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 .
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.
Claim Rejections - 35 USC § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 9, 13-17, 19-28, and 33-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite that the injection speed and mixing speed are about 0.5-0.9 ml/s when the first solution is injected into the second solution and about 0.1-0.9 ml/s when the second solution is injected into the first solution. There does not appear to be adequate support for the term “about” in this case. The specification provides the following support on page 27, paragraph 00102, reproduced below.
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This provides support for the values of 0.1 to 0.9 ml/s; also see the instant specification on page 16, paragraph 0051. However, neither the above-reproduced text nor the text on page 16, paragraph 0051 provides support for “about” 0.1 ml/s, “about” 0.5 ml/s, or “about” 0.9 ml/s.
Claim Rejections - 35 USC § 103 – Obviousness
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) 1-3, 9, 13-17, 19-22, 24-28 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1) and Benenato et al. (US 2019/0314292 A1).
Kauffmann is drawn to a method for manufacturing lipid nanoparticles comprising a nucleic acid which is mRNA, as of Kauffmann, page 1, title.
As to claim 1, part (a), Kauffmann teaches the following general procedure for producing a lipid nanoparticle comprising a nucleic acid, as of Kauffmann, page 34, figure 2-1, reproduced below.
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The above-reproduced method teaches obtaining an aqueous phase comprising a nucleic acid. Also see Kauffmann, page 134, relevant figure reproduced below.
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As to claim 1, part (b), the above-reproduced figure from Kauffmann, page 34, teaches obtaining an ethanol solution comprising lipid molecules capable of self-assembly. The aqueous and lipid solutions are intermixable because ethanol and water are miscible.
As to claim 1, part (c), Kauffmann teaches mixing the mRNA payload molecule with the aqueous solution.
As to claim 1, part (e), Kauffmann teaches mixing the aqueous and ethanolic solutions, as of the above-reproduced figure. Kafumann also teaches varying the concentrations of various components including the lipid to payload, as of Kaufmann, page 34, Table 2-1, relevant figure reproduced below.
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Kauffmann also teaches varying the types of lipid used, which is the type of self-assembly molecule, as of Kauffmann, page 146, reproduced below.
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As to claim 1, part (f), Kauffmann teaches measuring encapsulation efficiency, as well as particle size and polydispersity index, as of Kaufmann, page 146, table reproduced above from that page.
Kauffmann differs from the claimed invention because Kauffmann fails to teach a robotic liquid handler, which is required by steps (d) and (e) of claim 1. Kauffmann also does not teach the required rate of injection.
Brinker et al. (hereafter referred to as Brinker) is drawn to delivery of polynucleotides using silica particles, as of Brinker, title and abstract. Brinker teaches the following, as of paragraph 0441, reproduced below.
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Brinker differs from the claimed invention because the particles of Brinker contain silica which is not required by the instant claims; the presence of silica leads to a different method of making the claimed invention.
It would have been prima facie obvious for one of ordinary skill in the art to have used the robotic liquid handler of Brinker to have prepared phases and to have mixed formulations during the optimization process of Kauffmann. Kauffmann is drawn to a method of optimizing a method for producing lipid nanoparticles, and teaches preparing many different formulations with varied parameters, which is especially evident from Table B.2-1 on page 146 of Kauffmann. Brinker teaches that a robotic liquid handler may be used to screen different methods of making a formulation under different conditions in a high-throughput manner. As such, the skilled artisan would have been motivated to have used the robotic liquid handling system of Brinker to have conducted the optimization taught by Kauffmann in a high-throughput manner in order to have predictably sped up the determination of the optimum method of producing a lipid nanoparticle with a reasonable expectation of success.
As to claim 1, part (d), Brinker teaches using a robotic liquid handling system, as of Brinker paragraph 0441. While Brinker does not explicitly teach the word “wells”, it would nevertheless have been the case that the device in which the robotic handler would have inserted the liquids would have read on the required wells. As to claim 1, part (e), the skilled artisan would have been motivated to have used this robotic handler to have conducted the mixing required by part (e) of claim 1.
Neither Kauffmann nor Brinker teach the required rate of injection.
