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 . Preliminary amendment filed on 09/15/2023 has been entered. Claims 1-24 are cancelled. Claims 25-48 are pending in this application. Claims 29, 35, 37, 39, 40, 42, and 43 are withdrawn. Claims 25-28, 30-34, 36, 38, 41, and 44-48 are currently under examination.
Priority
This application is a 371 of PCT/EP2022/057241 filed on 03/18/2022 and claims foreign priority of EP 21163788.9 filed on 03/19/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. EP 21163788.9, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 41 and 45-47 recite “a carboxylic acid, a mineral acid”, “60-99% of the overall volume”, “1-40% of the overall volume”, “at least 2 times more than the molar concentration”, “0.80-15.0 equivalents relative to the total molar amount”, and/or “2.0-100.0 equivalents relative to the total molar amount”, which are not specifically disclosed in the prior-filed Application No. EP 21163788.9. Thus, the priority date of claims 41 and 45-47 is 03/18/2022.
Election/Restrictions
Applicant's election without traverse of Group I invention (claims 25-36 and 38-48) and species [Species A (oligonucleotide backbone): Compound according to Formula I, as recited in claim 27. Species B (liquid composition C): Aprotic solvent: non-halogenated aprotic solvent (claim 36); Base: cyclic amine recited in (claim 38); Acid: carboxylic acid, recited in (claim 41); and Alcohol: trifluoroethanol, hexafluoroisopropanol, and a mixture thereof (claim 44)] in the reply filed on 05/11/2026 is acknowledged. Claims 29, 35, 37, 39, 40, 42, and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Thus, claims 25-28, 30-34, 36, 38, 41, and 44-48 are currently under examination.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 09/15/2023 and 01/11/2024 have been considered.
Claim Objections
Claims 25, 27, 28, 36, 38, 41, 46, and 48 are objected to because of the following informalities: In claim 25, insert the missing word “synthesized” immediately before the recitation “oligonucleotide from the supporting” (in step f) to make distinction from other preceding oligonucleotide; change the incorrect recitations “a salt of a base with a strong acid” and “cation of the salt” in second line from the end of the claim to “a salt from a base with a strong acid” and “cation of the base”, respectively, because the “salt” has both base and acid components. In claims 27 and 28, change the incorrect recitation “may be” (4th and 5th lines from the bottom of page 3; last 3 lines of claim 28), which means probably, to “is”; also in claim 27, replace the incorrect recitation “a supporting moiety” (last line on page 3), which has been recited in the preceding claim, with “the supporting moiety”. In claims 36, 38, 41, 46, and 48, insert the missing word “liquid” immediately before the recitation “composition C” to be consistent with the “liquid composition C” in preceding claims. Appropriate correction is required.
Claims 27 and 28 are objected to because they include reference characters which are not enclosed within parentheses. Reference characters corresponding to elements recited in the detailed description of the drawings and used in conjunction with the recitation of the same element or group of elements in the claims should be enclosed within parentheses so as to avoid confusion with other numbers or characters which may appear in the claims. See MPEP § 608.01(m). Applicant is advised to enclose the recitations “Formula I” and “Formula II” beneath the corresponding chemical structures with parenthesis.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 25-28, 30-34, 36, 38, 41, and 44-48 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. Claims 27, 28, 30-34, 36, 38, 41, 44-46 and 48 depend from claim 25.
Claims 25, 26, and 47 recite the limitation "the compound" (line 7 of claim 25), “the desired type” (line 5 of claim 26), or “nucleobases” (line 5 of claim 47). There is insufficient antecedent basis for this limitation in the claim. Applicant is advised to delete the recitation "the compound" (line 7 of claim 25); to change the recitation “the desired type” (line 5 of claim 26) to “a desired type”; and to replace the recitation “nucleobases” (line 5 of claim 47) with “protected nucleoside or oligonucleotide in step b)”.
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.
Claims 25-28, 30, 31, 34, 36, and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kicsak et al. (Org. Biomol. Chem., 2016, 14, 3190, hereinafter referred to as Kicsak ‘2016) incorporated by the reference of Caruthers (J. Chem Educ., 1989, 66, 577, hereinafter referred to as Caruthers ‘1989) and evidenced by McLaughlin et al. (J. Am. Chem. Soc. 1960, 82, 21, 5618–5621, hereinafter referred to as McLaughlin ‘1960).
