DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 24 February 2026 has been entered, and the arguments presented therein have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
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 21-23 are 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.
Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made. See MPEP 2173.05(d). The claim limitation “wherein one or more active agents is a bioactive agents, such as a therapeutic agent or vaccine” is indefinite because it is unclear whether the claim is drawn to all bioactive agents, or is limited only to therapeutic agents and vaccines. As best understood by the examiner, certain diagnostic agents would be within the scope of a bioactive agent but are not therapeutic agents or vaccines, and it is not clear if these are within the claim scope. See MPEP 2173.05(d), item (B).
Claim 27 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 27 recites that the lipid vesicles comprise cationic lipid vesicles selected from, then the claims recite the chemical names of two known cationic lipids. In view of the claim language, it is unclear if the claim requires that the vesicles be made entirely of the recited cationic lipids or whether the claim requires that the vesicles include the recited cationic lipids.
The examiner suggests the following language to overcome the applied rejection.
Claim 27 (Proposed Amendment): The method according to claim 1 wherein the lipid vesicles [[ ]] are cationic lipid vesicles comprising a cationic lipid selected from, DDA (dimethyl dioctadecyl anmmonium bromide) and DOTAP (1 ,2-dioleoyl-3 -trimethylanmmonium-propane).
For the purposes of examination under prior art, the examiner will proceed with examination with the understanding that claim 27 is interpreted in the manner set forth above. The examiner clarifies that the above-proposed amendment overcomes only the indefiniteness rejection, and does not overcome all rejections of claim 27.
Claim 37 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.
Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made. See MPEP 2173.05(d). The claim limitation “wherein the pegylated lipids include…pegylated diacyl glycerol (PEG-DAG) e.g. 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoyl glycerol (PEG-DMG)” is indefinite because it is unclear whether the claim is limited to the narrower limitation of PEG-DMG or is drawn to the broader limitation of PEG-DAG. The use of the phrase “e.g.” results in similar issues on the fourth to last line of claim 37.
For the purposes of examination under prior art, the examiner will interpret the claim as if it is drawn to the broader limitation.
In order to overcome this issue, the examiner recommends that applicant amend the claims to remove the terminology “e.g.” in the claims.
Claim Rejections - 35 USC § 112(d) – Failure to Limit Parent Claim
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16 recites that when the one or more active agents is hydrophobic, then the one or more active agents may be included in the lipid phase. The term “may” indicates that inclusion in the lipid phase is optional. As such, it does not appear that claim 16 further limits claim 7 upon which it depends because the further limitation required by claim 16 is optional.
Claim Interpretation
“Volume Weighted:” Claim 1 recites “more than 90% (volume weighted).” The examiner understands the phrase “volume weighted” to be further limiting and not an optional limitation, as it explains how the value of more than 90% is calculated.
First and Second Phases: Claim 1 recites a first liquid phase and a second liquid phase. Claim 2 recites that the first liquid phase is the lipid phase and the second liquid phase is the aqueous phase, whereas claim 3 recites that the first liquid phase is the aqueous phase and the second liquid phase is the lipid phase.
Looking to the last six lines of claim 1, it appears to the examiner that the particular phase that is designated the first phase and the particular phase that is designated the second phase appears to be essentially arbitrary. This is because the provision of both phases appears to be separately controlled, and the second phase is required to be in a crossflow to the first direction. As such, in the case of prior art teaching both phases in crossflow to each other, both the first phase would have been in crossflow to the second phase and vice versa.
“Phase” and Solubility: The examiner further notes the following with regard to the term phase. As best understood by the examiner, the term “phase”, as used in the manner indicated in the instant application, does not exclude the case in which the first and second phases are miscible. This is because in the examples in the instant application, the one phase comprises lipids dissolved in ethanol, and the other phase comprises aqueous buffer; see the instant specification on page 39, Example 4. The skilled artisan would have been aware that water and ethanol are miscible; nevertheless, the claims recite these to be separate phases. As such, two miscible liquids are recited to be separate phases by the instant claims.
