguments filed 10/21/2025 have been fully considered but they are not persuasive. Applicant argues that the chemical structures have been corrected. However, this is not the case. None of these objected claims have been amended. The same issues remain as indicated in the office action of 07/03/2025, thus the objection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-55 and 57-65 are rejected under 35 U.S.C. 103 as being unpatentable over Iyer et al. (WO 2018/009648 A1; cited in applicant IDS filed 31 Aug 2021), further in view of Pav et al. (Org. Lett., 2007), further in view of Adams et al. (US 9,718,848 B2).
Regarding claims 1-17 and 39-40, Iyer discloses compounds of the following formula in which: Z is O, B1 and B2 may be a purinyl nucleobase which includes adenine, X1 and Y1 may be O or S, and R1 and R2 may be halo (claim 1), including fluorine (cmd 12 on page 98),
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Regarding claims 18, 21-23, 25, 28-32 and 35-36, Iyer teaches prodrugs of cyclic dinucleotides including cyclic thiodiphosphates (paragraph bridging pages 65-66 and Example 1 on page 77). Examples are found in Table 2 and include compound 13 (claim 28, pages 98). Iyer thereby teaches a compound where X1 and X3 where X is SR1, R1 is L1-R2, L1 is C7 alkyarylene, R2 is -O(C=O)-C11 alkyl.
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Regarding claims 33-34 and 38, Iyer teaches the prodrug group shown in formula (IIId) and (IIIc), R2a is C3 alkyl (claim 28, page 97, compound 17).
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Regarding claim 44, Iyer teaches composition comprising the compounds and pharmaceutically acceptable excipients (paragraph bridging pages 65-66).
Regarding claims 45-55 and 57-65, Iyer discloses a method of activating STING (page 27, paragraph 3 and claim 46) through interaction with cytokines (page 28, paragraph 2) for the treatment of cancer (claim 45) by the administration of cyclic dinucleotides, and also teaches that compounds modulating STING are expected to be used in the treatment of hepatitis B (page 34, paragraph 1).
Iyer does not teach a P-C bond in the cyclic dinucleotide (claim 1).
Pav teaches that cyclic nucleoside phosphonates with a bridging P-C linkage are known to exhibit extraordinary chemical and nuclease stabilities (page 5469, paragraph 1). Thus, Pav suggests modifying cyclic mononucleoside phosphates by replacing the 3’-5’ phosphate with the C-phosphonate including the bridging P−C linkage in order to improve chemical and nuclease stability.
It would have been prima facia obvious before the effective filing date of the claimed invention to modify the cyclic dinucleotide of Iyer by replacing the 3’-5’ phosphate with the C-phosphonate including the bridging P−C linkage, as taught by Pav, because both references teach a cyclic nucleotide and Pav teaches that the modification of the phosphate of the nucleotide will improve chemical and nuclease stability. A person of ordinary skill in the art prior to the effective filing date of the claimed invention would have a reasonable expectation of success in making this modification to achieve the predictable result of a nucleotide with improved stability.
Iyer in view of Pav does not expressly teach a compound of formula (I) in which R2 is -O(C=O)-R2a or -(C=O)-R2a (claim 19), or where R2a is independently C1-C20 alkyl or -(C1-C6 alkylene)-(C3-C14 cycloalkyl) (claims 20, 24, 26-27, 37, and 41-42), or the synthesis of claim 43.
Adams discloses cyclic dinucleotides and teaches two different and complementary approaches that can be employed to enhance and maintain the potency of cyclic dinucleotides (CDN): substitution of sulfur for oxygen in the non-bridging positions of the phosphodiester and the use of a prodrug strategy to enhance cell penetration and protect the CDN from degradation (col. 19, lines 40-65).
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Regarding claims 19-20, 24, 26-27, and 41, Adams discloses the above compound (claim 4, col. 115, line 55), in which X1 or X3 is X is SR1, R1 is L1-R2, L1 is C1 alkylene, and R2 is -O(C=O)-C4 alkyl. This compound bears the complementary approaches of substitution of sulfur for oxygen in the non-bridging positions of the phosphodiester (in the triangle above) and the use of a prodrug (in the circle above). This prodrug configuration is compared to compound 1 on page 15 of the instant claim 41. Regarding claim 37, Adams teaches that the sulfur at the non-bridging positions of the phosphodiester may be oxygen (claim 1).
