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.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-11 in the reply filed on 2 December 2025 is acknowledged.
Claims 12-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2 December 2025.
Claim Interpretation Regarding the term “Oil”
The examiner has included this section of the office action to explain how the term “oil” is being interpreted.
The ordinary definition of the term “oil” is understood by the examiner to refer to a non-polar liquid that is immiscible with water and is often of a higher viscosity than water.
However, it appears that applicant has redefined the term “oil” to further include various alcohols such as ethanol. This determination is made at least in view of the instant specification on page 12, paragraph 71, relevant text reproduced below.
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As such, the examiner understands the scope of the term “oil” to include alcohols miscible with water such as ethanol.
An applicant is entitled to be their own lexicographer and may rebut the presumption that claim terms are to be given their ordinary and customary meaning by clearly setting forth a definition of the term that is different from its ordinary and customary meaning(s) in the specification at the relevant time. See MPEP 2111.01(IV)(A). In this case, it is the examiner’s position that applicant has redefined the term “oil” to include materials that would not ordinarily have been considered to be oils. As applicant has clearly redefined the term “oil”, there is no case of indefiniteness related to this issue.
Claim Interpretation Regarding Lipids and Introduction to the Art Area
Prior to setting forth the grounds of rejection, the examiner provides the following explanation regarding the art area of the instant application.
The instantly claimed invention appears to be drawn to a method for making lipid nanoparticles for delivery of nucleic acids. One of the most well-known examples of lipid nanoparticles for delivery of nucleic acids are the mRNA COVID-19 vaccines from Moderna and Pfizer-BioNTech. These vaccines were discussed by Schoenmaker et al. (International Journal of Pharmaceutics, Vol. 601, 2021, Article 120856, pages 1-13).
Schoenmaker et al. (hereafter referred to as Schoenmaker) is drawn to lipid nanoparticle COVID-19 vaccines, which comprise mRNA and a lipid nanoparticle, as of Schoenmaker, title and abstract; the examiner notes here that some of the prior art, especially from prior to the COVID-19 pandemic, uses siRNA or DNA as the nucleic acid rather than mRNA. Schoenmaker teaches the following components of the lipid nanoparticle, as of page 8, figure 6, reproduced below.
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As such, the lipid components of the compositions of Schoenmaker include four lipids. These lipids are (1) an ionizable cationic lipid, (2) a first helper lipid which is DSPC, (3) a second helper lipid which is cholesterol, and (4) a PEGylated lipid.
Looking to the instant claims, it appears that the claims recite a method of making a lipid nanoparticle with four lipids, but use different terminology to describe each lipid as compared with the terminology used by Schoenmaker. The examiner has provided an explanation regarding this issue.
First, claim 9 appears to define DSPC (distearoyl phosphatidylcholine) and DOPE (dioleoyl phosphatidylethanolamine) as non-ionizable lipids. The examiner takes the position that according to the ordinary definition of “non-ionizable”, DSPC and DOPE would not have been considered non-ionizable because they are actually zwitterionic, containing both a positive and negative charge, and contain a phosphate group which is ionized at neutral and high pH but not ionized at low pH and is therefore ionizable. With that being said, it appears that applicant has redefined the phrase “non-ionizable lipid” to include DSPC and DOPE. An applicant is entitled to be their own lexicographer and may rebut the presumption that claim terms are to be given their ordinary and customary meaning by clearly setting forth a definition of the term that is different from its ordinary and customary meaning(s) in the specification at the relevant time. See MPEP 2111.01(IV)(A). In this case, applicant appears to have adequately redefined the phrase “non-ionizable lipid.”
Secondly, applicant appears to have defined the required neutral lipid as being drawn to PEGylated lipids in claim 10.
Third, applicant appears to have defined the conjugated lipid as including phospholipid and cholesterol. The examiner takes the position that, according to the ordinary definition of “conjugated lipid”, cholesterol would not have been considered to have been a conjugated lipid. With that being said, it appears that applicant has redefined the phrase “conjugated” to include cholesterol. An applicant is entitled to be their own lexicographer and may rebut the presumption that claim terms are to be given their ordinary and customary meaning by clearly setting forth a definition of the term that is different from its ordinary and customary meaning(s) in the specification at the relevant time. See MPEP 2111.01(IV)(A). In this case, applicant appears to have adequately redefined the phrase “conjugated lipid.”
As such, it is the examiner’s position that Schoenmaker teaches all of the lipids required by the instant claims. With that being said, Schoenmaker does not anticipate the claimed invention because Schoenmaker is silent as to the method of making the lipid nanoparticle composition.
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 and 6-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cullis et al. (US 2012/0276209 A1).
