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 .
Claims 1, 7, 9, 11, 15-17, 30-32, 37-40 and 49-54 are pending in the application. Claims 2-6, 8, 10, 12-14, 18-29, 33-36, and 41-48 have been canceled. Preliminary amendment filed 20 February 2024.
Priority
This application is a 371 of PCT/US2022/018447 filed 03/02/2022, which claims the benefit of 63155515 filed 03/02/2021.
The parent application 63155515 to which priority is claimed is seen to provide adequate support under 35 U.S.C. 112 for claims 1, 7, 9, 11, 15-17, 30-32, 37-40 and 49-54 of this application.
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.
Claim(s) 1, 7, 9, 11, 15-17, 30-32, 37-40 and 49-54 are rejected under 35 U.S.C. 103 as being unpatentable over Sasuga et al (US 2020/0054966 A1) in view of Muynck et al (Journal of Chromatography A, 2006, 1101, 115-121) and further in view of Dellinger et al (US 2020/0181124 A1).
Sasuga et al teaches a process for separating a designated oligomeric compound from at least one contaminant in a sample solution (para 0065; as in claim 1). The process comprises providing an HPLC column packed with a stationary phase, and adding equilibration solution to equilibrate the column. After this equilibration, a solution of a mixture of oligonucleotides serving as a sample is added to the column and gradient elution using water-soluble organic solvent may be adopted to facilitate the elution a target oligonucleotide. After that, the eluent passed at the time of equilibration is passed again to equilibrate the column (para 0036-0037; steps a-d and f in claim 1). The column can be washed by passing an alkaline solution through the column. This can be done before or after the liquid chromatography is performed (paras 0043-0044; step e in claim 1).
As mobile phase (elution solution) a mixed liquid of an aqueous solution of a volatile salt and water-soluble organic solvent is used. The concentration of the salt is from 1mM to 100mM and the pH can be from 5 to 9 and is preferably 6.5 to 7.5. The organic solvent can be from 30% to 90% (paras 0033-034; as in claim 1; and pH limitations as in claims 15-17). Since the elution solution has a water-soluble organic solvent and a salt and the pH can be greater than 7 the equilibration solution and washing solution, and the pH of the equilibration solution and the elution solution can also be the same other than the ratio (para 0046; as in claim 1; pH limitation of claim 31; and limitation of claim 32). The water-soluble organic solvent can be an alcohol having one to three carbons and acetonitrile (para 0032; limitation of claims 37-38). Since Sasuga teaches a salt concentration of 100mM, one of ordinary skill in the art can adjust the concentration of the salt to be in the range of 150-200nM for optimizing the equilibration and elution (as in claim 39). In the method of Sasuga a 10- to 70-mer is preferably separated as a sample (para 0018; as in claim 49). At para 0065 Sasuga teaches separation of synthetic oligonucleotides and non-full-length impurities. In view of this teachings the artisan would have a reasonable expectation of success in separating a designated oligomeric compound wherein at least one contaminant is an unconjugated oligonucleotide of 10-30 oligonucleotides and the unconjugated modified oligonucleotide as in claims 53 and 54.
Sasuga et al does not teach the use of boronic acid as a component in its equilibration and washing solutions and its concentration as in claim 1 and does not teach the limitations of claims 7, 9, 11, 40 and 50-52.
Muynck et al teaches that boronic acid forms complexes with polyhydroxy compounds like sugars. This phenomenon has been used for derivatization and separation of carbohydrates and other compounds containing vicinal diols by chromatography (page 116, left col., paras 1-3). Fig. 1 at page 116 shows the complexation between a sugar and borate ion as in claim 1. Even though Muynck does not exemplify separation of an oligonucleotide conjugated to at least one carbohydrate group as in claim 1 and the use of the boronic acids as in claims 7 and 9, one of ordinary skill in the art will recognize that since the complexation of the sugar hydroxyls with the boronic acid enables the separation of the sugars, there is a reasonable expectation of success that the same type of complexation can take place between the vicinal hydroxyl groups of a sugar conjugated to a modified oligonucleotide and enable its separation using an HPLC column. This renders obvious the separation of the designated oligomeric compound having the GalNAc sugar as in claims 50-51 and the conjugate as in claim 52 with a reasonable expectation of success. Therefore, the artisan would include boronic acid as a component in the equilibration and elution solutions in the method of claim 1. In Fig. 2, Muynck mentions concentrations of boric acid used in its method. Using this as a guide, the artisan can adjust the concentration of the boronic acid as in claim 1, 11 and 30 for optimizing the separation and would also use the boronic acids recited in claims 7 and 9 as components in the equilibration and elution solutions as in claim 1.
Dellinger teaches the use of sodium phosphate and sodium chloride as elution solutions for separating oligonucleotides (para 0173; as in claim 40). There is reasonable expectation of success in using these two salt solutions as equilibration and elution solutions in the claimed method.
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, oligonucleotides are known in the art to be separated from contaminants via HPLC using equilibration solutions and elution solutions comprising the salts and organic solvents as instantly claimed. It is known in the art that complexation of sugars by boric acid and boronic acids enables separation of sugars. Thus, it is obvious to combine prior art elements and arrive at the claimed method of separation of a designated oligomeric compound having at least one carbohydrate moiety as a conjugate group.
Thus, the claimed invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art. One of ordinary skill in the art will be motivated to use the claimed method and also suggested by the prior art since sugars have been separated via complexation with boric and boronic acids. The artisan would have a reasonable expectation that modified oligonucleotides conjugated to a carbohydrate moiety will also form a complex with boronic acid via the carbohydrate moiety and this would enable the separation of the modified oligonucleotide from contaminants as instantly claimed.
Conclusion
1. Pending claims 1, 7, 9, 11, 15-17, 30-32, 37-40 and 49-54 are rejected.
2. Claims 2-6, 8, 10, 12-14, 18-29, 33-36, and 41-48 have been canceled.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GANAPATHY KRISHNAN whose telephone number is (571)272-0654. The examiner can normally be reached M-F 8.30am-5pm.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693