Benenato et al. (hereafter referred to as Benenato) is drawn to compositions comprising lipids, as of Benenato, title and abstract. Benanto teaches optimization of the formulation, as of Benenato, page 288, right column, Table 23. Benanto teaches a rate of injection of the lipid solution (in ethanol – this reads on the second solution) into the mRNA solution (this reads on the first solution) of 12 mL/minute, as of Benanto, paragraph 1627. Given that there are 60 seconds in a minute, the examiner understands this rate to be 0.2 mL/seconds. The examiner notes that the adding the lipid solution to the mRNA solution reads on adding the second solution to the first solution, and the value of 0.2 mL/seconds is within the claim scope of 0.1 to 0.9 mL/seconds.
Benenato does not appear to teach a robotic liquid handler.
It would have been prima facie obvious for one of ordinary skill in the art to have added the ethanolic lipid solution into the aqueous solution and to have optimized the flow rate to have been in the range taught by Benenato. Benenato is drawn to a method of making a lipid nanoparticle formulation and optimizing said formulation, as of Benenato, page 288, Example 18. Benenato teaches forming a lipid solution and a nucleic acid solution and teaches a particular manner of adding these together as well as a particular flow rate that appears to be useful for the production of lipid nanoparticles. As such, the skilled artisan would have been motivated to have modified the method of Kauffmann in view of Brinker to have added the lipid solution and aqueous solution in the manner taught by Benenato and with the flow rate taught by Benenato for predictable formation of lipid nanoparticles with a reasonable expectation of success.
As to claims 2-3, Kauffmann teaches a siRNA payload as of page 111, last line. Kauffmann also teaches a mRNA payload, as of the title.
As to claim 9, Kauffmann teaches a CRISPR/Cas9 payload, as of Kauffmann, page 127, section 7.2.4. The Cas9 protein would have read on the required polypeptide. Brinker also teaches delivery of CRISPR materials, as of the abstract of Brinker.
As to claim 13, Kauffmann teaches dissolving the payload (i.e. nucleic acid) in the first solution (i.e. aqueous solution), as of Kauffmann, page 34, figure 2-1, reproduced above.
As to claim 14, the examiner understands this claim to require that the payload be dissolved in the second solution, which is the same solution which comprises an organic phase. The skilled artisan would have been motivated to have dissolved hydrophobic payloads in this phase that are not water-soluble. Brinker teaches such hydrophobic payloads such as paclitaxel in paragraph 0080, wherein paclitaxel is an anti-cancer agent that would have been well-known to have been hydrophobic.
As to claim 15, Kauffmann teaches a pH 3 citrate aqueous buffer, as of Kauffmann, page 45, bottom paragraph.
As to claim 16, Kauffmann teaches a pH 3 citrate aqueous buffer, as of Kauffmann, page 45, bottom paragraph. The skilled artisan would have understood this to have been pH and osmolality controlled.
As to claim 17, Kauffmann teaches an ethanol phase, as of Kauffmann, page 34, figure 2-1, reproduced above.
As to claim 19, Kauffmann teaches ionizable lipid, phospholipid, cholesterol, and lipid-anchored PEG, as of Kauffmann, page 34, figure 2-1, reproduced above. These read on multiple species of lipid molecules.
As to claim 20, Kauffmann teaches ionizable lipid, phospholipid, cholesterol, and lipid-anchored PEG, as of Kauffmann, page 34, figure 2-1, reproduced above. These read on all of the required species recited by the claim.
As to claim 21, Kauffmann teaches ionizable lipid, phospholipid, cholesterol, and lipid-anchored PEG, as of Kauffmann, page 34, figure 2-1, reproduced above. These read on multiple species of lipid.
As to claim 22, Kauffmann appears to teach varying the concentration of lipid:mRNA ratio, as of Kauffmann, page 34, Table 2-1 and page 146, Table B.2-1, reproduced above. This would have resulted in the total concentration of lipid having been varied.
As to claims 24-25, Kauffmann teaches varying the mole percent of PEGylated lipid from 0.5 mol% to 3.5 mol%, as of Kauffmann, page 146, Table B.2-1. For example, example A-05 utilizes 0.5 mol% PEGylated lipid, and example B-21 utilizes 3.5 mol% PEGylated lipid.
