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 . 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.
Priority
The instant application claims domestic benefit to US provisional application no. 63/453,832 filed on 03/22/2023.
Status of the Claims
Claims 1-24 are pending and being examined on the merits herein.
Claim Interpretation
Claim 19 recites “the base is a mixture of 30% ammonia in a solvent at a v/v ratio of no more than 3:1”.
The recited “base” mixture is being interpreted such that the volume of 30% ammonia solution and the volume of another solvent is no more than 3:1. For example, mixing an aqueous 30% ammonia solution with aqueous methylamine at a v/v ratio of 1:1 would meet the limitation of the recited “base” mixture. Support for this interpretation is provided in the instant specification (paragraph 0028 page 7).
Claim Rejections - 35 USC § 112(b)
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.
Claim 12 is 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 12 recites “tetraethylammonium fluoride hydrate (TEAF*xH2O)”.
Claim 12 is indefinite because the recited “x” within the “(TEAF*xH2O)” appears to be a variable, however the claim does not define the “x” variable.
Furthermore, if the recited “x” is interpreted as a defined variable, it is also unclear if the parenthetical “(TEAF*xH2O)” is meant to further limit the recited “tetraethylammonium fluoride hydrate” or is merely exemplary and not required.
For purposes of examination, claim 12 is being interpreted such that the recited deprotecting reagent is a tetraethylammonium fluoride hydrate.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 4, and 6-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021).
Nair discloses monomers and methods for synthesizing oligonucleotides comprising at least one nucleoside comprising a 3'-hydroxyl group (Abstract). Nair discloses that generally their method comprises coupling a free hydroxyl group on a nucleoside or oligonucleotide with a nucleoside phosphoramidite monomer having a triisopropylsilylether (TIPS) protected 3’-hydroxyl group (paragraph 0004).
Nair demonstrates a siRNA synthesis with 3’-O-protected nucleosides in Example 4 (paragraphs 0099-00106).
Nair shows in Table 3 representative oligonucleotides that were synthesized to determine the most optimal RNA protecting group that will be compatible with their cleavage and deprotection methods (which involves prolonged exposure to aqueous base) and will minimize side reactions such as premature falling off protecting groups which may lead to RNA hydrolysis/cleavage (paragraph 0099).
SEQ ID. 6 in Table 3 (page 25) contains the 23mer RNA sequence aUfcaaAf(U-3’-OTIPS)CfAfcuuuAfuUfgaguuuc.
SEQ ID. 6 in Nair anticipates instant claims 1-2, 4, and 6-7 for the following reasons.
The starting monomer “a” meets the recited (A-2’) structure because J is a phosphate (phosphorous-containing group), R2 is H, B is adenine (unmodified nucleobase), and the 3’ position is O connected to the next monomer. The last monomer “c” meets the recited (E-3’) structure because R2 is H, B is cytosine (unmodified nucleobase), and this monomer is connected to the previous monomer at the 5’ position via a phosphate group (X and Y are O).
All of the monomers in between meet either the recited C-2’ or C-3’ structure. The Uf, Af, Cf, u, a, g, and c monomers meet the recited C-2’ structure because B is uracil, adenine, guanine, or cytosine (unmodified nucleobases), R2 is H or F (halo), and these monomers are connected to the previous monomer at the 5’ position via a phosphate group (X and Y are O) as well as connected to the next monomer via a 3’O linkage.
The U-3’-OTIPS in the sequence has the following structure shown below:
PNG
media_image1.png
249
200
media_image1.png
Greyscale
The U-3’-OTIPS meets the recited C-3’ structure because B is uracil (unmodified nucleobase), and the “TIPS” group is triisopropylsilylether (paragraph 0004), which meets the recited R3 structure where m is 0 and R4 are each isopropyl (alkyl). Furthermore, the U-3’-OTIPS structure shows the same O-linkage at the 2’ position to the next monomer, and while the structure above does not show a phosphorous group at the 5’ position, an ordinary skilled artisan would readily understand the 5’ position is phosphate connected to the previous monomer.