This definition of the term “phase” differs from that used by prior art in the emulsion field. In such prior art in the emulsion field, the terms “oil phase” and “aqueous phase” are often used to refer to liquid phases that are not miscible with each other. This definition of the term “phase” is not understood to apply to the instant claims, at least because the recited liposomes and lipid nanoparticles do not appear to be emulsions.
“Liposome” and “Lipid Nanoparticle”: The instant claims recite the terms “liposomes” and “lipid nanoparticles.” These appear to be defined as of page 29, top paragraph of the instant specification, which is reproduced below.
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The skilled artisan would have understood that the term “vesicle” refers to a particle with an interior aqueous phase. Additionally, the well-understood definition of the term “liposome” is that of a lipid vesicle; namely, a particle having an interior aqueous space and delimited by a lipid bilayer. For the purposes of examination under prior art, the examiner will proceed with the understanding that a liposome with a particle diameter in the nanometer range (e.g. less than 1 micron) is a lipid nanoparticle.
“PDI:”: Claim 80 recites the abbreviation “PDI:” This is understood to refer to “polydispersity index.” See the instant specification on page 35 line 3. The term “polydispersity index” is understood to be a well-known term drawn to a measurement of the variability of a particular measurement, such as particle size. A higher polydispersity means that the particles have a more variable size, whereas a lower polydispersity means that the particles have a more uniform size. In the art of liposomes and lipid nanoparticles, a lower polydispersity is generally desirable.
Claim 16: Claim 16 is understood to further limit claim 7 in that it is understood to exclude a case wherein the one or more active agents are hydrophobic, but are included in the aqueous phase rather than the lipid phase. As such, for this reason, claim 16 is understood to properly further limit claim 7 upon which it depends. Claim 16 does not exclude the case wherein the active agent is hydrophilic. The case wherein the active agent is hydrophobic but is included in the lipid phase is also within the scope of claim 16.
Claims 18-19: Claim 18 recites “wherein the lipid vesicles are produced unloaded and loaded afterwards (active loading).” As best understood by the examiner, “active loading” is a synonym for a method in which lipid vesicles are produced unloaded and loaded afterwards. As such, claim 18 is understood to be clear and definite and is not subject to a rejection under 35 U.S.C. 112(b). Claim 19 is interpreted similarly.
Claim 31 – pKa: The term “pKa” is a well-known term for the negative base ten logarithm of the acidity constant. Acids with lower pKa values are strong acids with larger acidity constants, and acids with higher pKa values are weaker acids. Protonated tertiary amines are acids and therefore subject to measurement via pKa.
As best understood by the examiner, when it comes to protonated tertiary amine cationic lipids, the pKa of such lipids in a liposome or lipid nanoparticle, which may be referred to as “apparent pKa” may differ from the pKa of such lipids outside a liposome or lipid nanoparticle, which may be referred to as “intrinsic pKa”. This issue is discussed by Brown et al. (US 2019/0151461 A1), especially as of paragraphs 0204-0205.
For the purposes of examination under prior art, the pKa recited by claim 31 is understood to either be the intrinsic or apparent pKa of the protonated tertiary amine lipid.
Response to Arguments Relating to Claim Interpretation Issues
Applicant provided arguments in applicant’s response on 24 February 2026 relating to issues regarding claim interpretation. However, these arguments do not appear to affect the propriety of the applied rejections. As such, these arguments relating to claim interpretation issues have not been substantively addressed by the examiner.
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) 1-4, 7, 10, 40, 52, and 80 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vladisavljevic et al. (Colloids and Surfaces A: Physicochem. Eng. Aspects 458 (2014), pages 168–177) in view of Williams et al. (WO 2019/092461 A1).