With regard to structural limitations “a method comprising the following steps: (a) providing a supporting moiety-bound nucleoside or oligonucleotide comprising a backbone hydroxyl moiety, which is protected by a di(p-methoxyphenyl)phenylmethyl protecting group (or a compound of Formula I:
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); (b) cleaving the di(p-methoxyphenyl)phenylmethyl protecting group from the nucleoside or oligonucleotide by incubating with a liquid composition C comprising at least one aprotic (or non-halogenated) solvent, at least one alcohol selected from hexafluoroisopropanol, and a base-strong acid salt, wherein the cation of the base has a pKa in the range of 1 to 4 and the strong acid has a pKa of less than 1, thereby generating a free backbone hydroxyl moiety; (c) reacting the free backbone hydroxyl group resulting from step (b) with a phosphorus moiety of a nucleoside or oligonucleotide building block, wherein the building block further comprises a hydroxyl group protected by a di(p-methoxyphenyl)phenylmethyl protecting group (or a compound of Formula II:
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), thereby producing a covalent linkage between the oxygen atom of the free hydroxyl group and the phosphorus atom of the building block; (d) modifying (or further oxidizing or sulfuring) the phosphorus moiety; (e) optionally repeating the sequence of steps (b) to (c) or (b) to (d); and (f) cleaving the synthesized oligonucleotide from the supporting moiety” (claims 25-28, 36, and 44), “further comprising a step (g) of blocking unreacted free hydroxyl groups after step (c) or after step (d); or step (b) is carried out in a batch reactor; or further comprising step (h): isolating the support-cleaved oligonucleotide” (claims 30, 31, and 34):
Kicsak ‘2016 disclosed a new reagent system consisting of a Lewis acid such as boron trifluoride diethyl etherate (BF3·Et2O), the mild protic acid hexafluoroisopropanol and the reducing quenching agent triethylsilane, was elaborated for O-, N- and S-detritylation of nucleoside. The method is compatible with acetyl, silyl, acetal and Fmoc groups. First, deprotection of 5′-O-trityl uridine 1 (
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) was studied using a reagent cocktail including boron trifluoride diethyl etherate as the Lewis acid, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a mild protic acid and the reducing agent triethylsilane (Table 1). Noteworthily, HFIP is capable of slowly removing 4,4′-dimethoxytrityl groups when it is used as a single agent. The complete cleavage of the protective group using the three-component reagent has taken place in 2–3 minutes (entry 1). Cleavage of the 4,4′-dimethoxytrityl groups of 2′-deoxynucleosides 4a (
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), 5a (
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) and 6a (
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) also proceeded rapidly, without depurination. The trityl ethers are especially important tools in nucleic acid synthesis for the protection of 5′-hydroxyl of nucleosides, and deprotection is generally accomplished with dichloroacetic acid in dichloromethane, reference #3 (page 3190, Abstract; right col., para. 2; page 3191, Table 1; left col., para. 1; Scheme 1; page 3190, left col., para. 1; page 3192; right col., reference #3: M. H. Caruthers, J. Chem Educ., 1989, 66, 577). Caruthers ‘1989 (incorporated by reference here) disclosed Synthesis of DNA on silica supports using deoxynucleoside phosphoramidites as synthons.
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The steps i-iv correspond to those listed in the table below. Abbreviations: ℗ the silica matrix, including the succinate linkage, compound 13 (
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), Figure 4; iPr, isopropyl: R is either methyl (CH3-) or ß-cyanoethyl (NCCH2CH2-).
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. Because of the repetitive nature of this chemistry, a large number of automatic instruments called gene machines have been developed to synthesize DNA (page 579, left col., Fig. 5 and Table; page 580, left col., para. 2). McLaughlin ‘1960 (cited here as evidence for the pKa of boron trifluoride diethyl etherate, BF3·Et2O) disclosed Dissociation Data for Diethyl Ether:Boron Trifluoride:
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(page 5620, left col., Table IV).