Claim(s) 1 and 3-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Giannaris et al. (Nucleic Acids Research, 1993 in PTO-892).
Giannaris discloses oligoribonucleotides containing 2’ to 5’ phosphodiester linkages (Abstract).
Giannaris discloses that these RNA oligomers were synthesized on a solid support by the ‘silyl-phosphoramidite’ method (Abstract).
Giannaris provides the general structure of the 2’ to 5’ linked RNA oligomers in Scheme 1 (page 4743) shown below:
PNG
media_image2.png
343
221
media_image2.png
Greyscale
This general 2’ to 5’ linked RNA oligonucleotide structure meets the general linkage structure of the recited oligonucleotide intermediate when A is A-3’, C is C-3’, and E is E3’ because each of these monomers are 2’ to 5’ phosphodiester linked monomers.
Furthermore, Giannaris discloses that their 2’ to 5’ linked oligonucleotides were synthesized by first preparing 3'-O-r-Butyldimethylsilyl ribonucleoside 2'-O-N,N'-diiso propyl(methyl) phosphoramidite monomers (second paragraph under section “Reagents” page 4743). These monomers contain the same OR3 protecting group recited in A-3’, C-3’, and E3’ because the butyldimethylsilyl is –(CH2)mSi(R4)3 where m is 0 and R4 are each alkyl groups.
Giannaris discloses that the 2’ to 5’ linked oligonucleotides was synthesized using an Applied Biosystems DNA 381 synthesizer in the “trityl off” mode and subsequently deprotected by treating the CPG-bound oligomer successively with thiophenol/triethylamine/dioxane (1:2:2:, 8 vol/vol/vol; 30 min, r.t.), cone. NH4OH/ ethanol (3:1, 55°C, 16 h), and TBAF (1.0 M in THF, r.t., 16 h) (see section “Solid-phase synthesis of oligonucleotides”, page 4743).
Giannaris shows in Table 1 (page 4746) several oligonucleotide sequences that were prepared including entirely 2’ to 5’ link oligomers that are 10 or 13 monomers long.
While Giannaris does not explicitly show a 3’-hydroxyl protected oligonucleotide intermediate as recited, the ordinary skilled artisan would have readily envisage that the synthesis for the 2’ to 5’ linked RNA oligomers disclosed in Table 1 of Giannaris would necessarily form the 3’hydroxyl protected oligonucleotide intermediate recited in instant claims 1 and 3-5 because as described in the synthesis method in Giannaris, the 2’ to 5’ linked RNA oligomer is synthesized using 3’O protected monomers that contains the same recited silyl protecting group, and after the monomer coupling to form the RNA oligomer is complete, the oligonucleotide is further deprotected, which indicates that the oligonucleotide intermediate formed prior to the deprotection step would have had every monomer with the recited 3’O protected silyl group.
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.
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.
Claim(s) 8-11 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021) in view of Laikhter et al. (US20080119563A1 in PTO-892).
The teachings of Nair are as described above.
Furthermore, Nair teaches that while chemical synthesis of modified oligonucleotides is routine, the ease and yield of many modified oligonucleotides is low and further discloses that commonly used protecting groups are unstable to conditions employed for deprotecting chemically synthesized oligonucleotides, especially for preparing oligonucleotides comprising at least one nucleoside comprising a 3’-hydroxyl group (paragraph 0003). Therefore, Nair has developed their method to overcome such limitations (paragraph 0003).
Nair discloses that generally their method comprises coupling a free hydroxyl group on a nucleoside or oligonucleotide with a nucleoside phosphoramidite monomer having a triisopropylsilylether (TIPS) protected 3’-hydroxyl group (paragraph 0004).
Nair teaches that coupling methods and reagents for coupling nucleoside phosphoarmidite monomers to hydroxyl groups are well known in the art and thus, their oligonucleotides can be prepared using procedures and equipment known those skilled in the art (paragraph 0022). Preferably, Nair discloses that solid phase synthesis procedures are employed using solid supports such as controlled pore glass or using automatic DNA synthesizers (paragraph 0022).