As to claims 26-27, Kauffmann teaches weight ratios of cationic lipid (N) to mRNA (P) of between 5 and 25, as of Kauffmann, page 146, Table B.2-1. This overlaps with the claimed range. While the prior art does not disclose the exact claimed values, but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I).
As to claim 28, Kauffmann teaches a lipid nanoparticle, as of Kauffmann, page 146, heading of Table B.2-1. This would have been a polymer lipid nanoparticle due to the presence of PEGylated lipid.
As to claim 33, Benenato teaches using ultraviolet-visible absorption spectroscopy to determine the amount of a therapeutic and/or prophylactic agent in a nanoparticle composition, as of Benenato, paragraph 0712. The examiner understands this to be drawn to using ultraviolet visible absorption to measure encapsulation efficiency.
With regard to all of the rejected claims, the examiner notes that Benenato, like Kauffmann, teaches optimizing various parameters with respect to the lipid nanoparticle synthesis, including the chemical identity of the ionizable cationic lipid as well as the amounts of each lipid. This is set forth at least as of Benenato, page 288, Table 23. Benenato also teaches optimization of ratios of lipid and therapeutic agent, as of page 287, Example 14, and optimization of phospholipid, structural lipid, and PEG lipid on page 288 Examples 16-18. Benenato teaches optimization of particle sizes on page 289 Example 19. As such, Benenato at least teaches varying the types of self-assembly molecule, the composition ratio of the self-assembly molecule, and the ratio and/or concentration of the self-assembly molecule to the payload, as well as optimizing particle size.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1) and Benenato et al. (US 2019/0314292 A1), the combination further in view of Hashiba et al. (Journal of Controlled Release, Vol. 327, 2020, pages 467-476 and 21 pages of supporting information).
Kauffmann is drawn to a method of optimizing the formation of lipid nanoparticles comprising nucleic acid. Brinker is drawn to the use of a robotic arm. Benenato is drawn to adding the lipid ethanolic solution into the aqueous solution at a particular flow rate. See the applied rejection over Kauffmann in view of Brinker and Benenato.
Neither Kauffmann, Brinker, nor Benenato teach an encapsulation efficiency of greater than 80%.
Hashiba et al. (hereafter referred to as Hashiba) is drawn to delivery of RNA via lipid nanoparticles, and teaches attempts to determine optimal formulations, as of Hashiba, page 467, title and abstract. Hashiba teaches the following process, as of Hashiba, page 469, figure 1, reproduced below.
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Hashiba teaches optimizing the formulations, as of Hashiba, supplementary table S2, reproduced below.
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The examiner notes that Example B-9 appears to comprise an encapsulation efficiency of 94.3%, a mean particle size of 96.7 nm, and a polydispersity index of 0.097.
It would have been prima facie obvious for one of ordinary skill in the art to have optimized the method of Kauffmann as modified by Brinker in the manner taught by Hashiba. Kauffmann is drawn to a method for optimizing the formation of lipid nanoparticles. Kauffmann is drawn to varying various parameters; however, the method of Kauffmann does not appear to have achieved an encapsulation efficiency exceeding about 60%. However, Hashiba has achieved significantly higher encapsulation efficiencies; namely, above 90%. As such, the skilled artisan would have been motivated to have modified the method of Kauffmann in the manner taught by Hashiba to have predictably increased encapsulation efficiency with a reasonable expectation of success.
As to claim 23, Hashiba teaches 8 mM lipids, as of Hashiba, page 468, right column, section 2.4. This exceeds the required range of between 0.4 mM and 4 mM. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In the instant case, no evidence of criticality appears to have been provided. Additionally, where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of mixing lipids in ethanol with nucleic acids in aqueous solution to form lipid nanoparticles has been taught by the prior art. As such, it would not have been inventive to have discovered the optimum or workable ranges of lipid concentration by routine experimentation.
Note Regarding Reference Date: Hashiba was published online on 25 August 2020. The earliest effective filing date of the instant application appears to be 9 December 2020, which is the filing date of provisional application 63/123,343, upon which the instant application ultimately claims benefit. As such, Hashiba was published earlier than the effective filing date of the instant application, and is prior art under AIA 35 U.S.C. 102(a)(1).
Claim(s) 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1) and Benenato et al. (US 2019/0314292 A1), the combination further in view of Maeki et al. (PLoS One, Vol. 12(11), e0187962, 2017, pages 1-16).