Regarding claim 42, Adams teaches that compound above may be modified such that the R2 may be a -O(C=O)-C1-20 alkyl, and R4 and R10 are both F (claim 1) thereby suggesting the first compound in instant claim 42.
Regarding claim 43, Adams teaches that the systhesis of the compounds may be prepared by the methods in the examples, and that this includes compounds where instant X1 is O R1 (col. 56, lines 1-5), and provides a method of making a substituted cyclic dinucleotide comprising reacting a cyclic dinucleotide with chloromethyl pivalate (Example 2, col. 58, line 1).
Further regarding claims 45-55 and 57-65, Adams teaches cyclic dinucleotides useful for the treatment of diseases in which modulation of STING is beneficial, for example infectious diseases, cancer, and as vaccine adjuvants (abstract), including Hepatitis B (col. 36, line 30). Further regarding claims 45, 48, 50 and 57-59, Adams teaches that the disclosed compounds modulate STING and that activation of STING leads to induction of cytokines (col 1, lines 57-60).
It would have been prima facia obvious before the effective filing date of the claimed invention to elect the thiophosphate prodrug moiety of Adams, which is taught to enhance cell penetration and protect the CDN from degradation, as an X substituent for the compounds Iyer to achieve the predictable result of nucleotide with improved stability and cellular uptake, as taught by Adams.
Response to Arguments
Applicant's arguments filed 10/21/2025 have been fully considered but they are not persuasive.
Applicant argues that Pav discusses compounds that are a 7-membered ring as opposed to the 13-membered macrocycle of the instant claims and thus does not provide a reasonable expectation of success for one of ordinary skill in the art to incorporate bridging P-C linkages into the compounds of Iyer (Remarks, page 26, paragraphs 1-2). Similarly the declaration argues that there is no reasonable scientific basis to expect that substitution of a phosphate linkage with a phosphonate linkage in a cyclic dinucleotide such as those described by Iyer would predictably lead to compounds with improved properties, including stability or biological activity (Declaration, paragraph 8). This is not persuasive.
As discussed in the above grounds of rejection, the P-C linkage of Pav is reported as providing stability against nucleases. Nucleases are known in the art to cleave the phosphodiester bonds of nucleotides. Pav as a whole teaches a method of improving the stability of phosphodiester linkages. This property of being cleaved by nucleases is a property of the nucleotide phosphodiester bonds and is not limited to the specific cyclic nucleotides taught by Pav. The phosphodiester bonds described by Pav are present in the cyclic dinucleotides of Iyer and have this same property regardless of the ring size into which they are incorporated. Thus one of ordinary skill in the art would have a reasonable expectation of success in increasing the stability of the compounds of Iyer by incorporating the P-C bridging linkage of Pav.
Applicant further argues that Iyer does not provide motivation for optimizing the stability of the molecule (Remarks, page 26, paragraph 3 and Declaration, paragraph 9). This is not persuasive.
It is not required that the suggestion for optimization be in the primary reference. As discussed in the above grounds of rejection, the secondary reference Pav teaches and suggests that the modification of the phosphate of the nucleotide will improve chemical and nuclease stability.
Applicant further argues that experimental testing of analogs demonstrates that replacement of phosphate linkages with phosphonate linkages produces highly unpredictable results. Applicant states that the 3’ position retains or enhances biological activity, whereas replacing the 5' linkage substantially reduces potency, and replacement of both phosphate linkages eliminates measurable STING agonist activity (page 27, paragraph 2). Declaration paragraph 11 provides experimental data for a comparison of replacement of these linkages. The chemical structures of the compared compounds are reproduced below for convenience.
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This argument is not persuasive. The argument advanced by Applicant relies on the unpredictability of results due to the location of the replacement of a phosphate linkage with a phosphonate linkage. To support an argument of unexpected results, Applicant must compare substitution at different positions using compounds within their claim scope versus compounds of the closest prior art in Iyer, which do not have any phosphonate linkages. The substitution of the phosphate linkage with a phosphonate linkage must be the only change between the compared compound such that one may determine that any differences in reactivity are due to the position of the phosphonate linkage, rather than any other differences such as substitution on the bases.
