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 .
DETAILED ACTION
This Office Action is responsive to Applicant’s amendment and remarks, filed on 04/30/2026 in which claims 2, 3, 16, 70, and 98 were amended, and claims 4-9, 12-15, 17-32, 34-37, 39-68, 71-78, 80-94, 96-97, and 99-118 were cancelled. Claims 1-3, 10, 11, 16, 33, 38, 69, 70, 79, 95, and 98 are pending in the instant application and are examined on the merits herein.
Priority
This application claims benefit of 63/388,688 filed on 07/13/2022.
Withdrawn Objections
Applicant’s amendment, filed on 04/302026, with respect to the objection of claims 2, 3, 70, and 98 for informalities, has been fully considered and is persuasive. Applicant amended claims 2, 3, 70, and 98 to remove the phrase “A compound” and added the phrase “The compound”. The objection is hereby withdrawn.
Applicant’s amendment, filed on 04/302026, with respect to the objection of claim 16 for informalities, has been fully considered and is persuasive. Applicant amended claims 16 to enlarge Formula II to make the subscript legible. The objection is hereby withdrawn.
Maintained Grounds of Objection and Rejection
Specification
The disclosure is objected to because of the following informalities: Formula II contains illegible text (instant specification page 11 and page 44).
Appropriate correction is required.
Duplicate Claim Warning
Applicant is advised that should claim 69 be found allowable, claim 95 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 70 be found allowable, claim 98 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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, 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.
Claims 1-3, 10, 11, 69, 70, 79, 95, and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Weis et al. (US 6,242,428 B1, published 06/05/2001, see PTO-892) and Patani et al. (Chem. Rev. published 07/25/1996, see PTO-892).
Weis is draw to nucleosides and nucleoside dimers containing an L-sugar in at least one of the nucleosides, and their pharmaceutical compositions (abstract). Weis teaches compounds with formulas shown below, where the IBA may be a phosphate group. The B1 and B2 units will consist of either a β -D, a β -L or an a -L nucleoside and at least one of B1 or B2 will be β -L or α-L. R1 and R2 will be the pyrimidine bases cytosine, thymine, uracil, or 5-fluorouridine (5 -FUdR), other 5-halo compounds, or the purine bases, adenosine, guanosine or inosine (column 4, lines 61-67). R1 and R2 may be the same or different nucleosides selected from the group consisting of β-D-deoxyfluorouridine, α-L-deoxyfluorouridine, β -L-deoxyfluorouridine, α -L-deoxycytidine, β-L-deoxycytidine, β-L-deoxyuridine, β-L-deoxyguanosine, β-L-deoxyadenosine, α-L-deoxyadenosine and nitrobenzylthionsine (claim 2). Wei teaches that the dimers can be bound by various linkages, including 5’[Wingdings font/0xE0]3’, 3'[Wingdings font/0xE0]5', 3'[Wingdings font/0xE0]3’, 5'[Wingdings font/0xE0]5', 2'[Wingdings font/0xE0]3’, 3'[Wingdings font/0xE0]2', 2'[Wingdings font/0xE0]2', 2'[Wingdings font/0xE0]5', 5'[Wingdings font/0xE0]2', or any other stereochemically permissible linkage (column 5, lines 1-3). Regarding claims 1-3, 10, and 11, the instantly claimed compounds are taught by Weis’s 3'[Wingdings font/0xE0]5' IBA compound when IBA is the phosphate group with the exception of the thiol group on the 6-thioguanine group and when R1 and R2 are selected to be either both deoxyguanosine or one deoxyguanosine and one deoxyfluorouridine.
Regarding claims 69, 70, 79, 95, and 98, the instantly claimed compounds are taught by Weis’s 5'[Wingdings font/0xE0]5' IBA compound when IBA is the phosphate group with the exception of the thiol group on the 6-thioguanine group and when R1 and R2 are selected to be either both deoxyguanosine or one deoxyguanosine and one deoxyfluorouridine.
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Weis formulas (page 2, Figure 1)
Weis does not teach the use of thioguanosine nucleotides.
Patani is drawn to a study of bioisosterism as a rational approach in drug design (title). Patani teaches that bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effect agents. The concept of bioisosterism is often considered to be qualitative and intuitive (page 3147). Patani teaches that the interchange of thiol for hydroxyl can be considered as an extension of the amino-hydroxyl replacement and has been used extensively in medicinal chemistry, including for the amino-hydroxyl replacement of guanine to 6-thioguanine. Patani teaches that substitution of the hydroxyl with the thiol resulted in enhanced potency in calcium channel blocking activity of 1,4,dihydropyrimidines (page 3151). Patani further teaches that the thiol group may be a suitable and informative bioisostere for the amino and hydroxyl groups in several different series of medicinal agents by the virtue of its size, lower electronegativity, and ability to hydrogen bond.