Vladisavljevic et al. (hereafter referred to as Vladisavljevic) is drawn to production of liposomes by using a particular membrane co-flow microfluidic device, as of Vladisavljevic, page 168, title and abstract, wherein the figure in the abstract is reproduced below.
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Vladisavljevic teaches three separate embodiments, wherein one of them is described as “cross-flow membrane system”, as of Vladisavljevic, page 170, caption of figure 2, which is reproduced below with annotation by the examiner.
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Vladisavljevic does not appear to teach the apparatus for conducting the crossflow mixing method.
Williams et al. (hereafter referred to as Williams) is drawn to a cross-flow device and method for producing a dispersion, as of Williams, title and abstract. The device of Williams comprises an outer tubular sleeve comprising a first inlet, as of item (1) of the abstract. The device of Williams comprises a second inlet distal from and inclined relative to the first inlet, as of item (7) of the abstract. The device of Williams comprises a tubular membrane comprising a plurality of pores and positioned inside the tubular sleeve, as of the abstract of Williams. Williams teaches a chamfered region, as of the last sentence of the abstract.
Williams does not teach lipid vesicles and/or liposomes.
It would have been prima facie obvious for one of ordinary skill in the art to have used the device of Williams to have conducted the crossflow method of Vladisalvljevic of producing lipid nanoparticle liposomes. Vladisalvljevic is drawn to a method of producing lipid nanoparticles via a crossflow apparatus. Williams teaches a crossflow apparatus for conducting mixing of liquid phases. As such, the skilled artisan would have been motivated to have used the device of Williams to have conducted the method of Vladisalvljevic to have predictably formed liposomes and/or lipid nanoparticles with a reasonable expectation of success.
As to claim 1, the claim requires a first liquid phase comprising lipids and a second liquid phase that is aqueous. Vladisavljevic teaches an organic phase comprising lipids in ethanol mixed with water, as of the experimental procedure described in page 170, section 2.2.1.
As to claim 1, the claim recites a membrane defining a plurality of pores. Vladisavljevic teaches a membrane as of page 170, section 2.2.1, right column. This membrane would appear to have evenly spaced, unconnected pores of uniform size and regular cylindrical cross-section, as of Vladisavljevic, page 169, right column, third paragraph, relevant text reproduced below.
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As to claim 1, the claim recites the second phase in crossflow to the first phase. Vladisavljevic teaches this as of at least page 170, figure 2, part (b).
As to claim 1, the claim requires that the lipid vesicles are homogeneously sized, that 9-% (volume weighted) of the homogeneously sized lipid vesicles are less than about 220 nm with a polydispersity of ≤0.3. Vladisavljevic teaches the following as of page 172, right column, figure 4, reproduced below.
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The above-reproduced particle distribution appears to show less than 10% of particles sized less than about 200 nm. Regarding the polydispersity index, the examiner notes that Vladisavljevic teaches the word “polydispersity” as of page 172, right column, section 2.4 but does not appear to provide a numerical value. Nevertheless, Vladisavljevic appears to provide teachings about how the particle size distribution can be altered by changing the orifice diameter, as of Vladisavljevic, page 176, left column, figure 9. Additionally, the apparatus of Williams appears to be the same apparatus required by the method of instant claim 7. As such, the skilled artisan would have expected that this apparatus would have been capable of preparing lipid vesicles with a polydispersity index within the claimed range. In the alternative, 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 a crossflow method to make lipid vesicles has been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of particle size by routine experimentation. The skilled artisan would also have had a reasonable expectation of successfully optimizing the particle size, at least by adjusting the orifice diameter, as per Vladisavljevic, page 176, left column, figure 9.
As to claim 2, Vladisavljevic teaches an organic phase comprising lipids in ethanol mixed with water, as of the experimental procedure described in page 170, section 2.2.1. In this case, the ethanol phase would appear to be the first phase and the second phase would appear to be the aqueous phase.
As to claim 3, this claim is rejected for essentially the same reason that claim 2 is rejected. See the section above entitled “Claim Interpretation” for an explanation of how the first phase and second phase are interpreted.