Nair discloses once synthesis is complete, the oligonucleotide can be deprotected using methods and reagents to remove any protecting groups on the oligonucleotide to obtain the desired product (paragraph 0027).
Nair discloses that the deprotecting steps involve removing non-TIPS protecting groups then removing TIPS protecting groups (paragraph 0028). Nair discloses that removing the silyl containing hydroxyl protecting (TIPS-protected hydroxyl group) is well known in the art and generally uses a deprotecting reagent that comprises fluoride anions such as HF pyridine (paragraph 0028). Nair discloses that the deprotecting step can be carried out at room temperature or at elevated temperatures ranging from 35 C to 65 C (paragraph 0028), and the deprotection times are on the order of a few minutes to hours such as 2-5 hours (paragraph 0028).
Nair discloses after deprotection, the desired product can be isolated and purified using methods known in the art such as filtration and/or HPLC purification (paragraph 0029).
While Nair teaches a method of removing 3’hydroxyl silyl protecting group (3’ TIPS protecting group) using an agent comprising fluoride anions such as HF pyridine, Nair does not disclose the use of a recited agent such as tetraethylammonium fluoride (TEAF) in DMSO.
Laikhter discloses the use of tetralkyl ammonium fluoride derivatives or pyridine hydrogen fluoride complexes to remove silyl protecting groups in oligoribonucleotide synthesis (Abstract).
Laikhter discloses that synthesis of oligoribonucleotides have paralleled the methods of synthesis of deoxyribonucleic acid (DNA), but RNA synthesis has traditionally been more burdensome due to the 2′ hydroxyl group present in RNA (paragraph 0003). The 5′ hydroxyl group and the 2′ position need to be protected during synthesis, but each position's protecting group needs to be removed at different times (paragraph 0003). Therefore, the method of Laikhter involves the use of silyl protecting groups and methods to deprotect them.
Laikhter discloses that the deprotecting agent can be tetraethylammonium fluoride (TEAF) and that the TEAF is in a mixture containing dimethyl sulfoxide (DMSO) (claims 2-3 and 5).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the HF pyridine deprotecting agent disclosed in Nair with the TEAF – DMSO deprotecting mixture disclosed in Laikhter to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (HF pyridine) for another (TEAF in DMSO) to obtain predictable results and would have a reasonable expectation of success in doing so because Laikhter teaches using either the same pyridine hydrogen fluoride or TEAF in DMSO for performing the same function of deprotecting silyl groups on the hydroxyl groups of a nucleoside for a RNA oligonucleotide synthesis method.
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021) in view of Laikhter et al. (US20080119563A1 in PTO-892), as applied to claims 8 and 11 above, and further in view of Kupihar et al. (Pharmaceutics, 2023 published 01/11/2023 in PTO-892).
The combined teachings of Nair and Laikhter are as described above and teach the method of instant claims 8 and 11 as discussed above.
The combined references, which teaches the use of TEAF as deprotecting agent, does not teach that it is in a hydrate form.
Kupihar discloses the synthesis and the application of a thiol-modified thymidine nucleoside phosphoramidite to prepare ligatable oligonucleotide conjugates (Abstract). Kupihar discloses that their conjugates can be applied various purposes from monomer synthesis to templated ligation (Abstract).
Kupihar discloses incorporating their monomer into oligonucleotide sequences by synthesizing a dinucleotide using standard cyanoethyl phosphoramidite chemistry as well as into internal positions of 10mer oligonucleotide (first paragraph page 9).
