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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 30, 2026 has been entered.
DETAILED ACTION
Claims 1 – 2, 5, 8, 10, 13 – 18, 20, 22 – 23, 26, and 31 are pending in this application, wherein claim 1 is amended, claims 3 – 4, 6 – 7, 9, 11 – 12, 19, 21, 24 – 25, and 27 – 30 are canceled, and claims 13 – 18, 20, 22 – 23, 26, and 31 are withdrawn.
Claims 1 – 2, 5, 8, and 10 are currently examined.
Priority
This application is a national stage application of PCT/CN2020/125164, filed October 30, 2020, which claims benefit of foreign priority document CN202010828506.7, filed August 18, 2020; this foreign priority document is not in English. Applicant filed a certified translation of the foreign priority document on October 21, 2025.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Rejections
The rejection of claims 1 – 2, 5, 8, and 10 in the previous Office Action, dated April 30, 2026, under 35 U.S.C. 103 as being unpatentable over Horie et al. in view of Chow et al. and Gosselin et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 6 and 11 – 12 in the previous Office Action, dated April 30, 2026, under 35 U.S.C. 103 as being unpatentable over Horie et al. in view of Chow et al. and Gosselin et al. as applied to claims 1 – 2, 5, 8, and 10 above, and further in view of Hayashi et al. has been considered and is withdrawn in view of the amended claim 1.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
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 1 – 2, 5, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Horie et al. (EP3106519A1) in view of Chow et al. (US5656741), Gosselin et al. (WO2009/140125A2), Le Joubioux et al. (Journal of Molecular Catalysis B: Enzymatic, 2013, Vol. 95, PTO-892), and Polushin et al. (Nucleic Acids Research, 1994, Vol. 22, Issue 4, page 639 – 645, PTO-892).
Horie et al. teach a method of cutting out RNA oligonucleotide from a solid phase carrier (para. [0001]). The method comprises a step of bringing the support carrying the RNA oligonucleotide in contact with an aqueous solution containing an alkylamine and a monovalent inorganic salt. The aqueous solution further comprises an alcohol (para. [0013]). The alkylamine is a primary alkylamine, such as butylamine (para. [0029]) and the alcohol is butanol (para. [0032]). The content of alcohol in the aqueous solution is preferably 1 – 80% by volume (para. [0033]). The volume ratio of alkylamine:alcohol used in the examples is 1:1 (para. [0057]). Horie et al. further disclose aqueous methylamine solution/alcohol mixtures having selected relative amounts, including 40% aqueous methylamine solution/isopropanol at volume ratios of 9:1, 8:2, 6:4, and 95:5 in the disclosed oligonucleotide cleavage experiments (para. [0062]). The disclosed method is able to suppress the production of a byproduct and increase the yield of the object RNA oligonucleotide (para. [0012]). In addition, Horie et al. disclose that cleavage with aqueous sodium hydroxide solution containing NaCl has also been used previously (para. [0005]). Thus, Horie et al. teach the “amine” and “butanol” of claim 1, “butylamine” of claim 2, and “n-butanol” of claim 5, and further provide evidence that aqueous sodium hydroxide solution is known for oligonucleotide cleavage.
However, Horie et al. do not teach the claimed aminolysis solution comprising amino alcohol, wherein the amino alcohol comprises amino butanol and/or amino pentanol, wherein the amino pentanol is 4-amino-1-pentanol. Horie et al. do not teach the concentration of alkaline aqueous solution that is 4 – 10 M. Horie et al. do not explicitly teach the volume ratio of the components recited in claims 1 and 10.
Gosselin et al. teach an efficient and safer (easy to handle and environmentally less hazardous) protocol for cleavage and deprotection of synthetic oligonucleotides utilizing ethanolamine. The method cleaves the synthetic oligonucleotides from the solid support allowing the isolation and subsequent purification of the oligonucleotides (page 1, lines 19 – 24). Gosselin et al. teach that 10 mL of ethanolamine is used (page 4, line 19). Thus, Gosselin et al. teach the use of an amino alcohol, i.e. ethanolamine, for cleavage and deprotection of synthetic oligonucleotide from a solid support, which reads on the “amino alcohol” limitation of claim 1.