Cullis et al. (hereafter referred to as Cullis) is drawn to lipid nanoparticles and a method of making said lipid nanoparticles, as of Cullis, title and abstract. In one embodiment, Cullis teaches providing a nucleic acid (siRNA) in aqueous solution, separately providing a solution of four lipids in ethanol, and mixing these together, as of Cullis, page 17, Example 2, paragraph 0244, relevant text reproduced below.
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DLin-KC2-DMA reads on the required ionizable lipid, DSPC reads on the required non-ionizable lipid, cholesterol reads on the required conjugated lipid, and the PEG-lipid of Cullis reads on the required neutral lipid. While this example cites figure 15B of Cullis, it is noted that Cullis teaches multiple examples of usable mixers for the ethanolic and aqueous phases as of figures 4-15 of Cullis, wherein the examiner has reproduced below the mixer of figure 6 of Cullis.
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Cullis differs from the claimed invention because Cullis appears to teach mixing all four of the lipid components in an organic solvent to form a single organic phase, and mixing this with the aqueous phase comprising nucleic acid; this differs from the claimed method which requires a first organic phase comprising the ionizable lipid and a second organic phase comprising the other three lipids. Nevertheless, this difference is insufficient to overcome the prima facie case of obviousness. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results, and selection of any order of mixing ingredients is prima facie obvious. See MPEP 2144.04(IV)(C).
As to claim 1, the claim recites a first step of preparing an aqueous phase including nucleic acid. Cullis teaches this in at least paragraph 0244.
As to claim 1, the claim requires a second step of preparing a first oil phase and a third step of preparing a second oil phase. Cullis teaches preparing a single oil phase (actually an ethanol phase with dissolved lipids); however, this oil phase would have had all of the lipids required by the instant claims. The idea of separating the ionizable lipid into a different oil phase as compared with the other lipids is not a sufficient to difference to overcome the applied prima facie case of obviousness; see MPEP 2144.04(IV)(C), as explained above.
As to claim 1, the claim requires a fifth and sixth step of injecting and flowing the aqueous phase and oil phase into a first and second channel. This is taught by Cullis, at least paragraphs 0026-0029.
As to claim 1, the claim requires a seventh step that the aqueous phase and oil phase intersect with each other to flow through a stirring channel as a mixture solution. This would appear to be evident in the mixers taught by Cullis, figures 4-15, including figure 6 which is reproduced above.
As to claim 1, the claim requires an eighth step of flowing a second oil phase solution through a third channel. The examiner notes that various embodiments of Cullis teach more than two channels. This is taught at least as of Cullis, figures 6 and 12. With that being said, while Cullis does not teach a second oil phase that has different lipids dissolved therein as compared with the first oil phase, this would not have overcome the applied rejection. The idea of separating the ionizable lipid into a different oil phase as compared with the other lipids is not a sufficient to difference to overcome the applied prima facie case of obviousness; see MPEP 2144.04(IV)(C), as explained above.
As to claim 1, the last step of the claim recites forming lipid nanoparticles. Cullis teaches this at least as of the reference title. Also see Cullis, figure 27, reproduced below.
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As to claim 2, the claim recites that the mixer contains a stirring unit and a non-stirring unit. The examiner notes that Cullis does not use this terminology. Nevertheless, the mixer of Cullis appears to be essentially the same as the claimed mixer. In support of this position, the examiner has reproduced figure 6 of Cullis side-by-side with Figure 1 of the instant application.
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In both the mixer from Cullis as well as the mixer from the instant invention, thre appear to be inlets through which the solutions are injected, followed by a portion in which the solution goes from one side to another multiple times. As this appears to be the same mixer type as required by the instantly claimed invention, the skilled artisan would have expected that the mixer of Cullis would have comprised the both the stirring unit and the non-stirring unit. See MPEP 2112 and 2114(II).
As to claim 3, the mixer of Cullis, figure 3 appears to include multiple channels that would read on the required nth stirring channel.
As to claim 4, as best understood by the examiner, figure 1 of the instant application appears to show mixing of the third component as of the first channel; in contrast, figure 6 of Cullis appears to show mixing of the third component (referred to as inlet 3) as of the fourth channel. This is because item #610a appears to go up and back four times before the stream from inlet 3 is let in. The examiner understands the channels of Cullis to read on the required mixing modules; as such, mixing the third inlet at the fourth channel would appear to be between the first mixing module and the fifth mixing module and would therefore be within the claim scope. Regardless, the issue of the number of times in which the mixing channel of the first two inlets goes back and forth before the third inlet stream is mixed would appear to be a change in form, proportion or degree that would be insufficient to overcome the applied rejection. It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions. See MPEP 2144.05(II)(A), end of paragraph. Additionally, Cullis is drawn to a microfluidic method, as of paragraph 0005, which utilizes laminar flow, as of Cullis, paragraphs 0022 and 0024.