As to claim 4, Vladisavljevic teaches liposomes, as of page 170, title. Said liposomes are sized at 80.3 nm, as of page 168, “Highlights” section, rendering the liposomes to be lipid nanoparticles due to their nano size.
As to claim 7, the device of Williams comprises an outer tubular sleeve and a tubular membrane. The skilled artisan would have been motivated to have predictably controlled the provision of liquids in the method of Williams with a reasonable expectation of success.
As to claim 10, Vladisalvljevic teaches liposomes and lipid nanoparticles, as of the title and abstract.
As to claim 40, Williams teaches an optional insert in the abstract.
As to claim 52, Williams teaches a plurality of tubular membranes, as of Williams, page 7, lines 20-25.
As to claim 80, the apparatus of Williams appears to be the same apparatus required by the method of instant claim 7. As such, the skilled artisan would have expected that this apparatus would have been capable of preparing lipid vesicles with a polydispersity index within the claimed range.
Note Regarding Reference Date: The earliest effective filing date of the instant application appears to be 22 July 2020, based upon a foreign priority claim to a British application. Williams was published on 16 May 2019. As such, Williams appears to have been published over a year prior to the effective filing date of the instant application. As such, Williams is prior art under AIA 35 U.S.C. 102(a)(1). The exceptions under AIA 35 U.S.C. 102(b)(1)(A) or 102(b)(1)(B) would not appear to be applicable because Williams was published over a year prior to the earliest effective filing date of the instant application.
Claim(s) 16 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vladisavljevic et al. (Colloids and Surfaces A: Physicochem. Eng. Aspects 458 (2014), pages 168–177) in view of Williams et al. (WO 2019/092461 A1), the combination further in view of Laouini et al. (RSC Advances, Vol. 3, 2013, pages 4985-4994).
Vladisavljevic is drawn to a method of preparing lipid nanoparticles using crossflow. Williams is drawn to a particular crossflow apparatus. See the rejection above over Vladisavljevic in view of Williams.
Neither Vladisavljevic nor Williams teach a hydrophobic active agent.
Laouini et al. (hereafter referred to as Laouini) is drawn to a method of preparing liposomes encapsulated with Vitamin E, as of Laouini, page 4985, title and abstract. In the method of Laouini, lipids and Vitamin E were dissolved in ethanol, and then this ethanol phase was combined with an aqueous phase using the device of Laouini using a crossflow apparatus in order to produce liposomes, as of Laouini, page 4987, left column, section 2.2.
It would have been prima facie obvious for one of ordinary skill in the art to have formulated liposomes with a hydrophobic active, and to have done so by dissolving the hydrophobic active in the ethanol phase which also comprises lipids. Vladisavljevic teaches forming liposomes and teaches active hydrophobic agents generically as of page 169, left column. Laouini teaches that Vitamin E, which is a hydrophobic active agent, may be introduced by dissolving Vitamin E in the ethanol phase with lipids. As such, the skilled artisan would have been motivated to have dissolved the Vitamin E in the ethanol solvent and lipid phase for predictable formulation into liposomes with a reasonable expectation of success.
As to claim 16, Vitamin E, as of Laouini, reads on the required hydrophobic active agent.
As to claim 19, the method of Laouini entails producing lipid vesicles already loaded.
Claim(s) 13-15, 19, 21, 26, 29, 31-32, 36-37, and 100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vladisavljevic et al. (Colloids and Surfaces A: Physicochem. Eng. Aspects 458 (2014), pages 168–177) in view of Williams et al. (WO 2019/092461 A1), the combination further in view of Smith (US 2018/0243230 A1).
Vladisavljevic is drawn to a method of making liposomes using a membrane crossflow method, wherein said liposomes are lipid nanoparticles. Williams is drawn to an apparatus used for a crossflow method. See the rejection above over Vladisavljevic in view of Williams by themselves.