Chow et al. teach reagents that are useful for rapid processing of synthetic oligonucleotides, include a basic reagent for the cleavage and deprotection of the synthesized oligonucleotides from a support. The basic reagent optionally includes a wetting agent useful for the cleavage from lipophilic supports (Abstract). In a preferred embodiment, the basic reagent is provided in the form of a 2 M sodium hydroxide solution (Col. 6, lines 2 – 4). Using higher concentration of sodium hydroxide, the deprotection time can be shorten (Col. 10, lines 9 – 11). The wetting agents have the function of an accelerator of sodium hydroxide reactivity. The wetting agent is preferably added in an amount that is miscible with the basic solution yet sufficient to improve the wettability of the support and attached oligonucleotide (Col. 7, lines 55 – 58). Examples of suitable wetting agents includes alcohols and alkylamines, wherein the alkyl group is butyl (Col. 7, lines 60 – 63; Col. 8, lines 1 – 3). Chow et al. further teach that 0.5 mL of sodium hydroxide is used and about 5 volumes of reagent B for precipitation and neutralization follow. Thus, Chow et al. teach an alkaline aqueous solution comprising sodium hydroxide for cleavage and deprotection of synthetic oligonucleotides, which reads on the limitations “alkaline aqueous solution” of claim 1 and the “aqueous solution of NaOH” of claim 8. Chow et al. teach that increasing the concentration of sodium hydroxide shortens the deprotection time. Moreover, Chow et al. teach a 1:1 combination of methanol and 0.5 M NaOH, providing a final composition containing 0.25 M NaOH and 50% methanol, and further teach 0.5 M NaOH solution combined with methanol at a 4:1 ratio, providing a final composition containing 0.4 M NaOH and 20% methanol. In both cases, cleavage is about 95% complete within 5 minutes at room temperature and deprotection is complete within 30 minutes to 1 hour at 85 ⁰C (Col. 15, lines 16 – 26).
Le Joubioux et al. teach 4-amino-1-pentanol as a bifunctional amino alcohol and experimentally demonstrate both O-acylation and N-acylation of 4-amino-1-pentanol using myristic acid as an acyl donor (Abstract). Le Joubioux et al. specifically measure N-acylation of 4-amino-1-pentanol and identify N-myristyl 4-amino-1-pentanol as an amide product by reporting the C=O, amide and N-H, amide from the IR peaks (page 101, Table 1; Right Col., para. 2), thereby demonstrating that the amino functionality of 4-amino-1-pentanol is chemically operative in acyl-group reaction chemistry. Thus, Le Joubioux et al. teach the specifically recited amino alcohol, 4-amino-1-pentanol, which reads on the limitation of claim 1 requiring that the amino pentanol is 4-amino-1-pentanol.
