Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This office action is a response to applicant’s communication submitted July 23, 2026, wherein claims 1, 12, and 16 are amended and claims 10 and 11 are canceled. This application is a continuation of PCT/EP2022/053556, filed February 15, 2022, which claims priority to foreign application EP21157508.9, filed February 17, 2021.
Claims 1-9 and 12-16 are pending in this application.
Claims 1-9 and 12-16 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted July 23, 2026, with respect to the rejection of claims 12 and 16 under 35 USC 112(b) for being unclear as to whether or not they require an additional measurement step, has been fully considered and found to be persuasive to remove the rejection as the claims have been amended to clearly recite such a step. Therefore the rejection is withdrawn.
The following rejections of record in the previous action are maintained:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-9 and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Cramer et al. (PCT international publication WO2012/059510, Reference of record in previous action)
Independent claim 1 claims a method or removing a 5’O- protecting group form a P-linked oligonucleotide comprising contacting said oligonucleotide with a solution of a protic acid in a mixture of toluene and acetonitrile. Dependent claims 2 and 3 further define the protic acid, for example dichloroacetic acid. Dependent claims 4 and 5 define the specific protecting group, for example 4,4’-dimentoxytrityl, 4-methoxytrityl, or trityl.
Cramer et al. discloses a method for reducing or controlling pressure in a solid support column during oligonucleotide synthesis. (p. 2 lines 5-11) The synthesis process described in the reference includes a step of detritylation to remove a protecting group from either the 5’- or 3’- end of the oligonucleotide. (p. 7 lines 25-28) In one embodiment the protecting group is a 5’- protecting group which is a trityl, dimethoxytrityl, or monomethoxytrityl, all of which are recited in present claims 4-5. (p. 8 lines 8-9) The protecting group is removed by treatment with an acid, which can be selected from haloacetic acids including dichloroacetic acid as recited in present claims 2-3. (p. 9 lines 26-28) The acid used as the deprotection reagent can be dissolved in a solvent selected from a list including toluene. (p. 9 line 33 – p. 10 line 5) While Cramer et al. does not specifically describe an embodiment wherein the solvent is a mixture of toluene and acetonitrile, the reference does state that the detritylation solution can comprise acetonitrile in combination with any of the foregoing solvents, (p. 10 lines 11-13) of which toluene is one. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to carry out the deblocking step described by Cramer et al. using DCA as the acid and a mixture of toluene and acetonitrile as the solvent. Doing so would have merely involved following the direct suggestions of the prior art by picking elements from lists of options presented by the art.
Regarding the limitations requiring that the depurination related impurities be below 8% and the level of N-1 impurities be below 3%, Cramer et al. describes both depurination and N-1 mer deletion as undesirable side reactions that can compromise the quality of the product, and suggests optimizing the contact time between the oligonucleotide and the acid detritylation reagent in order to maximize the overall quality of the product. (p. 11 lines 17-26) Regarding N-1 mers, Cramer et al. discloses batches 1 and 2 wherein this impurity is controlled to below 3.0%, (p. 30 table 1) indicating that this is an achievable result. Furthermore, given that the prior art recognizes the levels of these two impurities as important and suggests optimizing the contact time so as to avoid excessive amounts of either impurity, this would be taken by one of ordinary skill in the art as suggesting that one of ordinary skill in the art perform further measurement steps to evaluate the amounts of these impurities, as suggested by claims 12 and 16.
Regarding claims 6 and 13, while Cramer et al. does not specifically state what proportion of acetonitrile can be combined with the other solvent such as toluene, one of ordinary skill in the art, in combining the two solvents, would have necessarily had to determine an appropriate ratio to combine them in. In doing so, it would have been obvious to one of ordinary skill in the art to select an appropriate amount of acetonitrile, falling within the broad range recited in claim 7.
Regarding claim 7, Cramer et al. discloses a preferred acid concentration of about 3% DCA, falling within the claimed range. Regarding claim 15, Cramer et al. discloses higher possible concentrations of DCA including for example about 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, and 10%. (p. 10 lines 20-26)
Regarding claim 8, while Cramer et al. does not specifically describe the optimal flow rate during detritylation in toluene:acetonitrile solvent in terms of CV/min, (column volumes per minute) example 1 provided by Cramer describes a method in which on oligonucleotide is synthesized on a solid phase loaded into a column, and a detritylation step is included in the protocol. (p. 28 lines 13-29) Furthermore a pressure increase was noted during detritylation which led the experimenter to control the flow rate during detritylation so as to avoid pressure increases. (p. 29 lines 3-14) It would have therefore been obvious to one of ordinary skill in the art at the time of the invention to determine the optimal flow rate to maximize the yield of the reaction while avoiding pressure increases. Furthermore note that the bed height in the columns is about 10 cm. (p. 30 table 1) Therefore the base flow rate of 400 cm/hr described in batch 2 is about 10 column volumes per hour, or about 0.17 CV/min, which falls within the scope of claim 8. Therefore if one of ordinary skill in the art were to successfully use washing steps to avoid pressure buildup, the optimal flow rate would presumably fall within the claimed range.