As to claim 6, Cullis teaches a ratio of ionizable cationic lipid of 30 mol% to 60 mol% in paragraph 0216. This appears to overlap with the claimed range of 10 mol% to 30 mol% at the end point of 30 mol%. This overlap results in a prima facie case of obviousness. 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 6, in the alternative, Cullis teaches a concentration of ionizable cationic lipid that differs from the claimed concentration. Nevertheless, this difference in concentration is insufficient to overcome the applied rejection. 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 this case, no evidence of criticality appears to have been presented. 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 a method of making a lipid nanoparticle comprising ionizable cationic lipid, phospholipid, cholesterol, and PEG-lipid have been taught by Cullis. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of these elements via routine experimentation.
As to claim 7, Cullis teaches a N/P ratio of 4 in paragraph 0226; the examiner understands this to read on a 4:1 ratio of charge of ionizable lipid to charge of nucleic acid. The examiner understands this to be within the claim scope.
As to claim 8, Cullis teaches siRNA, as of Cullis, at least paragraph 0226.
As to claim 9, Cullis teaches DSPC, as of paragraph 0226.
As to claim 10, Cullis teaches PEG-s-DMG in paragraph 0115; this reads on the required DMG-PEG.
As to claim 11, Cullis teaches cholesterol as of paragraphs 0065 and 0226.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cullis et al. (US 2012/0276209 A1) in view of Hoge et al. (US 2016/0038612 A1).
Cullis is drawn to a method of encapsulating nucleic acids in lipid nanoparticles using particular mixers. See the rejection above over Cullis.
Cullis is silent as to the polydispersity index of the produced lipid nanoparticles.
Hoge et al. (hereafter referred to as Hoge) is drawn to nucleic acids for encoding a desired protein or peptide, as of Hoge, title and abstract. Hoge teaches that the mRNA may be in a lipid nanoparticle, as of paragraph 0066 of Hoge. Hoge teaches the following method of making lipid nanoparticles, as of pages 206-207, paragraphs 1413-1414, relevant text reproduced below.
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Hoge appears to achieve polydispersity index values of between 0.12 at maximum and 0.03 at minimum, as of Hoge, page 209, Tables 14-15, wherein Table 15 has been reproduced below, wherein the abbreviation “PDI” refers to polydispersity index.
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As such, Hoge appears to teach a polydispersity index range with a maximum of about 0.12.
Hoge differs from the claimed method because Hoge, like Cullis, does not appear to teach providing the ionizable cationic lipid in a separate solution as compared with the solution with the other three lipids.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Cullis in the manner taught by Hoge. Cullis is drawn to a method of producing lipid nanoparticles comprising nucleic acids, and teaches multiple methods by which lipids in ethanol can be mixed with an aqueous solution comprising the nucleic acid. Hoge also teaches producing a lipid nanoparticle comprising a nucleic acid by mixing an ethanolic solution comprising lipids with an aqueous solution comprising nucleic acids. As such, the skilled artisan would have been motivated to have modified the method of Cullis in the manner taught by Hoge in order to have predictably formed a lipid nanoparticle comprising a nucleic acid with a reasonable expectation of success.
As to claim 5, the claim requires a polydispersity index of less than 0.2. Cullis does not teach this. Nevertheless, Hoge teaches a polydispersity index range of 0.02-0.12. This is within the claimed range. As such, the skilled artisan would have been motivated to have optimized the method of Cullis to have achieved a polydispersity index of between 0.02-0.12. The skilled artisan would have had a reasonable expectation that the polydispersity index could have been optimized in the range of 0.02-0.12 because this range was taught by Cullis. In order to properly support a rejection on the basis that an invention is the result of "routine optimization", the examiner must make findings of relevant facts, and present the underpinning reasoning in sufficient detail. The articulated rationale must include an explanation of why it would have been routine optimization to arrive at the claimed invention and why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range. See MPEP 2144.05(II)(B). In this case, the skilled artisan would have had a reasonable expectation of formulating the claimed polydispersity index range in view of the teachings of Hoge.
Additional Relevant Prior Art
As additional relevant prior art, the examiner cites Schariter et al. (US 2020/0306191 A1). Schariter et al. (hereafter referred to as Schariter) is drawn to a method of making lipid nanoparticles for delivery of nucleic acid, as of Schariter, title and abstract. Schariter teaches the following method on page 55, paragraph 0643, relevant text reproduced below.