It would have been prima facie obvious to combine the teachings of Weis and Patani before the effective filing date of the claimed invention by modifying the guanine on the compounds taught by Weis to be 6-thioguanine as taught by Patani to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the guanine on the formulas taught by Weis to be 6-thioguanine because Patani teaches that the interchange of the thiol for the hydroxyl has been used extensively in medicinal chemistry including the amino-hydroxyl replacement of guanine to 6-thioguanine. One of ordinary skill in the art would have a reasonable expectation of success because Patani teaches the amino-hydroxyl replacement of guanine to 6-thioguanine.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Abramova et al. (Bioorg. Med. Chem, published 07/25/2007, see PTO-892), and Patani et al. (Chem. Rev. published 07/25/1996, see PTO-892).
Abramova is draw to the synthesis of dinucleotide 5’-triphosphates (title). Abramova teaches the compound of the starting material wherein B is guanosine that with the exception of a guanosine instead of a thioguanosine meets the limitations of instant formula II (Scheme 1, page 1).
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Starting Material (Scheme 1, page 1)
Abramova does not teach the use of thioguanosine nucleotides.
The teachings of Patani are discussed above.
It would have been prima facie obvious to combine the teachings of Abramova and Patani before the effective filing date of the claimed invention by modifying the guanine on the compounds taught by Abramova to be 6-thioguanine as taught by Patani to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the guanine on the formula taught by Abramova to be 6-thioguanine because Patani teaches that the interchange of the thiol for the hydroxyl has been used extensively in medicinal chemistry including the amino-hydroxyl replacement of guanine to 6-thioguanine. One of ordinary skill in the art would have a reasonable expectation of success because Patani teaches the amino-hydroxyl replacement of guanine to 6-thioguanine.
Claims 33 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Weis et al. (US 6,242,428 B1, published 06/05/2001, see PTO-892), Patani et al. (Chem. Rev. published 07/25/1996, see PTO-892), and Gryaznov et al. (WO 2019/087144, published 2019/05/09, see PTO-892).
The teachings of Weis are discussed above.
Weis does not teach the use of thioguanosine nucleotides. Weis does not teach the 5’ phosphate group or the further modification of attaching a tocopherol or palmitic acid group.
The teachings of Patani are discussed above.
Gryaznov is drawn to oligonucleotide constructs and uses thereof (title). Gryaznoy teaches oligodeoxyribonucleotides (ODNs) constructs comprising CpG oligodeoxynucleotides conjugated, through linkers, to lipid moieties (paragraph 0013). The design of the ODN constructs includes the number and positioning of cytosineguanine (CpG) motifs and their internucleotide linkages, as well as the structure and location of lipid moieties and the presence or absence of a linker. Lipid moieties can include lipid molecules, such as cholesterol and tocopherol, that are conjugated to the ODN construct (paragraph 0014). The lipid moieties may include tocopherol or palmitic acid (paragraph 0071). The linker may be ethylene glycol ((CH2)2O)o wherein o is 1-15, covalently linked via a phosphodiester linkage (paragraph 0023). Gryaznov exemplifies an ODN construct with tocopherol as the lipid moiety (paragraph 00122).
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Gryaznov example.
Regarding instant claim 33, it would have been prima facie obvious to combine the teachings of Weis, Patani, and Graznov by modifying the guanosine on the dinucleotide taught by Weis to be thioguanosine as taught by Patani and modifying the 5’ hydroxy group to be a phosphate covalently bound palmitic acid as the lipid moiety without a linker as taught by Graznov to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the guanosine and the 5’hydroxy group of the compounds taught by Weis to be thioguanosine and a phosphate covalently linked to palmitic acid because Patani teaches the amino-hydroxyl replacement of guanine to 6-thioguanine and Graznov teaches that 5’ of an oligonucleotide may be a phosphate that is covalently linked to a lipid moiety and that the lipid moiety may be palmitic acid. One of ordinary skill in the art would have a reasonable expectation of success because Patani teaches the amino-hydroxyl replacement of guanine to 6-thioguanine and Graznov teaches the modification of covalently linking a lipid moiety to a 5’ phosphate on an oligonucleotide.