However, the structures compared by applicant have additional differences beyond that of the phosphonate linkages. For example, the compound representing two methyl phosphonate linkages does not have a halogen, and there is an additional amino group on one of the bases (circled in the image above). The representatives of the 3’ and 5’ linkages also have different halogen substitutions. Thus it is unclear what differences in activity are due to the differences linkages and what is due to the other structural differences. There is also no comparison to a compound with no phosphate linkages to represent the closest prior art. Finally, there is no statistical analysis provided to show whether any experimental differences are statistically significant. MPEP 2144.08(A)(4)(d) states that “If the claimed invention and the structurally similar prior art species share any useful property, that will generally be sufficient to motivate an artisan of ordinary skill to make the claimed species...Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious.” MPEP 2144.08(A)(4)I states that “obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties.” MPEP 716.02(b) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and are of both statistical and practical significance.
Applicant further argues that it is not possible to apply the synthetic strategies of Pav for the preparation of the phosphate containing cyclic dinucleotides of Iyer and thus it would not have been obvious to synthesize cyclic dinucleotides of Iyer bearing phosphonate linkages (Remarks, page 27, paragraph 3 and Declaration, paragraph 10). This is not persuasive.
Pav is not relied upon to teach the synthesis of cyclic dinucleotides but rather provides direction to one of ordinary skill in the art to incorporate P-C bonds in linkages between nucleosides. While not needed for demonstration of obviousness and solely to rebut Applicant’s argument, the introduction of O-methyl-(H)-phosphinate moieties to nucleosides is known in the art such that one of ordinary skill in the art would be capable of synthesizing the compounds suggested by Iyer and Pav. Kostov (Organic Letters, 2016) teaches a straightforward synthesis of 4-toluenesulfonyloxymethyl-(H)-phosphinate as a reagent of the preparation of these nucleosides. Using this reagent -CH2-P(H)(O)(OH) is introduced to the hydroxyl of a nucleoside to provide O-methyl-(H)-phosphinate derivatives at different positions and on nucleosides of different bases.
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Thus the synthesis of phosphonates is known in the art and the nucleosides 12a-d of Kostov are suitable as starting materials for the synthesis of the cyclic dinucleotides suggested by Iyer and Pav such that one of ordinary skill in the art would be capable of synthesizing the compounds suggested by Iyer and Pav.
Finally, Applicant argues that the cyclic dinucleotides of the present invention contain only one phosphonate and one phosphate linker and that the motivation to modify the compounds of Iyer according to the teachings of Pav would only suggest compounds with two phosphonate linkers because modifying only one phosphate linker of the compounds of Iyer with the bridging P-C linkage of Pav would be useless as the remaining phosphate linker could still be cleaved (Remarks, paragraph bridging pages 27-28). Similarly, Applicant argues that precursor compound IVa of claim 43, which also has only one phosphate linker, is not suggested by the teachings of Iyer, Pav, and Adams for the same reasons (Remarks, page 29, paragraph 1). This is not persuasive.
As discussed in the above grounds of rejection, Iyer discloses a method of activating STING through interaction with cytokines for the treatment of cancer by the administration of cyclic dinucleotides containing phosphate linkages, and also teaches that compounds modulating STING are expected to be used in the treatment of hepatitis B. Thus Iyer discloses that the compounds are used in multiple different biological applications and one of ordinary skill in the art would understand that the structure and activity of the compounds would be optimized to the particular biological application. Pav teaches a method of replacing 3’-5’ phosphate bonds with a C-phosphonate P−C linkage in order to modify chemical and nuclease stability of phosphate linkages. One of ordinary skill in the art would have known that different levels of stability could be imparted by incorporating different numbers of phosphonate linkages in the compounds of Iyer and so would optimize the compounds of Iyer to the desired stability for the method of activating STING in particular biological applications by considering different numbers of phosphonate linkages to impart different levels of stability. This would similarly result in a synthesis of those compounds through intermediates which contain the optimized number of phosphonate linkages to produce the suggested final compounds.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record.
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 extension fee 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693