Vladisavljevic does not exemplify particular active agents (e.g. mRNA).
Smith is drawn to lipid nanoparticles comprising mRNA, as of Smith, title and abstract and figure 3, reproduced below.
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Smith teaches preparing the lipid nanoparticles via mixing an aqueous solution comprising mRNA and an ethanol solution comprising lipids, as of paragraph 0138 of Smith.
Smith does not teach a crossflow device/method, as the T-configuration described in paragraph 0138 would not appear to read on this requirement.
It would have been prima facie obvious for one of ordinary skill in the art to have combined the aqueous and ethanol phase of Smith using the device of Vladisavljevic. Smith is drawn to a method of making lipid nanoparticles by mixing ethanol comprising lipids with an aqueous phase comprising active agent. Vladisavljevic teaches that an ethanol phase and a lipid phase can be mixed using a crossflow method. As such, the skilled artisan would have been motivated to have used the crossflow method of Vladisavljevic to have mixed the ethanol and aqueous phase of Smith to have predictably produced a lipid nanoparticle, as desired by Smith, with a reasonable expectation of success.
As to claim 13, Smith, paragraph 0138, teaches mRNA in an aqueous solution. This is understood to read on active agents in the aqueous phase.
As to claim 14, Smith teaches an aqueous solution comprising 20 mM sodium citrate, as of paragraph 0140. This is understood to read on the required buffer because sodium citrate buffers against the inclusion of low pH agents. Smith also teaches a buffer in paragraph 0051.
As to claim 15, Smith teaches Tris buffer in paragraph 0146.
As to claim 19, the method of Smith, paragraph 0138, would appear to suggest producing the lipid vesicles loaded.
As to claim 21, the mRNA of Smith, e.g. as in paragraph 0004, is understood to read on the required therapeutic agent.
As to claim 26, Smith teaches cationic lipids, at least as of paragraph 0040 of Smith.
As to claim 29, Smith teaches DSPC in at least paragraph 0079.
As to claim 31, Smith teaches an [apparent] pKa of about 6 to about 8.5 in paragraph 0064. 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 32, Smith appears to teach the relevant lipids in paragraph 0069.
As to claims 36-37, Smith teaches PEG-DMG in at least paragraph 0083.
As to claim 100, Smith teaches DODMA in paragraph 0069, which reads on this claimed requirement.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vladisavljevic et al. (Colloids and Surfaces A: Physicochem. Eng. Aspects 458 (2014), pages 168–177) in view of Williams et al. (WO 2019/092461 A1), the combination further in view of Zhu et al. (US 2014/0348900 A1).
Vladisavljevic is drawn to a method of making liposomes using a membrane crossflow method, wherein said liposomes are lipid nanoparticles. Williams is drawn to an apparatus used for a crossflow method. See the rejection above over Vladisavljevic in view of Williams by themselves.
Vladisavljevic does not teach a method in which the lipid vesicles are produced unloaded and loaded afterwards.
Zhu et al. (hereafter referred to as Zhu) is drawn to a method and device for producing lipid nanoparticles, as of Zhu, title and abstract. This method entails mixing an organic lipid solution stream with an aqueous stream, as of Zhu, title and abstract. Zhu teaches the following, as of paragraphs 0118-0120, reproduced below.
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As such, Zhu teaches making the liposomes empty, followed by loading of the active agent, and teaches that this method is preferred.
As best understood by the examiner, Zhu does not teach crossflow.
It would have been prima facie obvious for one of ordinary skill in the art to have formulated liposomes via the method of Vladisavljevic empty, followed by adding active agent later. Vladisavljevic is drawn to a method of forming liposomes, and suggests the inclusion of an active agent, as of Vladisavljevic, page 169, left column. Zhu teaches that a loaded liposome can be formed via forming the liposome empty followed by loading afterwards, and teaches that this method is preferred. As such, the skilled artisan would have been motivated to have predictably prepared liposomes via the method of Vladisavljevic empty followed by loading in the manner taught by Zhu in order to have predictably prepared loaded liposomes with a reasonable expectation of success.
