LIPID NANOPARTICLE PREPARATION METHOD AND PREPARATION APPARATUS THEREFOR

DETAILED ACTION Applicants’ arguments, filed 31 July 2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 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. PNG media_image1.png 340 854 media_image1.png Greyscale 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. Applicant does not appear to have presented arguments disputing the positions taken in this section of the office action, as of applicant’s response on 31 July 2026. As such, the positions taken above have been maintained 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) 1-5 and 7-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cullis et al. (US 2012/0276209 A1) in view of Schariter et al. (US 2020/0306191 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. PNG media_image2.png 222 400 media_image2.png Greyscale 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. PNG media_image3.png 528 766 media_image3.png Greyscale Cullis does not teach adding the PEG-lipid separately from other lipids. 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. PNG media_image4.png 258 400 media_image4.png Greyscale 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. It would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Cullis to add the PEG-lipid in a separate step from the other lipids, as taught by Schariter. Both Cullis and Schariter teach preparation of lipid nanoparticles comprising nucleic acid. Cullis teaches addition of all four lipids in a single step. In contrast, Schariter teaches addition of all of the lipids except the PEGylated lipid in a first step, and addition of the PEGylated lipid in the second step, and both methods appear to result in the formation of lipid nanoparticles. As such, the skilled artisan would have been motivated to have modified the order in which the various lipids were added in order to have predictably formed a lipid nanoparticle with a reasonable expectation of success. 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. Schariter also differs from the claimed invention because in the first step of Schariter, the ionizable cationic lipid, phospholipid, and sterol were added, with the PEG-lipid being added in the second step, whereas in the claimed method, only the ionizable cationic lipid is added in the first step, with the phospholipid and sterol being added in later steps. Nevertheless, these differences are 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 of intersecting the aqueous phase and first oil phase to form a first mixture and flowing the first mixture through a stirring channel. 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. PNG media_image5.png 360 516 media_image5.png Greyscale As to claim 1, 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 1, the claim requires a flow rate for mixing the aqueous phase and the first solution of from 3:1 to 9:1. The examiner takes the position that it would have been prima facie obvious for the skilled artisan to have optimized this ratio to have achieved the claimed range for the following reasons. Cullis teaches that the flow rate of mixing the organic and aqueous solutions (referred to as the first and second streams) may be varied, as of Cullis, paragraphs 0046 and paragraph 0072, in which Cullis tests different particle populations made under different conditions with respect to flow rate variance. These teachings render the flow rate of the organic to aqueous solution to be a result-effective variable. 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), second paragraph. The examiner admits here that the flow rate ratio taught in paragraph 0046 and 0072 is not exactly the same as the flow rate ratio of the instantly claimed invention because the organic phase in Cullis includes all four lipids, whereas the flow rate ratio recited by the instant claims as the first solution includes only the ionizable lipid. Nevertheless, the above-indicated teachings in Cullis would have provided the skilled artisan with motivation to have optimized this ratio for the above-indicated reasons. 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. PNG media_image6.png 596 582 media_image6.png Greyscale PNG media_image7.png 570 766 media_image7.png Greyscale 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 5, Schariter teaches the following, as of paragraph 0536, relevant text reproduced below. PNG media_image8.png 194 398 media_image8.png Greyscale This appears to be a polydispersity index within the claimed range. 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) and Schariter et al. (US 2020/0306191 A1), the combination further 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. Schariter teaches adding the PEG-lipid separately from the other lipids. See the rejection above over Cullis by themselves. For the purposes of this rejection by itself, the examiner understands, purely en arguendo and in regard to this ground of rejection only, that 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. PNG media_image9.png 80 406 media_image9.png Greyscale PNG media_image10.png 348 398 media_image10.png Greyscale 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. PNG media_image11.png 554 408 media_image11.png Greyscale 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. Claim(s) 1-5 and 7-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cullis et al. (US 2012/0276209 A1) in view of Schariter et al. (US 2020/0306191 A1), the combination further in view of Leavitt et al. (WO 2020/077007 A1). Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cullis et al. (US 2012/0276209 A1) and Schariter et al. (US 2020/0306191 A1), and Hoge et al. (US 2016/0038612 A1), the combination further in view of Leavitt et al. (WO 2020/077007 A1). Cullis is drawn to a method of making lipid nanoparticles comprising mixing lipids, e.g. a cationic lipid which may be ionizable, cholesterol, a helper/neutral lipid and a PEGylated lipid dissolved in organic solvent with an aqueous solution comprising a nucleic acid active agent. Schariter is drawn to the general idea of adding the four lipids in separate stages of the reaction. See the rejection above over Cullis in view of Schariter. For the purposes of this rejection, the examiner understands Cullis and Schariter to teach a percentage of ionizable cationic lipid well above the recited range of 10% to 19.9% by mole with respect to total lipids. Leavitt et al. (hereafter referred to as Leavitt) is drawn to lipid vesicles which are referred to as transfection competent vesicles, as of Leavitt, title and abstract. Leavitt teaches the following as of page 5, paragraph 0014, relevant text reproduced below. PNG media_image12.png 250 590 media_image12.png Greyscale As such, Leavitt teaches ionizable cationic lipid in an amount as low as 10 mol%. Leavitt differs from the claimed invention because the method of synthesis of the particle taught by Leavitt appears to lack an organic solvent. It would have been prima facie obvious for one of ordinary skill in the art to have modified the amount of ionizable cationic lipid, as of Cullis Schariter and Hoge, to have been in the range taught by Leavitt. Cullis, Schariter, Hoge and Leavitt are drawn to lipid nanoparticles for delivery of a nucleic acid. Leavitt teaches that amounts of ionizable cationic lipid of about 10 mol% to about 20 mol% are suitable for achieving successful delivery. As such, the skilled artisan would have been motivated to have modified the amount of cationic lipid in Cullis, Schariter, and Hoge to have been in the range taught by Leavitt for predictable delivery of said nucleic acid in a manner that the therapeutic activity of the nucleic acid would have been predictably achieved with a reasonable expectation of success. Response to Arguments Applicant has presented arguments regarding the previously applied rejections, as of applicant’s response on 31 July 2026 (hereafter referred to as applicant’s response). These arguments are addressed below. Applicant makes the following argument as of page 7 of applicant’s response, relevant text reproduced below. PNG media_image13.png 242 640 media_image13.png Greyscale This is not persuasive. The examiner takes the position that it would have been prima facie obvious for the skilled artisan to have optimized this ratio to have achieved the claimed range for the following reasons. Cullis teaches that the flow rate of mixing the organic and aqueous solutions (referred to as the first and second streams) may be varied, as of Cullis, paragraphs 0046 and paragraph 0072, in which Cullis tests different particle populations made under different conditions with respect to flow rate variance. These teachings render the flow rate of the organic to aqueous solution to be a result-effective variable. 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), second paragraph. The examiner admits here that the flow rate ratio taught in paragraph 0046 and 0072 is not exactly the same as the flow rate ratio of the instantly claimed invention because the organic phase in Cullis includes all four lipids, whereas the flow rate ratio recited by the instant claims as the first solution includes only the ionizable lipid. Nevertheless, the above-indicated teachings in Cullis would have provided the skilled artisan with motivation to have optimized this ratio for the above-indicated reasons. Applicant provides arguments regarding the percentage of ionizable cationic lipid with respect to the total amount lipids, as of applicant’s response, starting on page 7, second to last line, and going through the end of the second paragraph of page 9 of applicant’s response. These arguments are not persuasive. As an initial matter, the examiner has cited Leavitt et al. (WO 2020/077007 A1), which does teach amounts of ionizable cationic lipid of 10 mol% and 20 mol%, as of paragraph 0014 of Leavitt. This would appear to be within the claimed range or to overlap with the claimed range. Secondly, the examiner notes that generally, differences in concentration between the claimed invention and prior art 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). With that being said, applicant does