Kupihar demonstrates the synthesis of their t-Bu-SS-protected thymidine phosphoramidite monomer in Scheme 1 (page 9) and shows that the silyl groups in nucleoside 8 (TBDMS) was removed (deprotected) using tetrabutylammonium fluoride (TBAF) trihydrate (fifth paragraph page 5).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the TEAF deprotecting agent disclosed in the combined teachings of Nair and Laikhter described above to be in a hydrate form as taught in Kupihar to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Kupihar provides guidance of using a trihydrate form of a similar tetraalkylammonium fluoride as a deprotecting agent to perform the same function of removing silyl groups off a nucleoside.
Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021) in view of Laikhter et al. (US20080119563A1 in PTO-892), as applied to claim 11 above, and further in view of Giannaris et al. (Nucleic Acids Research, 1993 in PTO-892) and Beaucage et al. (US20140051846A1 in PTO-892).
The combined teachings of Nair and Laikhter are as described above and teach the method of instant claims 8 and 11 as discussed above.
The combined references, which teaches the use of TEAF in DMSO, does not teach a 0.9 M concentration.
The teachings of Giannaris are as described above. Furthermore, Giannaris teaches that their oligonucleotide synthesis method involved the use of 1 M tetra-n-butylammonium fluoride (TBAF) as a desilylating reagent to remove the silyl group on the 3’OH position of the nucleosides (see section “Reagents” page 4743 and section “Solid-phase synthesis of oligonucleotides” page 4743).
Beaucage teaches O-protected nucleosides which are stable during various reaction steps involved in oligonucleotide synthesis (Abstract). Beaucage discloses the protecting groups can be easily removed after the after the synthesis of the oligonucleotide, for example, by reaction with tetrabutylammonium fluoride (TBAF) (Abstract).
Beaucage shows in FIG. 1 that their nucleosides (compounds 4 a-d) had silyl groups at the 3’OH and 5’OH positions. Beaucage further discloses that desilylation of compound 4a by treatment with 0.5 M TBAF in THF resulted in uridine being the only nucleosidic product detected by reversed-phase high performance liquid chromatography (RP-HPLC) analysis of the deprotection reaction (paragraph 0110).
It would have been prima facie obvious before the effective filing date of the claimed invention to have prepared the TEAF as disclosed by the combined teachings of Nair and Laikhter described above at a concentration of 0.9M as supported by the disclosures of Giannaris and Beaucage to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Giannaris and Beaucage teach the use of 1M and 0.5M concentration, respectively, of a similar tetraalkylammonium fluoride as a deprotecting agent to perform the same function of removing silyl groups off a nucleoside. Furthermore, while Giannaris does not explicitly teach the use of a 0.9M concentration, the 1M concentration in Giannaris is close such that the ordinary skilled artisan would have expected 0.9M to be a suitable concentration, which is further supported by the 0.5M concentration disclosed in Baeucage being suitable as well. See MPEP 2144.05 I
Alternatively, one of ordinary skill in the art before the effective filing date of the claimed invention would have performed routine optimization to arrive at the recited 0.9 M concentration for the TEAF as disclosed by the combined teachings of Nair and Laikhter described above because Giannaris and Beaucage teach the use of 1M and 0.5M concentration, respectively, of a similar tetraalkylammonium fluoride as a deprotecting agent to perform the same function of removing silyl groups off a nucleoside, which suggests that the ordinary skilled artisan would have a reasonable expectation that molar concentrations between 0.5M and 1M are also suitable for deprotecting the silyl groups on the nucleosides using tetraalkylammonium fluorides. See MPEP 2144.05 II
Claim(s) 17 and 20-24 are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021) in view of Laikhter et al. (US20080119563A1 in PTO-892), as applied to claim 8 above, and further in view of Bhan et al. (US6887990B1 in PTO-892).