Claim(s) 21-23 and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vladisavljevic et al. (Colloids and Surfaces A: Physicochem. Eng. Aspects 458 (2014), pages 168–177) in view of Williams et al. (WO 2019/092461 A1) and Smith (US 2018/0243230 A1), the combination further in view of Ciaramella et al. (US 2018/0311336 A1).
Vladisavljevic is drawn to a method of making liposomes using a membrane crossflow method, wherein said liposomes are lipid nanoparticles. Williams is drawn to an apparatus used for a crossflow method. See the rejection above over Vladisavljevic in view of Williams by themselves. Smith is drawn to lipid nanoparticles comprising mRNA. See the rejection above over Vladisavljevic in view of Smith.
Smith does not teach that the mRNA encodes an antigen, which the examiner understands to be required by claim 22.
Ciaramella et al. (hereafter referred to as Ciaramella) is drawn to RNA vaccines for influenza, as of Ciaramella, title and abstract. Ciaramella teaches that the RNA encodes at least one antigenic polypeptide or protein of a virus, as of Ciaramella, paragraph 0007.
Ciaramella does not teach crossflow.
It would have been prima facie obvious for one of ordinary skill in the art to have used the mRNA of Ciaramella as the mRNA in the method of Smith. Smith is drawn to a method utilizing mRNA, but is silent as to the therapeutic purpose of the mRNA. Ciaramella teaches that mRNA can encode an antigenic protein or peptide and thereby act as a vaccine. As such, the skilled artisan would have been motivated to have used the mRNA of Ciaramella in the method of Smith in order to have predictably encoded an antigenic polypeptide and thereby to have predictably had a therapeutic effect with a reasonable expectation of success.
As to claim 21, the mRNA of Ciaramella reads on the required vaccine.
As to claim 22, the mRNA of Ciaramellla encodes an antigenic protein/peptide and thereby reads on the claimed requirements.
As to claim 23, the mRNA of Ciaramella reads on the requirements of this claim.
As to claim 27, Ciaramella teaches DOTAP in paragraph 0496.
Response to Arguments
Applicant has presented arguments regarding the previously applied rejection, as of applicant’s response on 24 February 2026 (hereafter referred to as applicant’s response). These arguments are addressed below.
In applicant’s response, page 10, applicant takes the following position:
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This is not persuasive because applicant appears to be arguing subject matter that is not actually recited by the claims. Nothing in the instant claims exclude recirculation or limit the claimed method to only a single pass. Arguments related to limitations not claimed are not persuasive. See MPEP 2145(VI).
Applicant then presents arguments taking the position that the particle size distribution of Vladisavljevic includes a much larger percentage of particles exceeding 220 nm than the claimed invention, as of applicant’s response, pages 11-12. This is not persuasive. Vladisavljevic, page 172, right column, figure 4 shows that the vast majority of the particles are sized below 200 nm, let alone 220 nm. Looking at the figure, it would appear that well above half of the particles are sized below 100 nm, the majority of the particles are sized below 150 nm, and the vast majority of the particles are sized below 200 nm, let alone 220 nm.
Applicant then presents particle size data obtained from the following web site.
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This is not persuasive. The examiner visited the web site URL set forth above and was unable to find the particle size graphs relied upon by applicant in applicant’s response. The examiner has attached the front page of this web site to this office action, and has cited it in the attached PTO-892 form.
Applicant then provided the following graph, as of page 13 of applicant’s response, relevant figures reproduced below.