Polushin et al. teach accelerated deprotection of synthetic oligonucleotides using a multicomponent deprotection composition comprising hydrazine, ethanolamine, and methanol at a volume ratio of 1:5:5 (v/v/v) (Abstract; page 639, Left Col., para. 2). Polushin et al. teach that treatment with the hydrazine/ethanolamine/methanol mixture accomplishes deprotection within about 3 – 5 minutes at room temperature, whereas neat ethanolamine requires about 15 – 20 minutes under the disclosed conditions (page 642, Left Col., para. 3). Thus, Polushin et al. demonstrate in the relevant oligonucleotide deprotection art that an amino alcohol and an alcohol may be combined with another nitrogen-containing deprotection reagent at selected relative amounts and that selection of the components and the relative amounts affects oligonucleotide deprotection performance.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the oligonucleotide cleavage and deprotection composition of Horie et la. to further include an amino alcohol in view of Gosselin et al., to employ an alkaline aqueous solution, such as aqueous NaOH, in view of Chow et al., and to select 4-amino-1-pentanol as the amino alcohol in view of Le Joubioux et al. because Horie et al., Gosselin et al., and Chow et al. are all directed to the cleavage and/or deprotection of synthetic oligonucleotides from a solid support. Horie et al. teach the use of an alkylamine and alcohol for such cleavage, Gosselin et al. teach the use of amino alcohol for efficient cleavage and deprotection of synthetic oligonucleotides, and Chow et al. teach the use of aqueous NaOH for cleavage and deprotection and further teach that increasing the NaOH concentration shortens the deprotection time. Accordingly, one of ordinary skill in the art would have been motivated to employ these known cleavage/deprotection reagents together in order to provide an aminolysis composition capable of promoting efficient cleavage and deprotection of the oligonucleotide while maintaining the known cleavage/deprotection activity of the alkylamine, amino alcohol, and alkaline reagent.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to select 4-amino-1-pentanol as the amino alcohol in the modified composition in view of Le Joubioux et al. because Gosselin et al. establish that an amino alcohol is useful in oligonucleotide cleavage and deprotection, while Le Joubioux et al. teach the specifically recited 4-amino-1-pentanol as a known bifunctional amino alcohol and experimentally demonstrate that its amino functionality participates in N-acylation, including formation of N-myristyl 4-amino-1-pentanol. Thus, one of ordinary skill in the art would have recognized 4-amino-1-pentanol as a known amino alcohol having an operative amine functionality and would have had reason to select it as an alternative amino alcohol for providing the amino-alcohol functionality in view of Gosselin et al.
With respect to the recited relative amounts of amine, butanol, and amino alcohol, Horie et al. teach amine-containing solution/alcohol compositions having selected relative amounts, including 40% aqueous methylamine solution/isopropanol at volume ratios of 9:1, 8:2, 6:4, and 95:5. Polushin et al. further teach in the oligonucleotide deprotection art that an amino alcohol and an alcohol may be used at equal relative amounts, including ethanolamine and ethanol at a 1:1 volume ratio. Thus, one of ordinary skill in the art would have had reason to retain the amine-rich cleavage composition taught by Horie et al. while introducing an amino alcohol, as taught by Gosselin et al. and Polushin et al., in an amount comparable to the alcohol. For example, retaining the 9:1 amine-containing solution/alcohol relationship of Horie et al. while employing amino alcohol at an amount comparable to the alcohol provides an amine-containing solution:alcohol:amino alcohol relationship of about 9:1:1, which corresponds to the claimed (5 – 10):(1 – 5):1 relationship. The modification would have provided the known amino alcohol cleavage/deprotection functionality while retaining the amine-rich composition taught by Horie et al. to be effective for oligonucleotide cleavage. With respect to the alkaline aqueous solution, Chow et al. teach aqueous sodium hydroxide concentrations beginning at about 0.1 M for oligonucleotide cleavage/deprotection. Claim 1 requires only 0.01 – 0.1 volume part of a 4 – 10 M alkaline aqueous stock solution relative to the amine, butanol, and amino alcohol. Because the amount of alkali delivered to the final aminolysis composition depends on both the concentration of the alkaline stock solution and the volume added, one of ordinary skill in the art would have recognized that the low operative alkali concentration taught by Chow et al. may be supplied by using a more concentrated alkaline stock solution in a correspondingly smaller volume. For example, a claimed composition using an amine:butanol:amino alcohol:alkaline aqueous solution ratio of approximately 9:1:1:0.1 and a 10 M alkaline stock solution provides an effective alkali concentration of about 0.09 M in the final mixture, which is close to 0.1 M concentration taught by Chow et al. MPEP § 2144.05 explains that even when numerical ranges or amounts do not overlap, a prima facie case of obviousness may exist when the values are sufficiently close that one of ordinary skill in the art would have expected them to provide the same properties. In this case, the small differences between about 0.09 M and 0.1 M would not have been expected to materially alter the known cleavage/deprotection function of the alkaline reagent. Accordingly, the recited 0.01 – 0.1 volume part is not relied upon as an arbitrary ratio selected through routine optimization, but as an amount consistent with supplying a known operative level of alkali while limiting the volume of aqueous solution introduced into the aminolysis composition.