The combined teachings of Nair and Laikhter are as described above and teach the method of instant claim 8 as discussed above. Furthermore, Nair teaches that coupling methods and reagents for coupling nucleoside phosphoarmidite monomers to hydroxyl groups are well known in the art and thus, their oligonucleotides can be prepared using procedures and equipment known those skilled in the art (paragraph 0022). Preferably, Nair discloses that solid phase synthesis procedures are employed using solid supports such as controlled pore glass or using automatic DNA synthesizers (paragraph 0022). Nair discloses that once synthesis is complete, the oligonucleotide can be deprotected using methods and reagents to remove any protecting groups such as the non-TIPS and TIPS protecting groups on the oligonucleotide to obtain the desired product (paragraph 0027). Nair discloses that solid phase synthesis procedures are employed using solid supports such as controlled pore glass or using automatic DNA synthesizers (paragraph 0022). Nair also teaches that after deprotection, the desired product can be isolated and purified using methods known in the art such as filtration and/or HPLC purification (paragraph 0029).
The combined references, however, do not teach the recited prior steps of removing a phosphate protecting group such as cyanoethyl using a base under suitable conditions such as 20% diethyl amine (DEA) in acetonitrile as well as removing a solid support and amino protecting groups with a base under suitable conditions.
Bhan teach a method of purifying an oligonucleotide that comprises: a) providing an oligonucleotide containing a phosphate protecting group attached to a substrate, wherein the phosphate protecting group is 2-cyanoethyl; b) contacting the oligonucleotide with diethylamine to cleave the phosphate protecting groups from the oligonucleotide without detaching the oligonucleotide from the substrate; c) isolating the oligonucleotide attached to the substrate from the cleaved phosphate protecting groups; and d) contacting the oligonucleotide attached to the substrate with ammonium hydroxide to cleave the oligonucleotide from the substrate (claim 15).
Bhan discloses that the substrate can be controlled pore glass and others, which meets the limitation of a solid support (column 5 lines 33-37). Bhan discloses that the diethylamine (DEA) is provided as 20% v/v diethylamine in anhydrous acetonitrile (column 6 lines 10-11).
Bhan teaches that the ammonium hydroxide is also capable of removing exocyclic amine protecting groups found on the nucleobase in monomer building blocks such as benzoyl, isobutyrl, phenoxyacetyl, and acetyl protecting groups (column 1 lines 62-67 through column 2 lines 1-6). Bhan also discloses that after removal of the acrylonitrile containing reagent solution, the substrate can be next treated with concentrated ammonium hydroxide to release the oligonucleotide from the substrate with concomitant removal of other protecting groups (column 4 lines 49-53).
It would have been prima facie obvious before the effective filing date of the claimed invention to have incorporated the deprotecting steps of using 20% v/v diethylamine in acetonitrile to remove phosphate protecting groups on the oligonucleotide as well as the deprotection of exocyclic amino protecting groups and cleavage of a solid substrate using ammonium hydroxide as disclosed in Bhan into the oligonucleotide synthesis method as disclosed by the combined teachings of Nair and Laikhter described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because the combined teachings of Nair and Laikhter described above of disclose incorporating known methods and reagents for oligonucleotide synthesis such as the same solid support synthesis method as well as incorporating methods and reagents of removing non-TIPS (non-silyl) protecting groups from the oligonucleotide.
Claim(s) 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021) in view of Laikhter et al. (US20080119563A1 in PTO-892) and Bhan et al. (US6887990B1 in PTO-892), as applied to claim 17 above, and further in view of Glen Research (The Glen Report, Oct. 2008 in PTO-892).
The combined teachings of Nair, Laikhter, and Bhan are as described above and teach the method of instant claim 17 as discussed above. Furthermore, Nair discloses that non-TIPS protecting groups on the oligonucleotide can be deprotected (removed) by using bases such as ammonium hydroxide, methylamine, and mixtures thereof (paragraph 0027).
While the combined references teach deprotecting exocycling amino protecting groups using ammonium hydroxide, the combined references do not teach 30% ammonia in a solvent at a v/v ratio of no more than 3:1.
Glen Research discloses deprotection strategies for oligonucleotide synthesis (page 8), and discloses that deprotection of oligonucleotides can be visualized in three parts: cleavage of the solid support, phosphate deprotection such as removal of cyanoethyl protecting groups on the phosphate backbone, and base deprotection such as removal of protecting groups on the bases or modifier (second paragraph left column page 8).
