DETAILED ACTION
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 .
This application is a domestic application, filed 05 Jan 2023; claims benefit as a CON of PCT/EP2021/068832, filed 07 July 2021; and claims benefit of foreign priority document EP 20184839.7, filed 09 July 2020. This foreign priority document is in English.
Claims 1-2, 4-9, 11, 18-22, 24-25, and 27-30 are pending in the current application. Claims 22 and 24-25, drawn to non-elected inventions, are withdrawn. Claims 1-2, 4-9, 11, 18-21, and 27-30 are examined on the merits herein.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 4-9, 11, 18-21, and 27-30, in the reply filed on 19 Sep 2025 is acknowledged.
Claims 22 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 19 Sep 2025.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification includes embedded hyperlinks which include the prefix “http://” at page 4, around lines 20 and 25.
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 19 and 21 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.
Claim 19 recites “the amount of iodine used for the preparation of the oxidation solution is selected between 1.1 equivalents and 15 equivalents to the iodine.” This language renders the claim indefinite because the amount of iodine is necessarily equivalent to itself, and it is unclear how the amount of iodine can be greater than itself. Due to the high level of uncertainty in the meaning of this claim, claim 19 has not been further examined on the basis of prior art.
Regarding claim 21, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In this case the claim recites “10 to 40, preferably 10 to 25 nucleotides in length”, and it is unclear whether the preferred range is required. For example, Reddy et al. (US 5,783,684, issued 21 July 1998, cited in PTO-892) detailed further herein teaches a method of preparing an oligonucleotide 35mers in length, and the indicated language makes it unclear if the claim encompasses this teaching.
Claim Rejections - 35 USC § 102
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 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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4-9, 11, 18, 20-21, and 27-30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by McPherson et al. (US 2022/0251128, filed 15 May 2020, cited in PTO-892).
McPherson et al. discloses methods for synthesizing oligonucleotides having at least one phosphorothioate diester linkage and at least one phosphate diester internucleoside linkage. In certain embodiments, the present disclosure provides oxidation reagents that produce low amounts of unwanted phosphate diester impurities (abstract). The oxidation step comprises oxidation of an intermediary phosphite triester compound into a phosphodiester compound (figure 2, step 3), meeting the structural limitations of the claimed formulas I and II. The oxidizing agent can be used to produce highly pure oligonucleotides that contain only a low percentage of unwanted phosphate diester linkages. In certain embodiments, adding an iodide source to a pyridine, water, and iodine oxidizing reagent results in an oxidizing reagent that can be used promptly upon preparation (paragraph 11 spanning pages 1-2), meeting limitations of claim 1 and 6-7. In certain embodiments the oxidizing agent is a mixture of 0.05 M I2, 0.05 M KI, in a 9:1 volumetric ratio of pyridine and water (page 10, paragraph 235), meeting limitations of claims 1-2, 4-9, and 27-29. In working example 11, the oligonucleotide compound 682884 precursor is synthesized using the freshly prepared oxidizing agent to give a (P=O)1 impurity of 1.7% and no detectable incomplete oxidation (page 25, paragraph 362 to page 26, paragraph 363), meeting limitations of claims 18 and 30. The oligonucleotide compound 682884 contains 20 nucleotides (page 23, paragraph 338), meeting limitations of claim 21.
Regarding claim 11, McPherson et al. is silent as to the conductivity of the oxidation solution. MPEP 2112.01 especially at I. citing In re Best, 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly recited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to show the inventions of the applicant and the prior art are not the same or that the prior art inventions do not necessarily possess the characteristics of the claimed invention. In this case McPherson et al. discloses embodiments and working examples of the oxidizing agent being a mixture of 0.05 M I2, 0.05 M KI, in a 9:1 volumetric ratio of pyridine and water, which have the same components and concentrations as the solution used in the claimed invention, and this provides a reason to believe that the conductivity of the oxidation solution is necessarily the same as what is claimed.
Regarding claim 20, McPherson et al. does not explicitly disclose the reaction temperature of the oxidation reaction. However, McPherson et al. discloses the invention as an improvement in the field of current solid-phase synthesis manufacturing processes of phosphorothioate diester linked oligonucleotides (page 1, paragraphs 4-7). One of skill in the art would have understood that in the state of the art at the time of McPherson et al. this step of the process is performed at room temperature, implicitly meeting limitations of claim 20. Further, McPherson et al. describing the manufacturing processes at page 1, paragraph 9 does not specify heating or cooling for the reaction steps, implying that the reactions are performed at room temperature and implicitly meeting limitations of claim 20.
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 1-2, 4-8, 18, 20-21, 27-28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Reddy et al. (US 5,783,684, issued 21 July 1998, provided by Applicant in IDS filed 03 Dec 2024) in view of Zon (Argrawal, S., ed., Methods in Molecular Biology, Vol. 20 Protocols for Oligonucleotides and Analogs, 1993, Humana Press Inc., p165-189, cited in PTO-892).