With respect to the recited concentration of the alkaline aqueous solution, Chow et al. teach that the use of aqueous NaOH for oligonucleotide cleavage and deprotection, including operative dilute concentrations of NaOH. Although Chow et al. do not explicitly teach a 4 – 10 M alkaline aqueous stock solution, one of ordinary skill in the art would have recognized that the amount of alkali supplied to the reaction composition depends upon both the concentration of the alkaline solution and the volume of that solution added.. Thus, a desired amount of alkali may be provided either by adding a larger volume of a more dilute solution or a smaller volume of a more concentrated solution. In view of the claimed requirement that only 0.01 – 0.1 volume part of alkaline aqueous solution is added, use of a 4 – 10 M stock solution provides an approach of supplying an operative amount of alkali in the recited small volume. Accordingly, selection of a more concentrated alkaline stock solution together with a correspondingly smaller added volume would have been a predictable formulation choice for supplying the desired amount of alkaline reagent to the aminolysis composition. For example, at an amine:butanol:amino alcohol:alkaline aqueous solution ratio of 9:1:1:0.1 using a 10 M alkaline stock solution, the resulting alkali concentration in the final mixture is about 0.09 M, which is close to the 0.1 M concentration taught by Chow et al. MPEP § 2144.05 explains that even when numerical ranges or amounts do not overlap, a prima facie case of obviousness may exist when the values are sufficiently close that one of ordinary skill in the art would have expected them to provide the same properties. In this case, the small differences between about 0.09 M and 0.1 M would not have been expected to materially alter the known cleavage/deprotection function of the alkaline reagent. Thus, the recited 4 – 10 M concentration of the alkaline stock solution, when considered together with the recited small volume thereof, is consistent with providing an alkali concentration known in the prior art to be operative for oligonucleotide cleavage/deprotection. One of ordinary skill in the art would have had a reasonable expectation of success in making the modifications because Horie et al., Gosselin et al., Chow et al., and Polushin et al. each demonstrate that the respective classes of reagents are operative in the same general context of cleavage and/or deprotection of synthetic oligonucleotides from a solid support. Further, Le Joubioux et al. experimentally demonstrate that 4-amino-1-pentanol is a chemically operative bifunctional amino alcohol whose amino functionality undergoes N-acylation. Accordingly, one of ordinary skill in the art would have had a reasonable expectation that the modified composition would remain operative for oligonucleotide cleavage and deprotection because the proposed modification retains the amine-rich cleavage composition taught by Horie et al., incorporates an amino alcohol for its known cleavage/deprotection functionality as taught by Gosselin et al. and Polushin et al. and supplies an amount of alkaline reagent consistent with the operative alkaline conditions taught by Chow et al. The modification therefore applies known reagents for the known functions in an amounts supported by the prior art teachings rather than relying on an unpredictable change in reagent functionality.
Regarding claim 10, which further limits the volume ratio of amine:butanol:amino alcohol:alkaline aqueous solution to (6 – 8): (2 – 3):1:(0.04 – 0.06), Horie et al. teach an amine-containing solution/alcohol volume ratio of 8:2, which corresponds to the recited amine:butanol relationship of (6 -8):(2 – 3). Polushin et al further teach the use of an amino alcohol and alcohol at comparable relative amounts in oligonucleotide deprotection compositions. Thus, one of ordinary skill in the art would have had reason to retain the amine-rich 8:2 relationship taught by Horie et al. while introducing an amino alcohol in an amount comparable to the alcohol, thereby providing an amine:alcohol:amino alcohol relationship consistent with the narrower proportions recited in claim 10. With respect to the alkaline aqueous solution, Chow et al. teach the use of aqueous NaOH for oligonucleotide cleavage/deprotection, and one of ordinary skill in the art would have recognized that the amount of alkali supplied to the final composition may be controlled by the concentration of the alkaline stock solution and the volume added. Accordingly, use of a small amount of concentrated alkaline aqueous solution within the recited 0.04 – 0.06 volume part would have been a predictable means of supplying the alkaline reagent while limiting the amount of aqueous solution introduced into the aminolysis composition.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed June 30, 2026, have been fully considered and are found to be not persuasive in view of the rejection set forth herein.