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As such, Schariter teaches that at least some of the PEG-lipid is added at later method step as compared with the other lipids. However, Schariter appears to separate the lipids such that in the first step, all of the lipids are dissolved in ethanol, nanoparticles are formed, then some of the PEG-lipid is added later. This differs from the claimed method in which one stream appears to comprise the ionizable cationic lipid and the other stream appears to comprise the lipids other than the ionizable cationic lipid.
As such, in view of this difference, the examiner takes the position that Schariter is no closer to the claimed invention than is Cullis. As such, the examiner has not rejected the instant claims over Schariter. In selecting the references to be used in rejecting the claims, the examiner should carefully compare the references with one another and with the applicant’s disclosure to avoid an unnecessary number of rejections over similar references. The examiner is not called upon to cite all references that may be available, but only the "best." (See 37 CFR 1.104(c).) Multiplying references, any one of which is as good as, but no better than, the others, adds to the burden and cost of prosecution and should therefore be avoided. See MPEP 904.03, third paragraph in section. In this case, Schariter appears to be just as good as, but no better than Cullis; as such, the examiner has not rejected the instant claims over Schariter.
Also as relevant, the examiner cites Zhu (US 2018/0000735 A1). Zhu is drawn to a method of making lipid nanoparticles, as of Zhu, title and abstract, wherein said lipid nanoparticles may include, siRNA, as of at least paragraph 0042. Zhu appears to teach a manifold with multiple ports, as of Zhu, abstract. However, in the method of Zhu, it appears that Zhu intends to administer the aqueous solution via multiple ports rather than to administer the lipid solution via multiple ports. See Zhu, page 9, right column, claims 3-6 of Zhu. This contrasts with the claimed invention, in which the claims require that the lipid solution is administered via multiple ports.
Also as relevant prior art, the examiner cites Karamdad et al. (Chemical Communications, Vol. 52, 2016, pages 5277-5280). Karamdad et al. (hereafter referred to as Karamdad) teaches lipid membranes formed by microfluidics, as of Karamdad, page 5277, title and abstract. Karamdad teaches the following method on page 5278, figure 1, reproduced below.
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The method in the above-reproduced figure differs from the claimed method because the method in the above-reproduced figure is intended to produce giant unilamellar vesicles. These vesicles, with sizes in the tens to hundreds of micron range, are too large to read on the required lipid nanoparticles, which have a much smaller size. Additionally, Karamdad fails to teach an ionizable lipid. In contrast, Karamdad teaches lipids such as POPC and DOPC on page 5279, top of page. These lipids are zwitterionic lipids at neutral pH which comprise a quaternary ammonium moiety to achieve their positive charge, and are thereby permanently ionized rather than ionizable.
As additional relevant prior art, the examiner cites Terada et al. (Langmuir, Vol. 37, 2021, pages 1120-1128); this reference was published in January 2021 which is before the effective filing date of the instant application. Terada et al. (hereafter referred to as Terada) is drawn to methods of making lipid nanoparticles comprising ionizable cationic lipids and siRNA, as of Terada, page 1120, title and abstract. Terada teaches various examples and measures their polydispersity index, as of Terada, page 1123, Table 2, reproduced below, wherein the abbreviation “PDI” refers to polydispersity index.
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The examiner notes that less than all of the examples have a polydispersity index of 0.2 or less. Nevertheless, the skilled artisan would have been motivated to have decreased polydispersity index to increase particle uniformity, and the teachings of Terada would have provided a reasonable expectation that the skilled artisan could have successfully decreased polydispersity index to be 0.2 or less, as required by claim 5.
Terada is not anticipatory because Terada teaches a single inlet comprising a single lipidic phase (i.e. oil phase). See Terada, page 1120, figure in abstract, reproduced below.
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In contrast, the instantly claimed invention requires two separate oil phases.
The examiner takes the position that Terada is deficient for essentially the same reason that Hoge et al. (US 2016/0038612 A1) is deficient. As such, the examiner has not rejected the instant claims over Terada because such a rejection would appear to be duplicative of the rejection over Hoge that was written above. Multiplying references, any one of which is as good as, but no better than, the others, adds to the burden and cost of prosecution and should therefore be avoided. See MPEP 904.03, third paragraph in section. In this case, Terada appears to be just as good as, but no better than Hoge; as such, a rejection over Terada would appear to be duplicative of that over Hoge and therefore has not been written by the examiner.
With that being said, the teachings of Terada appear to lend support to the position that the skilled artisan at the time of filing would have had a reasonable expectation of successfully optimizing the process of making lipid nanoparticles to have achieved a polydispersity index in the range required by claim 5.
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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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612