Glen Research discloses concentrated ammonium hydroxide (28% to 33% ammonia in water) is used for the cleavage reaction, and is the most traditional deprotection method that dates back to the earliest days of oligonucleotide synthesis (last paragraph right column page 8). Glen Research discloses that ammonium hydroxide is water saturated with ammonia gas and that it is critical keep the solution fresh (last paragraph right column page 8).
Glen Research further discloses an UltraFAST cleavage and deprotection of oligonucleotides using a 1:1 mixture (v/v) of aqueous ammonium hydroxide and aqueous methylamine (second paragraph left column page 9).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the ammonium hydroxide for deprotecting exocyclic amino protecting groups and cleaving a solid substrate as disclosed by the combined teachings of Nair, Laikhter, and Bhan described above by using a 28% to 33% ammonia in water solvent combined with methylamine at a v/v ratio of 1:1 as disclosed in Glen Research to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because the combined teachings of Nair, Laikhter, and Bhan described above disclose the use of ammonium hydroxide and methylamine for the cleavage of a solid substrate as well as the removal of non-TIPS (non-silyl) protecting group from the oligonucleotide, and Glen Research provides further guidance that ammonium hydroxide can be combined with methylamine at a v/v ratio of 1:1 to perform the same functions. Furthermore, Glen Research provides additional guidance that ammonium hydroxide is typically an overlapping range of 28% to 33% ammonia in water, which renders the recited 30% ammonia obvious. See MPEP 2144.05 I.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021)
The claims of ‘706 recite a method for synthesizing oligonucleotides having at least one nucleoside with a 3’OH group and a 2’ to 5’ internucleoside linkage, the method comprising (i) coupling a free 5’hydroxyl group on a nucleoside or oligonucleotide with a nucleoside phsophoramidite monomer having a 2’-phsopharmidite group and a triisopropylsilylether (TIPS) protected 3’hdyroxyl group to form a phosphite triester intermediate, (ii) oxidizing or sulfurizing said phsophite triester intermediate to form a protected intermediate, and (iii) deprotecting the protected intermediate with a base, wherein eased treating with the base is at a temperature of 30 C or higher, wherein the nucleoside phsopharmidite monomer has the recited Formula (I). The claims of ‘706 recite that the oligonucleotide is 10-30 nucleotides long (claim 20). The claims of ‘706 recite that treatment with base is at a temperature between 32C and 65C for at least 4 hours (claims 11-14), and that the deprotecting agent to deprotect the TIPS group on the nucleoside comprises fluoride anions such as HF_pyridine (claims 16-17).
While the claims of ‘706 recite a method of synthesizing oligonucleotides having at least one nucleoside with a 3’OH group and a 2’ to 5’ internucleoside linkage, the claims of ‘706 do not explicitly recite that the oligonucleotide intermediate recited in instant claims 1-2, 4, 6-7 is formed.
The teachings of Nair are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention that the method recited in ‘706 can be used to produce the 23mer RNA sequence aUfcaaAf(U-3’-OTIPS)CfAfcuuuAfuUfgaguuuc disclosed in Nair to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the claims of ‘706 and Nair recite the same method steps, reagents, and protecting groups (TIPS) as well as producing the same oligonucleotide with at least one 2’ to 5’ linkage, and as discussed above, the 23mer RNA sequence of Nair meets the recited oligonucleotide intermediate recited in instant claims 1-2, 4, and 6-7.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Nair et al. (WO2021108291A1 in PTO-892, common inventors are listed however Nair was published outside of the one-year grace period on 06/03/2021) and Giannaris et al. (Nucleic Acids Research, 1993 in PTO-892).
The combination of the claims of ‘706 and Nair are as described above and recite the oligonucleotide intermediate of instant claim 1 as discussed above.
The combination, however, does not recite wherein A is A-3’ and E is E-3’ (the starting and ending monomers of the oligonucleotide).