Kauffmann is drawn to a method of optimizing the formation of lipid nanoparticles comprising nucleic acid. Brinker is drawn to the use of a robotic arm. Benenato is drawn to adding the lipid ethanolic solution into the aqueous solution at a particular flow rate. See the applied rejection over Kauffmann in view of Brinker and Benenato.
Neither Kauffmann, Brinker, nor Benenato teach the required lipid concentration in ethanol.
Maeki et al. (hereafter referred to as Maeki) is drawn to methods of making lipid nanoparticles or liposomes via the use of a micromixer, as of Maeki, page 1, title and abstract. Maeki teaches that lipid nanoparticle sizes increased with increasing lipid concentration, apparently in ethanol, as of Maeki, page 5, bottom paragraph.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the lipid concentration in the method of Kauffmann in the manner taught by Maeki. Kauffmann is drawn to methods of optimizing the protocol for producing lipid nanoparticles. Kauffmann appears to be silent regarding the concentration of lipid in ethanol. However, Maeki appears to teach that the concentration of the lipid in ethanol affects the size of the ultimately produced lipid nanoparticle. As such, the skilled artisan would have been motivated to have modified the method of Kauffmann to have produced lipid nanoparticles of varying sizes with a reasonable expectation of success.
As to claim 22, Maeki suggests varying the concentration of lipid, as of Maeki, page 5, bottom paragraph.
As to claim 23, Maeki does not appear to explicitly teach the specific concentration required by the instant claims. Nevertheless, the teachings of Maeki appear to indicate that lipid concentration is a result-effective variable because it affects the size of the particles produced. The presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. See MPEP 2144.05(II)(B), end of last paragraph in this section of the MPEP. As such, the skilled artisan would have been motivated to have optimized the lipid concentration in order to have predictably optimized the particle size of the produced particle with a reasonable expectation of success.
Claim(s) 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1) and Benenato et al. (US 2019/0314292 A1), the combination further in view of Zhang et al. (Analytical Chemistry, Vol. 84, 2012, pages 6088-6096 and S-1 through S-5).
Kauffmann is drawn to a method of optimizing the formation of lipid nanoparticles comprising nucleic acid. Brinker is drawn to the use of a robotic arm. Benenato is drawn to adding the lipid ethanolic solution into the aqueous solution at a particular flow rate. See the applied rejection over Kauffmann in view of Brinker and Benenato. Kauffmann teaches measuring particle diameter and polydispersity, at least as of page 39, Table 2-2, page 40, section 2.3.5, and elsewhere in the document.
Neither Kauffmann, Brinker, nor Benenato teach using UV-Vis (i.e. ultraviolet-visible) spectroscopy to measure particle size, polydispersity and distribution.
Zhang et al. (hereafter referred to as Zhang) is drawn to characterization of polydispersity of lipid nanoparticles comprising siRNA, as of Zhang, page 6088, title and abstract. The method of Zhang entails using a UV-Vis diode array detector in combination with size-exclusion chromatography for characterization of lipid nanoparticles, as of Zhang, page 6089, right column, section entitled “Size-Exclusion Chromatography of LNPs” and page 6093, left column. Various figures taught by Zhang include UV-Vis spectra of size-exclusion chromatography fractions, as of at least Zhang, figure S3.
Zhang does not appear to teach a robotic liquid handler.
It would have been prima facie obvious for one of ordinary skill in the art to have used a size exclusion chromatography in combination with UV-Vis spectroscopy, as of Zhang, to have measured particle size and distribution of the particles made by the method of Kauffmann in view of Brinker and Benenato. Kauffmann in view of Brinker and Benenato are drawn to methods of forming lipid nanoparticles, and teach measuring particle size, polydispersity, and distribution. While none of these references appear to teach the use of UV-Vis spectroscopy for measuring particle size and distribution, Zhang teaches that the skilled artisan would have been able to have used UV-Vis spectroscopy in combination with size-exclusion chromatography for measuring particle size, distribution, and polydispersity index. As such, the skilled artisan would have been motivated to have used the method of Zhang, which includes UV-Visible spectroscopy, to have predictably measured the particle size and distribution of the particles produced by the method of Kauffmann in view of Brinker and Benenato with a reasonable expectation of success.