present arguments related to the criticality of the amount of ionizable cationic lipid, as of applicant’s response, paragraph bridging pages 8-9. These arguments rely upon Cullis, figure 21, which has been reproduced below. PNG media_image14.png 370 450 media_image14.png Greyscale The examiner takes the position that this figure shows that the amount of siRNA to achieve low relative FVII protein levels (which is the therapeutic goal) differs depending upon the amount of ionizable cationic lipid used. Use of 40 mol% ionizable cationic lipid achieves <10 % FVII activity at about 1 mg/kg siRNA. Use of 50 mol% ionizable cationic lipid achieves this level at about 0.3 mg/kg siRNA. Use of 60 mol% ionizable cationic lipid achieves this at about 0.1 mg/kg siRNA. As such, the above-reproduced data would appear to indicate that higher levels of ionizable cationic lipid achieve more efficient delivery of siRNA. Nevertheless, this appears to be insufficient to rebut the applied prima facie case of obviousness. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use. See MPEP 2145(X)(D)(1). As such, a method of making composition comprising 10-19.9 mol% of ionizable cationic lipid does not become patentable simply because the teachings of Cullis indicate that this would have resulted in less efficient delivery of nucleic acid as compared with a composition having higher levels of ionizable cationic lipid. Additionally, it is unclear as to whether the data of Cullis that was featured in applicant’s response applies to the full range of ionizable cationic lipids, or only to Dlin-KC2-DMA. As best understood by the examiner, slight differences in the chemical structure of ionizable cationic lipids could result in different efficiencies of delivery. Additionally, it is unclear as to what extent the above-reproduced data, which applies to siRNA delivery is applicable to mRNA or CRISPR delivery. The general principle of delivery of these nucleic acids is similar, in that an ionizable cationic lipid containing nanoparticle helps the nucleic acid achieve intracellular delivery and thereby therapeutic efficacy. However, siRNAs are much smaller molecules than mRNAs. As such, it is unclear as to whether the beneficial results taught by Cullis would have applied to mRNA delivery. Applicant then makes arguments regarding alleged unexpected results as of applicant’s response, bottom of page 9, relevant text reproduced below. PNG media_image15.png 426 642 media_image15.png Greyscale Relevant discussion in the instant specification is set forth on pages 25-26 of the instant specification. The data in the specification appears to indicate lower polydispersity values for particle populations prepared by the claimed method rather than those of particle populations prepared by methods similar to that of Cullis wherein all four lipids were dissolved in organic solvent and mixed with an aqueous phase comprising nucleic acid. In order to overcome a prima facie case of obviousness based upon unexpected results, the claimed invention must be compared with the closest subject matter to actually exist in the prior art. See MPEP 716.02(e). In this case, it is unclear to the examiner that this resembles a comparison to the closest prior art because the subject matter in Schariter appears to be closer to the claimed invention than that of the comparative examples in the instant specification. This is at least because The method of Schariter entails adding the lipids in two separate steps, and Contrary to the comparative examples, the method of Schariter appears to achieve polydispersity indexes that are as good as what was presented in the inventive examples in the instant specification. See e.g. Schariter, figure 28, reproduced below, with annotation of the column related to polydispersity index (which is abbreviated as “PDI” by Schariter) by the examiner. PNG media_image16.png 524 784 media_image16.png Greyscale The instant specification discloses a polydispersity index of 0.15±0.01 for the inventive example, as of the instant specification on page 25, paragraph 140. The polydispersity indexes taught by Schariter appear to be as low as this (wherein a lower polydispersity index is more desired than a higher polydispersity index). As such, it is unclear as to whether the instantly claimed method has actually achieved a polydispersity index which is significantly better than that of Schariter. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP 716.02(b)(I). The examiner does not dispute that there is practical significance related to a low polydispersity index because increased particle uniformity provides a more consistent therapeutic result. However, the examiner disputes that the claimed invention has provided a statistically significant improvement in polydispersity index compared with what is taught by Schariter. 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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For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. ISAAC . SHOMER Primary Examiner Art Unit 1612 /ISAAC SHOMER/ Primary Examiner, Art Unit 1612