DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The amendment filed on 08/13/2026 has been entered. Claims 1-30 are cancelled. Claims 31-60 are pending in this application. Claims 31-45 and 52-60 are withdrawn. Claims 46-51 are currently under examination.
Priority
This application is a 371 of PCT/SE2022/050812 filed on 09/15/2022 and claims foreign priority of SWEDEN 2151135-7 filed on 09/16/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant's election without traverse of Group II invention (claims 46-51) in the reply filed on 08/13/2026 is acknowledged. Claims 31-45 and 52-60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Thus, claims 46-51 are currently under examination.
Information Disclosure Statement
Four information disclosure statement (IDS) filed on 03/20/2024, 06/13/2025, 05/27/2026, and 07/16/2026 have been considered.
Claim Objections
Claims 46, 47, and 49-51 are objected to because of the following informalities: In claim 46, change the incorrect recitation “The system” (line 1) to “A system” as an independent claim format; replace the incorrect recitation “at least a first” (lines 2 to 3, two occurrences) to “at least one” because the “a” means any and the “first” cannot be “at least”; change the incorrect recitation “the first” (a total of five occurrences) to “the at least one” to tie with the preceding “at least one”; insert the missing phrase “at least one” immediately before the recitations “column” (lines 5, 9, 10, and 12, a total of six occurrences), “valves” (lines 5 and 7, a total of two occurrences), “processor” (line 6), and “detector” (line 7) to tie with the preceding “at least one”; and delete the excessive “at least” (line 7) right after the recitation “connection”. In claim 47, insert the missing phrase “at least one” immediately before the recitation “column” (lines 2 and 3, a total of two occurrences); and insert the missing word “to” right before the recitation “provide” (line 2). In claim 49, change the incorrect recitation “further is” (line 1) to “is further”; and insert the missing phrase “at least one” immediately before the recitation “column” (line 3). In claim 50, change the incorrect recitation “device (arranged” (line 2) to “device, arranged”; insert the missing phrase “at least one” immediately before the recitation “column” (lines 2-4, a total of three occurrences); and replace the incorrect recitation “at least first reservoir” (lines 2 to 3) with “at least one reservoir”. In claim 51, change the incorrect recitation “at least first” (line 2) to “at least one”. Appropriate correction is required.
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.
Claim 47 is 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 47 recites the limitation "the third valve" or “the fourth valve” (lines 2 and 3). There is insufficient antecedent basis for this limitation in the claim. Applicant is advised to change the above recitations to “a first additional valve” and “a second additional valve”, respectively.
Claim Rejections - 35 USC § 102/103
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.
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.
(I) Claims 46-51 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Braden et al. (WO 2022/13 2681, published on June 23, 2022, PCT filed on December 14, 2021, and benefitted from US PRO 63/127,269 filed on December 18, 2020, hereinafter referred to as Braden ’681).
With regard to structural limitations “a system comprising a column packed with synthetic resin, at least one pump, at least one reservoir for monomers and reagents, at least one detector, and at least one processor (or further comprising a temperature regulating device between the at least one reservoir and the column, a first temperature sensor between the temperature regulating device and the column, and a second temperature sensor downstream the column; or further comprising a separately defined mixing chamber arranged in fluid communication with the at least one reservoir, and a gas bubble detector arranged upstream the mixing chamber), wherein tubing connects the at least on reservoir to the column, and wherein the at least one pump and at least one valves are arranged to direct the flow in the system, and wherein the at least one processor is in communicative connection with the at least one pump, the at least one valves, and the at least one detector, wherein the system is arranged to provide a fluidizing flow path arranged to direct a flow of solvent from the at least one reservoir to the bottom of the column so that solvent pass through the column from the bottom of the column to the top, and wherein the system is arranged to provide repacking flow path arranged to direct a flow of solvent from the at least one reservoir to the top of the column so that solvent pass through the column from the top to the bottom in one synthesis cycle (or a first additional valve to provide a waste outlet for the solvent flowing bottom-to-top of the column and a second additional valve to provide a waste outlet for the solvent flowing to-to-bottom of the column; or the flow path are tubing; or further providing a recirculation flow path to re-circulate solvents and reagents over the column)” (claims 46-51):