Applicant argues that the amended claim 1 now requires a particular multi-component aminolysis solution comprising an amine, butanol, an amino alcohol comprising amino butanol and/or amino pentanol, wherein the amino pentanol is 4-amino-1-pentanol, and an alkaline aqueous solution having a concentration of 4 – 10 M, at the recited volume ratio. Applicant further argues that, according to the specification, the amine, butanol, amino alcohol, and alkaline aqueous solution perform different but cooperative functions, whereas the amine and amino alcohol participate in cleavage/deprotection, butanol and the amino alcohol function as reaction solvents, and the alkaline aqueous solution is present in a small amount to accelerate aminolysis. Applicant contends that the identity of the amino alcohol and the concentration of the alkaline aqueous solution are important to obtaining the desired cleavage/deprotection efficiency, yield, purity and product appearance. However, the argument is not persuasive because the rejection does not rely on Horie et al. alone as teaching every element of the presently claimed aminolysis solution. Instead, the rejection is based on the combined teachings of Horie et al., Gosselin et al., Chow et al., Le Joubioux et al., and Polushin et al. Horie et al. teach an alkylamine and alcohol oligonucleotide cleavage system and explicitly disclose amine-containing solution/alcohol formulations having selected relative amounts, including amine-rich formulations; Gosselin et al. teach the use of an amino alcohol for cleavage and deprotection of synthetic oligonucleotides; Chow et al. teach use of aqueous NaOH for oligonucleotide cleavage and deprotection and provide guidance concerning the amount of alkaline reagent supplied to the reaction composition; Le Joubioux et al. teach the recited 4-amino-1-pentanol as a chemically operative bifunctional amino alcohol and experimentally demonstrate its N-acylation; and Polushin et al. further teach multicomponent oligonucleotide deprotection compositions containing an amino alcohol and alcohol at selected relative amounts. Thus, the rejection relies on complementary prior art teachings directed to the respective components, the functions, and the relative amounts rather than merely combining unrelated reagents known independently in the art.
Applicant argues that Horie et la., Chow et al., and Gosselin et al. fail to teach the amino alcohol now recited in claim 1. Applicant further argues that Hayashi et al. disclose 5-amino-1-pentanol only in the preparation of peptides, copolymers, or homopolymers rather than in an oligonucleotide cleavage/deprotection system, and that amended claim 1 excludes the embodiment wherein the amino alcohol is 5-amino-1-pentanol. Applicant therefore contends that a skilled artisan would have lacked motivation and a reasonable expectation of success in introducing the amino alcohol of Hayashi et al. into the systems of Horie et al., Chow et al., or Gosselin et al. However, Applicant’s arguments directed to Hayashi et al. do not overcome the presently applied rejection because the rejection has been modified in view of the amended claims and now further relies on Le Joubioux et al. for the specifically recited 4-amino-1-pentanol. Le Joubioux et al. explicitly employ 4-amino-1-pentanol as a bifunctional amino alcohol and demonstrate both O-acylation and N-acylation thereof, including formation of N-myristyl 4-amino-1-pentanol. Gosselin et al. provide the relevant oligonucleotide cleavage/deprotection teaching that an amino alcohol may be employed for that purpose, while Le Joubioux et al. establish that the 4-amino-1-pentanol is a known and chemically operative amino alcohol. Accordingly, one of ordinary skill in the art would have had reason to select 4-amino-1-pentanol as an alternative amino alcohol for providing the amino alcohol functionality taught by Gosselin et al., with a reasonable expectation that the compound would retain operative amino functionality.
