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
Preliminary amendment filed on 07/13/2023 is acknowledged. Claims 4-9, 12-15, 17-32, 34-37, 39-68, 80-94, 96-97, 99-104, and 105-118 were cancelled and claims 10, 11, 33, 38, and 79 were amended. 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.
Information Disclosure Statement
The information disclosure statement (IDS) dated 03/21/2024 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the IDS document has been placed in the application file and the information therein has been considered as to the merits.
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.
Claim Objections
Claims 2, 3, 70, and 98 are objected to because of the following informalities: the claims recite the limitation "A compound" and the phrase should be “the compound”.
Claim 16 is objected is objected to because of the following informalities: the Formula II contains illegible text. 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.
Conclusion
No claims allowed.
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/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693 /SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693