Reddy et al. discloses oxidizing compositions particularly for use in automated oligonucleotide synthesis containing a mixture of KI and I2 in solution, in equilibrium with KI3. One preferred composition contains 1.75% KI3 (providing 0.69% KI and 1.06% I2) in tetrahydrofuran/pyridine/water (93/5/2, v/v). These formulations enable synthesis of oligonucleotides of significantly higher quality (abstract). The oxidation step comprises oxidation of an intermediary phosphite triester compound into a phosphodiester compound (oxidation step of DNA Synthesis Cycle spanning columns 1-2 to 3-4), addressing the structural limitations of the claimed formulas I and II. This disclosure addresses limitations of claims 1-2, 4, and 6-7. In working example 1 the exemplary oxidizer formulation is prepared by combining 6.9 g potassium iodide and 10.6 g iodine in 100mL of solvent (column 5, lines 10-20), or approximately 0.0418 mol I2 to 0.0415 mol KI addressing limitations of claim 5. In working example 3 the oligonucleotide prepared is 35mers in length (column 6, lines 5-30), addressing limitations of claim 21. Reddy et al. teaches the ratio of the components in the tetrahydrofuran/pyridine/water mixture may be varied significantly: the percentage of tetrahydrofuran may be varied within the range of about 50% to about 98%, the pyridine from 1% to 40%, and the water from 0.5% to 30% (column 4, lines 50-60).
Regarding claims 6-7, Reddy et al. discloses the oxidizer formulation containing the organic solvents tetrahydrofuran and pyridine. MPEP 2111.03 at I. citing Amgen Inc. v. Amneal Pharmaceuticals LLC, 945 F.3d 1368, 1379, 2020 USPQ2d 3197 (Fed. Cir. 2020) providing the claim transition “comprising” allowed for additional component(s) that were functionally similar to the recited members of the Markush grouping. In this case claims 6-7 are interpreted as being open to additional component(s) that were functionally similar organic solvents, such as tetrahydrofuran in addition to the pyridine.
Regarding claim 20, Reddy et al. does not explicitly disclose the reaction temperature of the oxidation reaction. However, Reddy et al. discloses the invention as an improvement in the field of oligonucleotide synthesis using automated oligonucleotide synthesizers (column 3, lines 20-45). One of skill in the art would have understood that in the state of the art at the time of Reddy et al. this step of the process is performed at room temperature, implicitly meeting limitations of claim 20. Further, Reddy et al. describing the DNA Synthesis Cycle spanning columns 1-2 to 3-4 does not specify heating or cooling for the reaction steps, implying that the reactions are performed at room temperature and implicitly meeting limitations of claim 20.
Reddy et al. does not specifically disclose a process for the production of a mixed P═O/P═S backbone oligonucleotide (claim 1). Reddy et al. does not specifically disclose the method wherein the volume ratio of the organic solvent to water is from 1:1 to 20:1 (claim 8). Reddy et al. does not specifically disclose the method wherein the molar ratio of the iodine to the iodide in the oxidation solution between 1.0:1.0 and 1.0:2.0 (claim 27). Reddy et al. does not specifically disclose the method wherein the volume ratio of the organic solvent to water is about 9:1 (claim 28).
Zon teaches there are numerous applications of “oligonucleotide phosphorothioate analogs,” which is a term now generally meant to imply either DNA or RNA modified with one or more thiono-type linkages, 4/5 (page 165, paragraph 2; Structures 1-5 at top of page 166). The original approach developed for automated synthesis of phosphorothioate-containing DNA using phosphoramidite chemistry involved reaction of the internucleoside phosphite linkage with elemental sulfur (S8) in place of I2/H2O (page 168). The cycle for automated synthesis of PS-modified DNA is shown, where the step 3 may be sulfurization with TETD to give the thiono phosphotriester linkage or oxidation with I2/H2O to give a conventional phosphotriester linkage (page 170, figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Reddy et al. in view of Zon in order to apply the improvement of Reddy et al. within a method of making an phosphorothioate-containing oligonucleotide taught by Zon, and to further optimize the reaction conditions within the scope taught by Reddy et al. through routine experimentation. One of ordinary skill in the art would have been motivated to combine Reddy et al. in view of Zon with a reasonable expectation of success because Reddy et al. teaches an improvement in the field of oligonucleotide synthesis using automated oligonucleotide synthesizers, Zon teaches synthesis of phosphorothioate-containing oligonucleotides using automated oligonucleotide synthesizers and that the oligonucleotides may contain a mixed P═O/P═S backbone, suggesting it would have been obvious to improve similar methods in the same way be combining the improvement of Reddy et al. with the synthesis of phosphorothioate-containing oligonucleotides taught be desired by Zon. Regarding the molar ratio of the iodine to the iodide, Reddy et al. teaches the mixture of KI and I2 is in equilibrium with KI3, providing guidance to select a 1:1 molar ratio of KI and I2 because each KI3 dissociates to give 1 KI and 1 I2. Regarding the reaction conditions of the volume ratio of the organic solvent to water and the molar ratio of the iodine to the iodide, Reddy et al. teaches the ratio of the components in the tetrahydrofuran/pyridine/water mixture may be varied significantly. See also MPEP 2144.05 at II.A. providing “[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)
Regarding claims 18 and 30, Reddy et al. is silent as to the P=O content in the reaction solution. MPEP 2112.01 especially at I. citing In re Best, 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly recited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to show the inventions of the applicant and the prior art are not the same or that the prior art inventions do not necessarily possess the characteristics of the claimed invention. In this case Reddy et al. teaches these oxidizing formulations mixture of KI and I2 in place of I2 alone enable synthesis of oligonucleotides of significantly higher quality, providing reason to believe that this same improvement would necessarily result in the claimed amount of P=O content in the reaction solution.
Conclusion
No claim is found to be allowable.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693