Regarding instant claim 38, It would have been prima facie obvious to combine the teachings of Weis, Patani, and Graznov by modifying the guanosine on the dinucleotide taught by Weis to be thioguanosine as taught by Patani and by modifying the 5’ hydroxy group of Weis to be a phosphate with an ethylene glycol linker and tocopherol as the lipid moiety to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the guanosine and the 5’hydroxy group of the compounds taught by Weis to be a thioguanosine as taught by Patani and the phosphate covalently linked to an ethylene glycol linker further linked to tocopherol as taught by Graznov because Patani teaches the amino-hydroxyl replacement of guanine to 6-thioguanine and Graznov teaches that 5’ of an oligonucleotide may be a phosphate that is covalently linked via a linker such as ethylene glycol to a lipid moiety and that the lipid moiety may be tocopherol. One of ordinary skill in the art would have a reasonable expectation of success because Patani teaches the amino-hydroxyl replacement of guanine to 6-thioguanine and Graznov teaches an oligonucleotide that has a 5’ phosphate linked via an ethylene glycol linker which is covalently bound to tocopherol.
Response to Arguments
Applicant's arguments filed 04/30/2026 have been fully considered, but they are not persuasive.
Applicant argues that 1-3, 10, 11, 69, 70, 79, 95, and 98 are not obvious over the combined art of Weis and Patani because the mechanism of action of the compounds are not disclosed in either Weis and or Patani taken alone or together. The argument is unpersuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the mechanism of action of the compounds) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, the instant claims are compound claims and therefore any property due to the structure would be inherent to the structure of the compound. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Furthermore, MPEP 2145 states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.
Applicant argues that 1-3, 10, 11, 69, 70, 79, 95, and 98 are not obvious over the combined art of Weis and Patani because Patani is only a general review on bioisosterism for optimizing potency, selectivity, PK, or toxicity. Although Patani includes some nucleoside/purine examples it only provides broad conceptual guidance, but not specific compounds, dinucleotide structures, or cancer/telomere applications. The argument is unpersuasive. In response to applicant's argument that Patani only provides broad conceptual guidance, not specific compounds, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton."KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle."Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ."Id. at 418, 82 USPQ2d at 1396.Patani provided the teaching of the amino-hydroxyl replacement of guanine to 6-thioguanine and a motivation to replace it as it has a benefit of size, lower electronegativity, and ability to hydrogen bond
Applicant argues that regarding claim 16 rejection in view of Abramova et al. and Patani, Abramova et al. focus on synthetic methods for dinucleotide 5'-triphosphates ( or related polyphosphates) from 5'-monophosphorylated dinucleotides. Examples include: Conversion of 5'monophosphorylated 2'-deoxydinucleotides to 5'-triphosphates and dinucleotides with expanded functionality, often natural or slightly modified bases/sugars, for biochemical/enzymatic studies (e.g., as substrates or probes). The argument is unpersuasive. Abramova disclosed a compound as a starting material that when combined with Patani’s teaching of modifying guanine to 6-thoguanine. As the instant claim 16 is a structure claim, the intended use of Abramova’s starting material is irrelevant.
Applicant argues that regarding claim rejections 33 and 38 in view of Weiss, Patani and Gryaznov, Weis teaches away from the claimed structures and utility. Weis discloses L-sugar nucleosides and dimers primarily for antimalarial activity against Plasmodium falciparum (parasite nucleic acid interference). It uses unnatural L configurations (α-Lor β-L sugars), often with pyrimidine bases like 5-fluorouridine, and simple phosphodiester/methylphosphonate linkages without 5'-lipid or thio-phosphate derivatizations matching R3. In addition, Weis focuses on parasite selective incorporation. The argument is unpersuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the ultility) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant is arguing a teaching away based on the method of use of the compounds, but instant claims 33 and 38 are structure claims. Any teaching away from the application or intended use of the structures is not relevant to the instantly claimed structures.
Applicant argues that regarding claim rejections 33 and 38 in view of Weiss, Patani and Gryaznov, Gryaznov describes longer CpG oligodeoxynucleotides (ODNs) with lipid conjugates (cholesterol, tocopherol, palmitoyl) for TLR9 immune stimulation (e.g., HBV, cancer immunotherapy as adjuvants). These are sequence-specific immune modulators that are unrelated to the present application. The argument is unpersuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., intended use) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Instant claims 33 and 38 are structure claims and therefore, the application or intended use of the structures do not further limit the instantly claimed structures.
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.
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/S.L.S./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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