Braden ’681 disclosed a scale fluidized bed oligonucleotide synthesizer setup (Fig. 5):
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Begin with mU coupled onto NittoPhase HL 2' OMeU(bz) 300 resin (herein referred to as "mU-resin"). All feeds use peristaltic pumps and feed vessels. The amidite solutions are contained separately in feed vessels labeled "AM. IL" and connected to peristaltic pumps attached to valves V1A through V8A. The phosphorylating reagent is contained in a feed vessel labeled "AM. IL" and connected to a peristaltic pump attached to valve V9A. The activator and DEA solutions are contained feed vessels labeled "Activ. 5 gal" and "DEA," respectively. Acetonitrile is abbreviated as "ACN". The fluidization is done by blowing nitrogen gas up through the bottom filter screen by opening valves 58, 54, and 53 (V58, V54, V53) the same time the vent valve V52 opens. When this procedure states that liquid is pumped down through the resin bed, it means that the waste pump at the outlet of the reactor bottom runs at a target setpoint, while nitrogen pressure pushes on top of the resin bed to push the liquid down through. The purpose of the peristaltic pump is to meter the liquid flow through the bed at a controlled rate (page 8/195, lines 8 to 9; page 62/195, lines 2-15; page 63/195, lines 8-14). An oscillating fluidized bed oligonucleotide synthesizer (Fig. 3):
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. Equip a 1 cm diameter, 20 cm tall reactor with a filter and automated block valve (valve 24) at the bottom, and then enough 1.59 mm i.d. tubing from the reactor to one or more outlet valves (valves 9 and 10) to contain ~2.5 mL of effluent volume. Charge the reactor with 0.1040 g of the mU-resin. At each step, resin bed fluidization is performed at two different times: first when the reagent mixture is charged to the reactor and the resin is exposed to it, and second when the wash solvent is charged to the reactor. The reagent mixture or wash solvent (or portion thereof) is added to the feed zone and nitrogen pressure is applied, forcing the liquid into the reactor. This is achieved by closing valves 9 and 10, opening valve 24, and applying nitrogen pressure from the appropriate inlet (valves 41, 42, 43, 44, or 45). This forces the liquid in the reactor to flow through the resin bed and into the tubing between the reactor and valves 9 and 10 as the pressure gradient is equalized between the top of the reactor and the tubing between the bottom of the reactor and valves 9 and 10. The pressure at the top of the reactor is then released by opening the appropriate vent (valves 51, 52, 53, 54, or 55), creating a pressure gradient which is equalized to atmospheric pressure as the liquid flows up from the bottom of the reactor, agitating and fluidizing the resin bed. The nitrogen pressurizing and venting process is repeated the number of times specified, for at least a duration sufficient to fluidize the resin bed each time. If only a portion of reagent mixture or wash solvent is used in fluidizing the bed, the remaining reagent mixture or wash solvent is passed through the resin in a "plug flow" manner, wherein valve 9 is closed, valve 10 is opened, nitrogen pressure is applied to the top of the reactor, and pump 9 is actuated to meter liquid out of the bottom of the reactor as liquid (reagent mixture or wash solvent) is added to the top of the reactor. Detailed automation procedure for the sequence of pumps and valve operations for Example 1. Key: "O" means "open"; "C" means "close"; "P" means "pump", e.g. "P9" refers to "pump 9" in Figure 3 (page 21/195, lines 3-24; page 25/195, lines 9-11).
Thus, these teachings of Braden ’681 anticipate Applicant’s claims 46-51 because the above controlled flow rate, flowing of reagents up from the bottom followed by down from the top of the reactor column, and automation also require processor, detector, sensor, and cooling/heating control. Or, in an alternative, skilled artisan would follow the teachings of Braden ’681 to provide a specific device to control temperature, required by claim 50.
(II) Claims 46-51 are rejected under 35 U.S.C. 103 as being unpatentable over Brandt et al. (US 2013/021348, Aug. 22, 2013, hereinafter referred to as Brandt ‘348) in view of Anderson et al. (Applied Biochemistry and Biotechnology Vol. 54, p. 19-42, 1995, hereinafter referred to as Anderson ‘1995).
With regard to structural limitations “a system comprising a column packed with synthetic resin, at least one pump, at least one reservoir for monomers and reagents, at least one detector, and at least one processor (or further comprising a temperature regulating device between the at least one reservoir and the column, a first temperature sensor between the temperature regulating device and the column, and a second temperature sensor downstream the column; or further comprising a separately defined mixing chamber arranged in fluid communication with the at least one reservoir, and a gas bubble detector arranged upstream the mixing chamber), wherein tubing connects the at least on reservoir to the column, and wherein the at least one pump and at least one valves are arranged to direct the flow in the system, and wherein the at least one processor is in communicative connection with the at least one pump, the at least one valves, and the at least one detector, wherein the system is arranged to provide a fluidizing flow path arranged to direct a flow of solvent from the at least one reservoir to the bottom of the column so that solvent pass through the column from the bottom of the column to the top, and wherein the system is arranged to provide repacking flow path arranged to direct a flow of solvent from the at least one reservoir to the top of the column so that solvent pass through the column from the top to the bottom in one synthesis cycle (or a first additional valve to provide a waste outlet for the solvent flowing bottom-to-top of the column and a second additional valve to provide a waste outlet for the solvent flowing to-to-bottom of the column; or the flow path are tubing; or further providing a recirculation flow path to re-circulate solvents and reagents over the column)” (claims 46-51):
Brandt ‘348 disclosed a system and method and their advantages may be seen when NITTOPHASE (HL) is used as the beads in a reactor. The solvent transition step causes NITTOPHASE HL (relatively new polymer technology for oligonucleotide synthesis with 50% increase loading) bead to swell excessively (~13.0%). As the bead undergoes this rapid swelling it may cause a devastating pressure rise in the flow through vessel (column) and system shut down.
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. The system includes a column (used as a reactor) having a housing 6 with top plate 10 and bottom plate 11 within which a sliding piston is positioned. The piston includes a piston head 8 and a piston rod 9 that constrains a volume 54 within the column wherein fluid pressure is applied (or released) to the back side of the piston head to cause movement of the piston to consolidate a substrate bed of beads 7. An inlet line 60 communicates with the inlet column pressure sensor 68, the forward pressure regulator pressure reference 16 and an inlet passage 62 of the column, while an outlet passage 64 passes through the piston head 8 and piston rod 9 of the column and then connects to outlet line 66, which communicates with back pressure regulator pressure reference 40. Of course the liquid flow through the column may be reversed, so that 62 becomes the outlet passage and 64 becomes the inlet passage. One skilled in the art can easily understand that the system and method may be used with other reagents as solvents as variations in synthesis steps may require. The logic and pressure monitoring system controller 70, which communicates with an inlet column pressure sensor 68, may provide actuation to switching valve 50 actuator 72 to define and maintain compression of the bed 7 at desired optimum (page 5/6, [0024]; pages 3/6 to 4/6, [0011, 0016, 0017, 0019]).
Brandt ‘348 did not explicitly disclose the limitations “at least one reservoir for monomers and reagents (or further comprising a temperature regulating device between the at least one reservoir and the column, a first temperature sensor between the temperature regulating device and the column, and a second temperature sensor downstream the column; or further comprising a separately defined mixing chamber arranged in fluid communication with the at least one reservoir, and a gas bubble detector arranged upstream the mixing chamber)”, required by claims 46, 50, and 51.
Anderson ‘1995 disclosed schematic diagram of the production centrifugal oligonucleotide synthesizer. Reagent valves shown on the right are connected in series to provide reagents from up to 47 sources, and direct fluid through a spectrophotometer flow cell to the reversing valve. The reversing valve can vector incoming fluid to either rotor bottom (edge) as shown, to the rotor top (center), or to drain. Fluid exiting the rotor is vectored by the reversing valve through a second spectrophotometer flow cell to the waste vessel on the balance.
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. A wide variety of configurations have been employed to valve a series of different solutions into a reaction vessel and to monitor some aspects of the synthesis process--all under computer control. A variety of flow meters are available, and the best of these uses intermittent pulse heating of a stream, with downstream detection of each pulse (page 23, Fig. 1 and para. 2; page 27, para. 4).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the generic oligonucleotide synthesis as taught by Brandt ‘348 with specific oligonucleotide synthesizer having reagent reservoirs, flow control by intermittent pulse heating, a flow cell, and gas pressure control in view of Anderson ‘1995 because advantages may be seen when NITTOPHASE (HL) is used as the beads for oligonucleotide synthesis in a reactor and excessive swelling of the bead to shut down the system is minimized, described above. Thus, one of skill in the art would have a reasonable expectation that by substituting the generic oligonucleotide synthesis as taught by Brandt ‘348 with specific oligonucleotide synthesizer having reagent reservoirs, flow control by intermittent pulse heating, a flow cell, and gas pressure control in view of Anderson ‘1995, one would achieve Applicant’s claims 46-51. "Exemplary rationales that may support a conclusion of obviousness include: (B) Simple substitution of one known element for another to obtain predictable results". See MPEP § 2143 [R-01.2024] [I].
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691
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