Applicant further argues that the claimed volume ratio of amine:butanol:amino alcohol:alkaline aqueous solution is not the result of conventional optimization because multiple variables allegedly interact with one another. Applicant asserts that the particular proportions simultaneously affect solid phase carrier cleavage, protecting group removal, oligonucleotide yield and purity, salt peaks observed during mass spectrometry, and appearance of the product after drying. Applicant therefore contends that the prior art does not recognize the alleged coordinated relationship among these variables and does not teach that the particular combination and proportion recited in claim 1 can achieve the asserted technical effects. However, the argument is not persuasive. The rejection does not rely merely on a general assertion that multiple formulation variables may be optimized.. Horie et al. explicitly teach amine-containing solution/alcohol formulations having selected relative amounts, including 40% aqueous methylamine solution/isopropanol at volume ratios of 9:1, 8:2, 6:4, and 95:5, thereby providing explicitly guidance for amine-rich oligonucleotide cleavage formulations. Polushin et al. further teach use of an amino alcohol and an alcohol at selected relative amounts and demonstrate that multicomponent formulations containing an amino alcohol may provide rapid deprotection. Thus, one of ordinary skill in the art would have had reason to retain the amine-rich relationship taught by Horie et al. while incorporating an amino alcohol in view of Gosselin et al. and Polushin et al. in an amount comparable to the alcohol. For example, retaining the 9:1 amine-containing solution/alcohol relationship of Horie et al. while employing amino alcohol at an amount comparable to the alcohol provides an approximately 9:1:1 relationship among the amine-containing solution, alcohol, and amino alcohol, which is within the recited (5 – 10):(1 – 5):1 relationship. With respect to the recited 0.01 – 0.1 volume part of alkaline aqueous solution, Chow et al. teach that aqueous NaOH is operative for oligonucleotide cleavage/deprotection, including a concentration of about 0.1 M. One of ordinary skill in the art would have recognized that the amount of alkali supplied to a reaction composition depends on both the concentration of the alkaline stock solution and the volume of that solution added. Accordingly, when employing a concentrated alkaline aqueous stock solution, a correspondingly small volume would provide an operative amount of alkali while limiting the amount of water introduced into the predominantly organic aminolysis composition. For example, a composition having an amine:butanol:amino alcohol:alkaline aqueous solution ratio of 9:1:1:0.1 and using a 10 M alkaline aqueous stock solution provides an effective alkali concentration of about 0.09 M in the resulting mixture, which is close to the 0.1 M NaOH concentration taught by Chow et al. MPEP § 2144.05 explains that even when numerical ranges or amounts do not overlap, a prima facie case of obviousness may exist when the values are sufficiently close that one of ordinary skill in the art would have expected them to provide the same properties. In this case, the small differences between about 0.09 M and 0.1 M would not have been expected to materially alter the known cleavage/deprotection function of the alkaline reagent. Thus, the recited 0.01 – 0.1 volume part is consistent with supplying an amount of alkaline reagent known in the art to be operative for oligonucleotide cleavage/deprotection when a concentrated alkaline stock solution is employed. With respect to Applicant’s assertion that the claimed proportions are critical, the comparative evidence does not isolate the claimed proportions as the variable responsible for the asserted improvement. The comparative formulation changes multiple features, including the identities of the amine and alcohol, the presence or absence of an amino alcohol, the concentration of the alkaline aqueous solution, and the relative amounts of the components. Accordingly, the differences in cleavage/deprotection performance, yield, purity, salt peak, or product appearance may not attributed specifically to the claimed relative proportions. The evidence therefore does not establish that the claimed ratio produces an unexpected result or is critical over the scope of claim 1.