Regarding claim 9, Cramer et al. further describes washing the column with a detritylation washing fluid before and after detritylation. (p. 11 lines 27-34) This washing fluid can be the same solvent used for detritylation, and toluene is given by way of example. (p. 11 lien 35 – p. 12 line 3) Furthermore Cramer et al. describes acetonitrile as a component that can be added to the wash solvent. (p. 12 lines 18-19) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to use a wash solvent containing toluene and acetonitrile before and after the detritylation step, as doing so merely involves following the specific suggestions of the reference.
Regarding claim 14, while Cramer et al. does not specifically describe a step of mixing protic acid in toluene with acetonitrile, as discussed above Cramer et al. renders obvious a detritylation step using a solution of a protic acid in a combination of toluene and acetonitrile. Therefore it would have been obvious to one of ordinary skill in the art to make such a solution, for example by adding the acid and solvents together in whatever order one of ordinary skill in the art would deem convenient. The choice to mix the acid and toluene first, and then add the acetonitrile, merely involves arbitrarily choosing one of a limited number of options as to how to combine there three ingredients.
For these reasons the invention taken as a whole is prima facie obvious.
Response to Arguments
Applicant’s arguments, submitted July 23, 2026, with respect to the above grounds of rejection, have been fully considered and found to be persuasive to remove the rejection. Applicant argues that, based on the disclosures of Paul et al. and US6538128 (both of record in PTO-1449) acetonitrile is inferior as a reaction solvent for detritylation reactions compared to dichloromethane due to its binding to the acid used in the detritylation step. Applicant argues that there references teach away from using acetonitrile as a solvent in this step.
However, the teachings of the cited references must be taken in the context of the entire teaching of the art. For example Russell et al. (Reference included with PTO-892) describes detritylation in acetonitrile as occurring, though at a higher concentration of acid than in dichloromethane. (See p. 53 figure 1) It is further noted that the required acid concentration for reaction in acetonitrile is less than that required for reaction in toluene. US pre-grant publication 2021/0206797 (Cited in PTO-892) further describes a solid phase oligonucleotide synthesis reaction using acetonitrile as the deprotection solvent. Both of these references, which were published after the references cited by Applicant, suggest that those of ordinary skill in the art did not regard acetonitrile as unusable or undesirable in these reactions, and that there was no clear teaching against its use in the art. Still further, the examiner notes that in addition to the specific teachings cited by Applicant in the disclosure of US6538128, the reference also specifically criticizes the use of methylene chloride as a solvent in oligonucleotide synthesis based on its expense and difficulty of disposal of chlorinated solvents, and its tendency to form channel currents in polymer supports. Therefore even if dichloromethane were superior to acetonitrile in some respects, the prior art would not thereby absolutely discount the use of other solvents based on the known problems with dichloromethane.
Applicant further criticizes the list of solvents described by Cramer, noting that the list includes compounds that are solid at room temperature, and merely lists acetonitrile as one among many possible detritylation solvents. However, a patent is prior art for all it discloses, not merely preferred examples. Furthermore while an extensive list of alkylbenzene solvents is provided, toluene is later (p. 10 lines 25-26) described as a preferred alkylbenezene solvent and acetonitrile is specifically mentioned in a separate sentence (p. 10 lines 11-13) as being combinable with any of the recited alkylbenzene solvents, indicating that these are both specifically pointed out by the reference. Furthermore the fact that some of the recited solvents would be solid when present in pure form at room temperature is not relevant because the reference clearly describes them as potentially being used in combination with other alkylbenzene solvents or acetonitrile, in which state they would not be solid.
Applicant further argues that the results described in Cramer’s examples were of reactions carried out in toluene, and not in a mixed toluene:acetonitrile solvent, and that Cramer does not provide a solution for reducing depurination impurities. In fact, as discussed earlier, Cramer describes at least one solution, namely optimizing and controlling the contact time of the detritylation step to avoid excessive formation of either impurity. In such a circumstance, it would have been obvious to optimize the reaction conditions to reduce both impurities. Arriving at optimal solvent mixtures and reaction parameters would therefore be obvious absent a showing of unexpected results for the use of particular solvents in particular amounts. While Applicant states that the presently claimed invention solves the depurination problem and provides both low N-1 impurities and low depurination impurities, they do not point to concrete data showing that the specifically claimed combination of solvents unexpectedly provides superior control of these impurities compared to what would be expected based on prior art knowledge about how to adjust and optimize reaction conditions.
For these reasons the rejection nis deemed proper and maintained.
Conclusion
No claims are allowed in this action. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 9/11/2026
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