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 application is a continuation of PCT/EP2022/053556, filed February 15, 2022, which claims benefit of foreign application EP21157508.9, filed February 17, 2021. Claims 1-16 are pending in this application and examined on the merits herein. Applicant’s preliminary amendment submitted November 29, 2023, is acknowledged wherein claims 1-12 are amended and new claims 13-16 are introduced.
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 12 and 16 are 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 12 and 16 16 are process claims directed to a process for cleaving a protecting group from an oligonucleotide. They depend from claims 10 and 11, respectively, which specifically limits the amount of depurination and N-1 impurities in the oligonucleotide. However, claims 12 and 16 include the further limitation that the level of impurities “is measured in the resulting linear P-linked oligonucleotide after cleavage and deprotection and before any downstream processing is applied.” It is unclear based on the context of this limitation whether it is intended to positively recite a step of measuring the specific impurity at a specific time, or whether it is a product-by-process limitation merely requiring that the level of depurination or N-1 impurities at said time be below the recited value whether or not the person performing the process actually performs the measuring step at the indicated time. Therefore claim 16 is indefinite.
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 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Cramer et al. (PCT international publication WO2012/059510, Reference included with PTO-1449)
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 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 claims 10 and 11, Cramer et al. describes both detritylation 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.
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.
Conclusion
No claims are allowed in this action.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 1/16/2025