Applicant argues that Chow et al. disclose a preferred NaOH concentration of only 0.1 – 2 M, which is substantially different from the presently claimed 4 – 10 M range. Applicant acknowledges the teachings of Chow et al. that use of higher NaOH concentrations may shorten deprotection time, but argues that Chow et al. do not explicitly direct the skilled artisan to increase the concentration to 4 – 10 M or teach that a small amount of such a high concentration alkaline solution would maintain yield and purity while avoiding salt peaks and whitening. Applicant characterizes the claimed 4 – 10 M range as a critical range that balances aminolysis efficiency and oligonucleotide product quality. However, the argument is not persuasive. Applicant focuses on the recited concentration of the alkaline aqueous solution before that solution is incorporated into the claimed aminolysis composition. Claim 1, however, requires the 4 – 10 M alkaline aqueous solution to be present at only 0.01 – 0.1 volume part relative to the larger amounts of amine, butanol, and amino alcohol. Thus, the claimed aminolysis composition does not contain alkali at a concentration of 4 – 10 M; instead, only a small volume of the concentrated alkaline aqueous solution is introduced into the aminolysis composition, resulting in a lower effective alkali concentration in the final reaction mixture. Chow et al. teach the use of aqueous NaOH for cleavage and deprotection of synthetic oligonucleotides and establish that low effective concentrations of NaOH are operative for that purpose. A person of ordinary skill in the art would have recognized that the amount of alkali supplied to the reaction mixture depends upon both the concentration of the alkaline stock solution and the volume added, such that a desired amount of alkali may be provided either by a larger volume of a more dilute solution or by a smaller volume of a more concentrated solution. For example, at an amine:butanol:amino alcohol:alkaline aqueous solution ratio of 9:1:1:0.1 using a 10 M alkaline stock solution, the resulting alkaline concentration in the final mixture is about 0.09 M, which is close to the 0.1 M concentration as taught by Chow et al. MPEP § 2144.05 explains that even when numerical ranges or amounts do not overlap, a prima facie case of obviousness may exist when the values are sufficiently close that one of ordinary skill in the art would have expected them to provide the same properties. In this case, the small differences between about 0.09 M and 0.1 M would not have been expected to materially alter the known cleavage/deprotection function of the alkaline reagent. Thus, the recited 4 – 10 M concentration of the alkaline stock solution, when considered together with the recited small volume thereof, is consistent with providing an alkali concentration known in the prior art to be operative for oligonucleotide cleavage/deprotection. Applicant has not established that supplying the alkaline reagent through a 4 – 10 M stock solution at the recited small volume, rather than supplying a comparable amount of alkali using a more dilute solution at a larger volume, produces an unexpected result.
Finally, Applicant summarizes that the presently amended claim defines a multi-component aminolysis system distinguished from the prior art by the particular amino alcohol, the 4 – 10 M alkaline aqueous solution, and the claimed component proportions, and contends that the cited references provide neither motivation to form the claimed combination nor a reasonable expectation of achieving the asserted balance of aminolysis efficiency, deprotection, yield, purity, salt characteristics, and product appearance. However, the argument is not persuasive for the reasons discussed above. Horie et al. teach an amine-rich alkylamine/alcohol oligonucleotide cleavage composition and explicitly provide numerical guidance concerning the relative amounts of those components, Gosselin et al teach the use of an amino alcohol in oligonucleotide cleavage/deprotection, Polushin et al. provide further guidance concerning the use and relative amount of an amino alcohol in multicomponent oligonucleotide deprotection compositions, Le Joubioux et al. provide the 4-amino-1-pentanol as a known chemically operative amino alcohol, and Chow et al. teach aqueous alkaline reagent for oligonucleotide cleavage/deprotection and provide the operative alkaline conditions relied upon in the rejection. Taken together, these teachings provide a reason to retain the amine-rich cleavage formulation of Horie et al., incorporate an amino alcohol for its known cleavage/deprotection functionality, select 4-amino-1-pentanol as the amino alcohol, and supply an operative amount of alkaline reagent through the recited small volume of concentrated alkaline aqueous solution. One of ordinary skill in the art would therefore have had a reasonable expectation of success that the resulting composition would remain operative for oligonucleotide cleavage and deprotection because the proposed modifications employ known reagents for the known functions in amounts supported by the prior art teachings.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/JONATHAN S LAU/Primary Examiner, Art Unit 1693