Thus, these teachings of Kicsak ‘2016 incorporated by the reference of Caruthers ‘1989 and evidenced by McLaughlin ‘1960 anticipate Applicant’s claims 25-28, 30, 31, 34, 36, and 44 because the boron trifluoride diethyl etherate (BF3·Et2O, in which the BF3 is anion and the Et2O is cation having a calculated temperature-dependent pK(dissociation constant) of about or less than 1), hexafluoroisopropanol and triethylsilane of Kicsak ‘2016 correspond to claimed base-strong acid salt with pKa of 1 to 4 for the base and with pKa of less than 1 for the strong acid, hexafluoroisopropanol and aprotic (or non-halogenated) solvent, respectively.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 25-28, 30-34, 36, 38, 41, and 44-48 are rejected under 35 U.S.C. 103 as being unpatentable over Kicsak et al. (Org. Biomol. Chem., 2016, 14, 3190, hereinafter referred to as Kicsak ‘2016) incorporated by the reference of Caruthers (J. Chem Educ., 1989, 66, 577, hereinafter referred to as Caruthers ‘1989) and evidenced by McLaughlin et al. (J. Am. Chem. Soc. 1960, 82, 21, 5618–5621, hereinafter referred to as McLaughlin ‘1960), in view of Fox et al. (US 8,299,206, Oct. 30, 2012, hereinafter referred to as also Fox ‘206, also listed in the IDS filed on 09/15/2023). Claims 25-28, 30, 31, 34, 36, and 44 are rejected here because they have been rejected by the primary reference under 102 above. The above disclosure of Kicsak ‘2016 incorporated by the reference of Caruthers ‘1989 and evidenced by McLaughlin ‘1960, is therefore incorporated by the reference in its entirety here. The Kicsak ‘2016 incorporated by the reference of Caruthers ‘1989 and evidenced by McLaughlin ‘1960 did not explicitly disclose the structural limitations “the flow rate of the liquid composition C through the column reactor is below 300 cm/h in at least one iteration of step (b)”, “at a scale of 100 mmol oligonucleotide product or greater”, “the base contained in the liquid composition C is a cyclic amine (elected; or pyridine)”, “the strong acid contained in the composition C is a carboxylic acid (elected)”, “the aprotic solvent accounts for 60-99% or the alcohol accounts for 1-40% of the overall volume of the liquid composition C”, “the molar concentration of the alcohol is at least 2 times more than the molar concentration of the base”, and “total molar amount of the strong acid is in the range of 0.80-15.0 equivalents relative to the total molar amount of the di(p-methoxyphenyl)phenylmethyl groups”, required by claims 32, 33, 38, 41, and 45-48.
Fox ‘206 disclosed a deprotecting step comprising exposing the triarylmethyl-protected ring nitrogen to a reagent solution comprising a heterocyclic amine salt in a trifluoroethanol-containing solvent, the salt being a salt of a heterocyclic amine, having a pKa in the range of 1-4 in its protonated form, with an acid selected from a sulfonic acid, trifluoroacetic acid, and hydrochloric acid. The heterocyclic amine is preferably selected from the group consisting of: an electron withdrawing group-substituted pyridine, thiazole, pyridazine, pyrazole, triazole. Various pyridinium salts of strong acids in mixtures of trifluoroethanol (TFE) and dichloromethane (DCM) are excellent catalysts for removing the triarylmethyl protecting group, e.g. a trityl group. A minimum amount of TFE ( ̴10% v/v or greater) is preferred for reasonable reaction rates and solubilization of the pyridinium salts. The use of the TFE solvent is believed to enhance the selectivity of the detritylation reaction over amidate formation (hydrolysis) and phosphorodiamidate (PDA) cleavage (col. 2, lines 16-22; col. 5, lines 45-58).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the boron trifluoride diethyl etherate salt as taught by Kicsak ‘2016 incorporated by the reference of Caruthers ‘1989 and evidenced by McLaughlin ‘1960 with the pyridinium-trifluoroacetic acid salt in view of Fox ‘206 for detritylating di(p-methoxyphenyl)phenylmethyl (DMT) groups because the presence of hexafluoroisopropanol or trifluoroethanol enhances detritylation, such as DMT, without inducing depurinization or phosphorodiamidate cleavage, described above. Therefore, one of skill in the art would have a reasonable expectation that by substituting the boron trifluoride diethyl etherate salt as taught by Kicsak ‘2016 with the pyridinium-trifluoroacetic acid salt in view of Fox ‘206, followed by optimizing the nucleic acid synthesis conditions (flow rate, mmol scale of synthesis, volume, and/or molar concentration), one would achieve Applicant’s claims 25-28, 30-34, 36, 38, 41, and 44-48. "Exemplary rationales that may support a conclusion of obviousness include: (B) Simple substitution of one known element for another to obtain predictable results". See MPEP § 2143 [R-01.2024] [I]. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05 [R-01.2024] [II.A].
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691
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