Claim(s) 1-3, 9, 13-17, 19-22, 24-28 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1) and Benenato et al. (US 2019/0314292 A1), the combination further in view of Geldhof et al. (WO 2017/223135 A1).
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1), Benenato et al. (US 2019/0314292 A1) and Hashiba et al. (Journal of Controlled Release, Vol. 327, 2020, pages 467-476 and 21 pages of supporting information), the combination further in view of Geldhof et al. (WO 2017/223135 A1).
Claim(s) 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1), Benenato et al. (US 2019/0314292 A1) and Maeki et al. (PLoS One, Vol. 12(11), e0187962, 2017, pages 1-16), the combination further in view of Geldhof et al. (WO 2017/223135 A1).
Claim(s) 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kauffmann (“Optimization and Analysis of Lipid Nanoparticles for in vivo mRNA Delivery” PhD Thesis, Massachusetts Institute of Technology, June 2017, pages 1-167) in view of Brinker et al. (US 2018/0028686 A1) and Benenato et al. (US 2019/0314292 A1) and Zhang et al. (Analytical Chemistry, Vol. 84, 2012, pages 6088-6096 and S-1 through S-5), the combination further in view of Geldhof et al. (WO 2017/223135 A1).
Kauffmann is drawn to a method of optimization of lipid nanoparticle formation. Brinker is drawn to the use of robotic liquid handlers. Benenato teaches adding the lipid nanoparticle solution to the aqueous nucleic acid solution at a particular flow rate. Hashiba also drawn to methods of optimization of lipid nanoparticle formation, but teaches higher encapsulation efficiencies than what is taught by Kauffmann. Maeki teaches the effect of lipid concentration in ethanol on particle size optimization. Zhang teaches the use of UV-Visible spectroscopy to measure particle size, distribution, and polydispersity. See the above rejections.
For the purposes of this rejection, the examiner takes the position that while Brinker teaches a robotic liquid handler, Brinker does not teach the required wells.
Geldhof et al. (hereafter referred to as Geldhof) is drawn to methods for producing lipid nanoparticles comprising encapsulated mRNA, as of Geldhof, title and abstract. The method of Geldhof appears to include combining nucleic acids in aqueous buffer with lipids in a lower alkanol (e.g. ethanol), as of Geldhof, page 2 lines 11-26. Geldhof uses a liquid handling robot, as of Geldhof, page 31, including lines 12-26. This method entails the use of wells, as of Geldhof, page 4 line 37 through page 5 line 10 as well as page 6 line 39 through page 7 line 13.
It would have been prima facie obvious for one of ordinary skill in the art to have used the wells and/or well plates of Geldhof in the method of Kauffmann, Brinker, Benenato, and optionally other cited references. Both Kauffmann and Hashiba are drawn to methods of optimizing the synthesis of lipid nanoparticles, and entail trying large numbers of processes with different variations. The skilled artisan would have been motivated to have conducted each variant process in wells, as taught by Geldhof, in order to have predictably improved ease of experimentation and data collection with a reasonable expectation of success.
Response to Arguments Regarding Obviousness Rejection
Applicant has presented various arguments regarding the previously applied obviousness rejections, as of applicant’s response on 22 January 2026 (hereafter referred to as applicant’s response). These arguments are addressed below.
In applicant’s response, page 6, applicant makes the following argument, as of the second to last paragraph, which is reproduced below.
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Similar arguments regarding the previously applied rejections over Geldhof are reiterated on pages 7-8 of applicant’s response.
This is not persuasive in view of the newly applied rejection. This is because newly applied reference Benenato teaches lipid solution (i.e. ethanol) to buffer injections at 0.2 ml/seconds, which is within the claim scope, as of Benenato, paragraph 1627. This is within the claim scope.
Applicant then makes the following argument, as of the last paragraph of page 6, which is reproduced below.
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Similar arguments regarding the previously applied rejections over Geldhof are reiterated on pages 7-8 of applicant’s response.
This is not persuasive because Benenato teaches ethanol to buffer injections in paragraph 1627. Additionally, these arguments appear to argue subject matter that is not within the claim scope of claim 1. This is because claim 1 recites both ethanol to buffer injections as well as buffer to ethanol injections. Arguments related to unclaimed limitations are not persuasive. See MPEP 2145(VI).