The teachings of Giannaris are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the method as recited by the combination of the claims of ‘706 and Nair described above to produce an oligonucleotide 3’OH-TIPS protected intermediate that contain all 2’ to 5’ linkages as disclosed in Giannaris to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both combination of the claims of ‘706 and Nair described and Giannaris teach similar methods of synthesizing 2’ to 5’ linked oligonucleotides using a similar silyl-phosphoramidite method.
This is a provisional nonstatutory double patenting rejection.
Claims 8-11 and 14-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Laikhter et al. (US20080119563A1 in PTO-892).
The claims of ‘706 are as described above. Furthermore, the claims of ‘706 recite that treatment with base is at temperature between 32C and 65C for at least 4 hours (claims 11-14) and that the deprotecting agent to deprotect the 3;OH TIPS protected group on the nucleoside comprises fluoride anions such as HF pyridine (claims 16-17).
While the claims of ‘706 recite a method of deprotecting the 3’OH TIPS protected nucleoside by using a fluoride ion based reagent, the claims of ‘706 do not recite the use of a recited agent such as tetraethylammonium fluoride (TEAF) in DMSO.
The teachings of Laikhter are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the HF pyridine deprotecting agent as recited in the claims of ‘706 with the TEAF – DMSO mixture deprotecting mixture disclosed in Laikhter to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (HF pyridine) for another (TEAF in DMSO) to obtain predictable results and would have a reasonable expectation of success in doing so because Laikhter teaches using either the same pyridine hydrogen fluoride or TEAF in DMSO for performing the same function of deprotecting silyl groups on the hydroxyl groups of a nucleoside for a RNA oligonucleotide synthesis method. Furthermore, the claims of ‘706 recite overlapping ranges of temperature and duration for the base treatment, rendering the recited temperature and durations obvious. See MPEP 2144.05 I
This is a provisional nonstatutory double patenting rejection.
Claims 8 and 11-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Laikhter et al. (US20080119563A1 in PTO-892) and Kupihar et al. (Pharmaceutics, 2023 published 01/11/2023 in PTO-892).
The combination of the claims of ‘706 and Laikhter are as described above and recite the method of instant claims 8 and 11 as discussed above.
The combination, however, does not recite wherein the deprotecting reagent is TEAF hydrate.
The teachings of Kupihar are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to modify the TEAF deprotecting agent as recited by the combination of the claims of ‘706 and Laikhter to be in the hydrate form as disclosed in Kupihar for described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Kupihar provides guidance of using the trihydrate form of a similar tetraalkylammonium fluoride as a deprotecting agent to perform the same function of removing silyl groups off a nucleoside.
This is a provisional nonstatutory double patenting rejection.
Claims 8, 11, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Laikhter et al. (US20080119563A1 in PTO-892), Giannaris et al. (Nucleic Acids Research, 1993 in PTO-892), and Beaucage et al. (US20140051846A1 in PTO-892).
The combination of the claims of ‘706 and Laikhter are as described above and recite the method of instant claims 8 and 11 as discussed above.
The combination, however, does not recite a concentration of 0.9M.
The independent teachings of Giannaris and Beaucage are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have prepared the TEAF as disclosed by the combination of the claims of ‘706 and Laikhter described above at a concentration of 0.9M as supported by the disclosures of Giannaris and Beaucage to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Giannaris and Beaucage teach the use of 1M and 0.5M concentration, respectively, of a similar tetraalkylammonium fluoride as a deprotecting agent to perform the same function of removing silyl groups off a nucleoside. Furthermore, while Giannaris does not explicitly teach the use of a 0.9M concentration, the 1M concentration in Giannaris is close such that the ordinary skilled artisan would have expected 0.9M to be a suitable concentration, which is further supported by the 0.5M concentration disclosed in Baeucage being suitable as well. See MPEP 2144.05 I
Alternatively, one of ordinary skill in the art before the effective filing date of the claimed invention would have performed routine optimization to arrive at the recited 0.9 M concentration for the TEAF deprotecting agent as recited by the combination of the claims of ‘706 and Laikhter described above because Giannaris and Beaucage teach the use of 1M and 0.5M concentration, respectively, of a similar tetraalkylammonium fluoride as a deprotecting agent to perform the same function of removing silyl groups off a nucleoside, which suggests that the ordinary skilled artisan would have a reasonable expectation that molar concentrations between 0.5M and 1M are also suitable for deprotecting the silyl groups on the nucleosides using tetraalkylammonium fluorides. See MPEP 2144.05 II
This is a provisional nonstatutory double patenting rejection.