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This is not persuasive. The above-reproduced graph appears to compare the particle size distribution curve of Vladisavljevic to a hypothetical particle size distribution curve which applicant apparently obtained from www.malvernpanalytical.com but which was not available to the examiner on that web site. Applicant then appears to have converted the x-axis from a logarithmic axis, which was apparently obtained from www.malvernpanalytical.com, to a linear x-axis. However, applicant does not appear to have normalized the area of the hypothetical particle size curve to that of the particle size distribution curve from Vladisavljevic, rendering comparison of the curves to be unclear to the examiner. As such, this graph does not prove that Vladisavljevic has a greater polydispersity index than what is required by the instant claims.
Furthermore, even if, purely en arguendo, the arguments provided by applicant were to suggest that Vladisavljevic has a polydispersity that is too high to meet the claimed requirement, it is still the case that applicant’s arguments are unpersuasive. This is because the data presented by applicant appears to have attorney arguments; said attorney arguments would appear to be insufficient where evidence is necessary. See MPEP 716.01(c)(II) and MPEP 2145(I). In this case, a calculation performed to show that Vladisavljevic does not have the required polydispersity would appear to necessitate providing evidence, especially as this calculation utilizes information that is present neither in the prior art nor in the disclosure of the instant application.
Applicant then presents this graph on page 14 of applicant’s response, which is reproduced below.
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This graph does not appear to be part of the instant application, nor does it appear to have been taught by Vladisavljevic. As such, this graph appears to be an example of attorney arguments that are insufficient because evidence is necessary. See MPEP 716.01(c)(II) and MPEP 2145(I), as applied above.
Applicant then makes the following argument, as of page 14 of applicant’s response.
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This is not persuasive. The support provided by applicant in support of the above position (a) relies upon the “Malvern Panalytical” reference that has not actually been provided to the file record (b) appears to be attorney argument that is insufficient because evidence is required, and (c) does not actually provide an estimate or information as to how much of the volume of the particles of Vladisavljevic would have been sized above 220 nm. As such, applicant’s arguments are unpersuasive for at least those reasons.
Applicant then argues that Vladisavljevic does not teach the importance of achieving a low volume percentage of particles over 200 nm, as of applicant’s response, page 14. This is not persuasive, as Vladisavljevic does appear to teach a desire to form smaller particles, as of Vladisavljevic, at least page 176, paragraph bridging left and right columns.
Applicant then makes the following argument, as of page 15, top paragraph.
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This is not persuasive with respect to claim 1 at least because claim 1 does not require a tubular membrane as opposed to a flat membrane. As such, applicant appears to be arguing subject matter not actually recited by instant claim 1. Additionally, while claim 7 requires a tubular membrane, Williams appears to teach a tubular membrane. This was explained by page 9 of the prior office action mailed on 29 August 2025, citing the abstract of Williams.
Applicant then makes the following argument as of the top half of page 15, relevant text reproduced below.
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The relevant text from Vladisavljevic appears to have been set forth on page 176 and is reproduced below.
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The examiner agrees that the above-reproduced text is drawn to co-flow devices. However, contrary to applicant’s arguments, (a) nothing in Vladisavljevic makes it clear that “co-flow” means “coaxial-flow”, and (b) nothing in Vladisavljevic makes it clear that a co-flow capillary device would have been unsuitable with a cross flow method. In support of this position, the examiner notes that Vladisavljevic, page 172, right column, figure 4 makes it clear that the three methods being tested are the (a) the stirred cell method, (b) the cross flow method, and (c) the oscillating method. As such, this teaching fails to indicate that the “co-flow” and “cross-flow” are separate entities, and fails to indicate that teachings related to a co-flow apparatus are inapplicable to the cross-flow method of Vladisavljevic.
Applicant presents further arguments regarding claim 7, as of pages 15-16 of applicant’s response. Applicant’s arguments emphasize the fact that Vladisavljevic teaches a flat membrane, whereas claim 7 requires a tubular membrane. This is not persuasive because Williams appears to teach a tubular membrane. See the prior office action mailed on 29 August 2025, at least page 9.
Applicant provides arguments regarding the Laouini reference as of pages 16-17 of applicant’s response. Applicant’s arguments relating to Laouini are drawn to the fact that Laouini found an increase in mean vesicle size and an increase in polydispersity index, which goes against the requirements of the instant claims. In support of this position, applicant cited text on page 4988 of Laouini.
This is not persuasive. The cited text from Laouini indicates an increase in particle size and polydispersity was observed when the phospholipid concentration in the organic phase was made too high. As such, the skilled artisan would have been motivated to have reduced the phospholipid concentration in the organic phase to have achieved a lower particle size and polydispersity. Additionally, Laouini clearly teaches methods of achieving compositions comprising a mean particle size well below 200 nm, as of Laouini, page 4988, Table 1, reproduced below.
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As such, Laouini does appear to teach particle size distributions that are well below the 220 nm maximum required by the instant claims.
Applicant then addresses the Smith reference Smith (US 2018/0243230 A1), which the examiner relied upon to teach mRNA as an active agent. Applicant appears to object to the fact that Smith contemplates changing the pH before or during filtration, as of applicant’s response, page 18. This is not persuasive at least because (a) the instant claims do not appear to exclude changing the pH before or during filtration, (b) Smith indicates that changing the pH before or during filtration is optional because it only occurs in some embodiments, and (c) nothing in Vladisavljevic indicates that the method of Vladisavljevic is incompatible with changing pH during the course of the method.
Applicant then cites the instant specification on page 17, lines 16-20, which indicates that the method of the instant invention does not use turbulent flow. This is not sufficient to overcome the previously applied rejection over Smith because Smith teaches the use of a microfluidic device in paragraphs 0029 and 0115-0116. As best understood by the examiner, microfluidic methods utilize laminar flow rather than turbulent flow. As such, applicant’s arguments relating to laminar flow vs. turbulent flow do not appear to be persuasive.
Applicant also argues that Smith does not tech the importance of maintaining a high yield or having less than about 90% of the particles below 220 nm, as of applicant’s response, page 18, bottom paragraph. This is not persuasive. Smith teaches particles sized at maximum about 120 nm and polydispersity at a maximum of about 25%, as of Smith, figures 7A and 7B, reproduced below.
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As such, Smith appears to teach a particle size and polydispersity in the claimed range. Additionally, Smith teaches a desire to improve yield as of the abstract of Smith.
Applicant presents additional arguments regarding the previously cited reference Zhu et al. (US 2014/0348900 A1), as of applicant’s response, page 19. Relevant text is reproduced below.
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This is not persuasive. Zhu was cited to teach the concept of producing vesicles empty and loading the vesicles with active agent afterwards. This does not appear to relate to the issue of using a porous membrane with or without an insert assembly. This is because (a) the issue of the porous membrane and insert assembly relates to the production of the vesicles themselves, not to the concept of first producing vesicles then loading active agent, and (b) Vladisavljevic and Williams already teach the porous membrane and insert assembly. As such, arguments that Zhu fails to teach the porous membrane and insert assembly appear to be drawn to Zhu by itself rather than the combination of references. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See MPEP 2145(IV).
Applicant then presents arguments regarding Ciaramella et al. (US 2018/0311336 A1), as of applicant’s response on page 20. Applicant argues that Ciaramella does not teach a membrane or, in particular a crossflow membrane, as of applicant’s response, page 20.
This is not persuasive. Ciaramella appears to teach a wide variety of methods of making the composition, as of paragraphs 0470-0472. As such, the skilled artisan would have been motivated to have looked to a wide variety of references used to form liposomes and lipid nanoparticles, including but not limited to that of Vladisavljevic. As such, the skilled artisan would have been motivated to have combined Ciaramella with Vladisavljevic for the reasons set forth in the prior office action. Arguments that Ciaramella fails to teach a membrane or, in particular a crossflow membrane appear to address Ciaramella by itself rather than the combination of references and are therefore not persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See MPEP 2145(IV).
Conclusion
No claim is allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571)272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612