Applicant additionally makes the following argument regarding Geldof, as of applicant’s response, page 8, relevant text reproduced below.
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The examiner disagrees with applicant’s position that 1 ml/s is significantly different from 0.9 ml/s. Additionally, Geldof, when taken in view of Benenato, teaches that flow rates of between 0.2 ml/second and 5 ml/second are suitable for forming lipid nanoparticles. This appears to overlap with the claimed requirements. While the prior art does not disclose the exact claimed values, but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I). The range may be taught by multiple references; see MPEP 2144.05(I), last paragraph in section.
Additional Relevant Prior Art
As additional relevant prior art, the examiner cites Zhu (US 2014/0348900 A1). Zhu et al. (hereafter referred to as Zhu) is drawn to methods for the preparation of lipid nanoparticles or liposomes, as of Zhu, title and abstract. The teachings of Zhu are drawn to particular flow rates or flow velocities, as of Zhu, abstract. Zhu teaches mixing lipid and aqueous solutions at a wide range of flow rates, as of paragraph 0056 of Zhu. Example 6 of Zhu on page 8 is drawn to preparation of liposomes comprising siRNA; as best understood by the examiner, these liposomes would have been lipid nanoparticles due to their small size in the range of 80-160 nm, as set forth in figure 6, which is cited by example 6 of Zhu.
Also as relevant, the examiner cites Strodiot et al. (US 2021/0128474 A1), which was effectively filed prior to the effective filing date of the instant application and therefore appears to be prior art under AIA 35 U.S.C. 102(a)(2). Strodiot et al. (hereafter referred to as Strodiot) is drawn to methods of making liposomes encapsulating RNA, as of Strodiot, title and abstract, though Strodiot uses the term “lipid nanoparticle” in paragraph 0001. Strodiot provides extensive teachings regarding the flow rate, as of Strodiot, paragraph 0283, 0292, Example 2(A), and elsewhere in the reference, though Strodiot sometimes uses the units of mL/min/mm2.
As best understood by the examiner, Zhu and Strodiot, when taken together, at least show that flow rate would have been recognized as a result-effective variable when it comes to the production of lipid nanoparticles comprising nucleic acids. It would have been obvious for the skilled artisan to have optimized result effective variables; see MPEP 2144.05(II)(B). As such, it is the examiner’s position that Zhu and Strodiot support the general idea that it would have been obvious for the skilled artisan to have optimized the flow rate.
With that being said, the examiner has not rejected the instant claims as obvious over Zhu and Strodiot because these references do not appear to be needed to establish a prima facie case of obviousness. See MPEP 904.03.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 9, 13-17, 19-28 and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36-38, 44-45, 48, 50, 52, 54, 56-58, 61, 63, 66, 68, 106, 176-177, 210-211, and 215 of copending Application No. 18/642,305 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a method for manufacturing a lipid nanoparticle. This method entails providing lipids in organic phase with nucleic acids in aqueous phase, optimizing various parameters, determining the optimal parameters, then manufacturing the lipid nanoparticle.
The instant claims are drawn to a method for optimizing the manufacturing process for lipid nanoparticle. This method entails providing lipids in organic phase with nucleic acids in aqueous phase, optimizing various parameters, determining the optimal parameters, then manufacturing the lipid nanoparticle.
The instant and copending claims differ because the copending claims are drawn to optimizing the manufacturing process for lipid nanoparticles, whereas the instant claims are drawn to manufacturing lipid nanoparticles. Nevertheless, the method steps of copending claim 36 appears to be the same as that of instant claim 1. As such, the subject matter of copending claim 36 effectively anticipates that of instant claim 1, thereby resulting in a prima facie case of anticipatory-type non-statutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments Regarding Double Patenting
In applicant’s response on 22 January 2026 (hereafter referred to as applicant’s response), page 8, applicant notes MPEP 804(B)(1) which indicates that if a provisional non-statutory double patenting rejection is the only remaining rejection, the examiner should withdraw the rejection in the application having the earlier patent term filing date, as of page 9 of applicant’s response. This is not persuasive because the provisional non-statutory double patenting rejection is not the only remaining rejection in this case.
Conclusion
No claim is allowed.
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 ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612