Claims 8, 17, and 20-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Laikhter et al. (US20080119563A1 in PTO-892), Nair was published outside of the one-year grace period on 06/03/2021), and Bhan et al. (US6887990B1 in PTO-892).
The combination of the claims of ‘706 and Laikhter are as described above and recite the method of instant claim 8 as discussed above.
The combination, however, do not teach the recited prior steps of removing a phosphate protecting group such as cyanoethyl using a base under suitable conditions such as 20% diethyl amine (DEA) in acetonitrile, removing a solid support and amino protecting groups with a base under suitable conditions, and a step of purifying the oligonucleotide via a chromatographic purification.
The independent teachings of Nair and Bhan are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have incorporated the deprotecting steps of using 20% v/v diethylamine in acetonitrile to remove phosphate protecting groups on the oligonucleotide as well as the deprotection of exocyclic amino protecting groups and cleavage of a solid substrate using ammonium hydroxide as disclosed in Bhan with further guidance from Nair and also the further step of purifying the oligonucleotide using HPLC as disclosed in Nair into the oligonucleotide synthesis method as recited by the combination of the claims of ‘706 and Laikhter described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Nair discloses that the method of synthesizing 2’ to 5’ linked oligonucleotides using a silyl protecting groups as recited by the combination of the claims of ‘706 and Laikhter described above can also include known methods and reagents for oligonucleotide synthesis such as the same solid support synthesis method as well as incorporating methods and reagents of removing non-TIPS (non-silyl) protecting groups from the oligonucleotide and an additional step of purifying the oligonucleotide using HPLC.
This is a provisional nonstatutory double patenting rejection.
Claims 8 and 17-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/779,706 (‘706) in view of Laikhter et al. (US20080119563A1 in PTO-892), Nair was published outside of the one-year grace period on 06/03/2021), Bhan et al. (US6887990B1 in PTO-892), and Glen Research (The Glen Report, Oct. 2008 in PTO-892).
The combination of the claims of ‘706, Laikhter, Nair, and Bhan are as described above and recite the method of instant claims 8 and 17 as discussed above.
While the combined references teach deprotecting exocycling amino protecting groups using ammonium hydroxide, the combined references do not teach 30% ammonia in a solvent at a v/v ratio of no more than 3:1.
The teachings of Glen Research are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the ammonium hydroxide for deprotecting exocyclic amino protecting groups and cleaving a solid substrate as recited by combination of the claims of ‘706, Laikhter, Nair, and Bhan described above by using a 28% to 33% ammonia in water solvent combined with methylamine at a v/v ratio of 1:1 as disclosed in Glen Research to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because the combination of the claims of ‘706, Laikhter, Nair, and Bhan described above disclose the use of ammonium hydroxide and methylamine for the cleavage of a solid substrate as well as the removal of non-TIPS (non-silyl) protecting group from the oligonucleotide, and Glen Research provides further guidance that ammonium hydroxide can be combined with methylamine at a v/v ratio of 1:1 to perform the same functions. Furthermore, Glen Research provides additional guidance that ammonium hydroxide is typically an overlapping range of 28% to 33% ammonia in water, which renders the recited 30% ammonia obvious. See MPEP 2144.05 I.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-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, Scarlett Goon can be reached at 571-270-5241. 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.
/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights