DETAILED ACTION
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.
Claims 1-3, 5-9, 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Nakano “Efficient Coupled Transcription/Translation from PCR Template by a Hollow-Fiber Membrane Bioreactor” in view of Wochner (US 20170114378), von der Mulbe (US 20160326575) and Armour (US 20150299767).
With respect to claim 1, Nakano discloses a continuous-flow recombinant system for producing RNA polynucleotides in vitro comprising a continuous-flow bioreactor for producing target RNA output. The bioreactor includes a reaction chamber configured to hold an input reaction mixture having a free DNA template and a continuous-flow conduit configured to hold and circulate a feed solution. A hollow-fiber membrane having pores (i.e., “conduit apertures”) is formed between the reaction chamber and the continuous-flow conduit in order to form a gradient between the input reaction mixture and the feed solution. This is described on page 195.
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Nakano teaches that “mRNA synthesis in the hollow-fiber membrane bioreactor was found to continue for a longer duration than in the batch reaction. Therefore, it is quite reasonable to believe that the rapid exchange of both substrates and wastes through the membrane steadily maintained the easily changeable reaction conditions of the coupled transcription/translation, thereby eventually increasing mRNA synthesis”. Nakano further states that the input reaction mixture and the feed solution contain all necessary components for the in vivo generation of the target RNA transcribed from the DNA template. Nakano, however, does not teach that the reaction chamber is a continuous-flow reaction chamber.
Wochner discloses a continuous-flow recombinant system for producing RNA polynucleotides in vitro comprising a continuous-flow bioreactor (“Reaction module 1 is a reaction vessel used for a continuous or semi-batch process for synthesizing RNA molecules of a given sequence”) having a continuous-flow reaction chamber (Figure 18:22) configured to hold an input reaction mixture having a DNA template. At least one continuous-flow conduit (Figure 18:23) is configured to hold and circulate a feed solution through a series of conduit apertures formed by a membrane (Figure 18:21) in order to create a gradient between input reaction mixture and feed solution. This is taught in paragraphs [0245]-[0248].
Before the effective filing date of the claimed invention, it would have been obvious to configure the Nakano reaction chamber as a continuous-flow reaction chamber that continuously circulates a reaction mixture. Wochner teaches that this configuration is beneficial because allows the content of the reaction mixture to be monitored and adjusted in real time as it is recirculated (“a sequence-optimized ribonucleotide mix in the bioreactor 1 enables a real-time measurement of the nucleotide concentration in the filtration compartment 23 during the RNA transcription reaction”). Wochner further states that the continuously flowing reaction mixture may undergo monitoring for other critical process parameters, such as pH and conductivity. Those of ordinary skill would have understood how this improvement would allow for greater control over reaction conditions.
Nakano still differs from the claimed invention because Nakano does not appear to disclose the claimed protein removal component, DNA removal component and nucleotide precipitation component.
Wochner additionally discloses a RNA capture module (Figure 18:3) for purifying a mRNA product. The capture module contains a resin/solid phase to capture product RNA molecules in order to separate them from soluble components of the transcription reaction, as well as unused raw materials, such as nucleotides and enzymes. Accordingly, Wochner appears to teach a protein removal component and/or a DNA removal component
Von der Mulbe discloses a method for producing RNA in which a series of purifying steps are implemented to isolate the RNA product. Paragraph [0227] notes that nucleotides are removed via alcohol precipitation. Paragraphs [0301]-[0324] discuss the state of the art regarding DNA removal components that utilize chromatography and protein removal components that utilize chromatography. Affinity purification and hydroxyapatite chromatography are identified as suitable steps for generating DNA and protein fractions that are distinct from a recovered RNA fraction (“Differential elution (e.g. to separate protein, DNA and undesired RNA species from desired RNA species) is accomplished”).
Armour discloses a RNA purification method in which non-desired nucleic acid sequences are removed. Paragraph [0093] teaches that a nucleotide precipitation component is used to remove an NTP fraction (“A simple purification step may be performed to remove unincorporated nucleotides such as alcohol or polyethylene glycol precipitation, ion exchange purification, ultrafiltration, silica absorption, or reverse phase methods”).
Before the effective filing date of the claimed invention, it would have been obvious to ensure that the Nakano’s system includes a protein removal component, a DNA removal component and a nucleotide precipitation component. As evidenced by Wochner, von der Mulbe and Armour, it is known in the art to utilize different filtration, chromatography, precipitation, etc. separation steps to create distinct protein, DNA and nucleotide fractions when purifying a RNA product. These references show that sequential separation and polishing steps are typically used to increase purification efficiency. It is prima facie obvious to apply a known technique (e.g., chromatography) to a known device ready for improvement to yield predictable results. See MPEP 2143.
With respect to claims 2 and 3, Nakano, Wochner, van der Mulbe and Armour disclose the combination as described above. These cited references further teach the provision of linear and circular DNA templates that encode an antigenic polypeptide.
With respect to claims 5 and 6, Nakano, Wochner, van der Mulbe and Armour disclose the combination as described above. Nakano further teaches on at least page 195 (“In Vitro-Coupled Transcription/Translation”; “Hollow-Fiber Membrane Bioreactor”) that the input reaction mixture comprises a quantity of RNA polymerase and a reaction buffer, and that the feed solution includes a quantity of isolated NTPs and a reaction buffer.
With respect to claims 7-9, Nakano, Wochner, van der Mulbe and Armour disclose the combination as described above. As previously discussed, the van der Mulbe and Armour references teach the state of the art regarding protein and DNA affinity columns, as well as alcohol precipitation systems configured to isolate target mRNA and unincorporated NTPs (“Methods for the extraction and purification of nucleic acids are well known in the art. For example, nucleic acids can be purified by organic extraction with phenol, phenol/chloroform/isoamyl alcohol, or similar formulations, including TRIzol and TriReagent. Other non-limiting examples of extraction techniques include: (1) organic extraction followed by ethanol precipitation, e.g., using a phenol/chloroform organic reagent”).
With respect to claim 14, Nakano, Wochner, van der Mulbe and Armour disclose the combination as described above. Wochner further teaches the use of an input reservoir (Figure 18:24) and an input valve (Figure 18:43) configured to control the injection of feed solution into the continuous-flow conduit.
With respect to claim 15, Nakano, Wochner, van der Mulbe and Armour disclose the combination as described above. Wochner further teaches the use of an output reservoir (Figure 18:5) and an output valve (Figure 18:51) to allow extraction of the mRNA output. Collection reservoirs and valves are considered to be well known in the art.
Response to Arguments
In response to Applicant’s amendment filed 09 February 2026, the previous rejections have been withdrawn. However, upon further consideration, a new ground of rejection is made in view of the Nakano reference.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 NATHAN ANDREW BOWERS whose telephone number is (571)272-8613. The examiner can normally be reached M-F 7am-5pm.
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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799