DETAILED ACTION
Applicants’ arguments, filed 9 September 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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
Claim 1 has been amended to introduce the term “plurality.” This term has been defined on page 7 of the specification, relevant text reproduced below.
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As such, the examiner understands the term “plurality” to be drawn to at minimum 1 structure.
Claim 1 requires that the particle is surrounded by an outer layer comprising an amphiphilic copolymer. For the purposes of examination under prior art, the examiner understands that a composition wherein one block of the amphiphilic copolymer is the outer layer and the other block of the amphiphilic copolymer is an inner layer or core to be within the claim scope. The examiner further notes here that it is improper to import claim limitations from the specification (and drawings), as of MPEP 2111.01(II). As such, the instant claims are not understood to be limited to the structure shown on the right side of figure 1A of the instant drawings. As best understood by the examiner, the examiner and applicant appear to be in a dispute regarding the appropriate definition of the term “surrounded.” This is discussed in greater detail in the “Response to Arguments” section below.
Claim 1 has been amended to recite a polymer shell. As best understood by the examiner, a polymeric structure on the exterior of the particle is understood to meet this claim requirement. The examiner does not understand the claim to require that the shell be completely continuous with no gaps between the external area (which is most likely a liquid aqueous phase at room temperature) and the internal area of the particle.
As to claim 31, this claim recites that the particle size and/or polydispersity are irresponsive to temperature change within the range of 25°C to 85°C. However, the magnitude of the temperature change nor the time period during which irresponsiveness occurs are not recited by the claim. As such, the examiner understands the following case to be within the claim scope.
The examiner notes a hypothetical case in which particles are irresponsive to temperature change for 1 minute following temperature increase from 25°C to 26°C, but aggregate 10 minutes after the temperature has been increased from 25°C to 26°C.
The examiner takes the position that particles which exhibit the characteristics described in the above-reproduced paragraph are understood to meet the limitations of claim 31.
Note Regarding Multiple Numerical Ranges in Claims
The examiner notes that various claims, including but not limited to claim 9, recite multiple numerical ranges. The inclusion of multiple numerical ranges in the same claim is not understood to render the instant claim indefinite because these numerical ranges are clearly presented in the alternative.
In support of the examiner’s decision not to reject multiple numerical ranges in the claim as indefinite, the examiner cites MPEP 2173.05(h)(I), which states the following as of the last paragraph in this section of the MPEP. The mere fact that a compound may be embraced by more than one member of a Markush group recited in the claim does not necessarily render the scope of the claim unclear. For example, the Markush group, "selected from the group consisting of amino, halogen, nitro, chloro and alkyl" should be acceptable even though "halogen" is generic to "chloro." In a similar vein, the examiner takes the position that although claim 9 recites a broader range (e.g. between 1:50 and 1000:1) and a narrower range (e.g. between 8:1 and 28:1), this should be acceptable even though the broader range is generic to the narrower range.
As such, the instant claims which recite a broader and narrower range in the same claim have not been rejected as indefinite for this reason.
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, 7-8, 10-11, and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (Nanoscale Research Letters, Vol. 14:193, 2019, pages 1-9) in view of He et al. (Biomacromolecules, Vol. 5, 2004, pages 2042-2047).
Lu et al. (hereafter referred to as Lu) is drawn to a cationic micelle for siRNA delivery, as of Lu, page 1, title and abstract. Lu teaches the following structure, as of page 4, figure 1, reproduced in part below.
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Lu teaches mPEG-PCL, which is an amphiphilic copolymer. Lu teaches siRNA, as of Lu, page 1, title and abstract, which is a payload molecule. Lu teaches DOTAP, which is a cationic lipid. The above-reproduced figure appears to show one lipid nanoparticle surrounded by the mPEG-PCL, which would appear to read on the required plurality of lipid structures.
Lu differs from the claimed invention because there is no evidence that the mPEG-PCL has a hydrophilic portion that is between 25 and 40 wt% and a hydrophobic portion that is between 60 and 75 wt%.
He et al. (hereafter referred to as He) is drawn to di-block copolymers of poly(ethylene glycol) and polycaprolactone, as of He, page 2042, title and abstract. These may be used in drug delivery as drug release carriers, as of He, page 2042, left column. He teaches the following examples, as of He, page 2043, Table 1, reproduced below.
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He teaches an example wherein the hydrophobic PCL appears to be 61.5%, resulting the PEG being 38.5% so that both equal 100%; this would appear to be within the claim scope.
He differs from the claimed invention because He does not teach a cationic lipid.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the molecular weight of the PEG-PCL copolymer of Lu to have been in the range taught by He. Lu is drawn to a drug delivery and release vehicle comprising a PEG-PCL copolymer. He teaches that a wide range of ratios of PEG to PCL molecular weights of PEG-PCL copolymers have been prepared, and teaches that such polymers may be useful for drug release. As such, the skilled artisan would have been motivated to have prepared the PEG-PCL copolymer of Lu in the molecular weight range taught by He in order to have formed a drug delivery vehicle with a reasonable expectation of success. Where the general conditions of a claim are disclosed in the prior art (e.g. a PEG-PCL copolymer such as the mPEG-PCL copolymer of Lu), it is not inventive to discover the optimum or workable ranges (e.g. of PEG and PCL molecular weight) by routine experimentation. See MPEP 2144.05(II)(A). Additionally, 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). In this case, that the PEG to PCL molecular weights and ratios is the entire subject of the He publication would indicate that this ratio is a result-effective variable; as such, the skilled artisan would have been motivated to have modified and/or optimized this ratio.
As to claim 1, the claim requires that the amphiphilic copolymer be the outer layer. This appears to have been met as per the above-reproduced figure. The above-reproduced figure, when viewed in its original color, shows PCL groups (shown in light blue) as being more external with respect to the particle structure as compared with lipids (wherein the headgroup of the DOTAP lipid is shown in pink). This would appear to read on the required outer layer comprising the amphiphilic copolymer.
In the alternative as to claim 1, the claim requires that the amphiphilic copolymer be the outer layer. As best understood by the examiner, both the compositions of the prior art and the instant application comprise nucleic acid, PEG-PCL, and DOTAP. Therefore, the skilled artisan would have expected the composition of the prior art to have inherently adopted an orientation that is the same as that required by the instant application even if this was not explicitly disclosed by the prior art. Something which is old (e.g. the composition of Lu) does not become patentable upon the discovery of a new property (that the particle has an orientation such that the amphiphilic polymer is part of the outer layer), and this feature need not have been recognized at the time of filing. See MPEP 2112(I & II). Additionally, once the examiner presents a reference appearing to be substantially identical, and the examiner presents evidence or reasoning to show inherency, the burden of production shifts to the applicant. See MPEP 2112(V). In this case, the composition of Lu, like the composition described in the instant application, comprises PEG-PCL and DOTAP and is in the form of a nanoparticle. As such, this is understood to be sufficient to shift the burden to applicant in accordance with the provisions of MPEP 2112(V).
As to claims 1-2, the claim requires a submicron particle, which claim 2 further limits to a particle sized with a largest maximum dimension of less than 1 μm. Lu teaches the following particle sizes, as of page 4, Table 1.
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The particle sizes shown in the above-reproduced table, of about 68-145 nm, are within the claim scope.
As to claim 3, Lu teaches siRNA as the payload; this reads on the required biomolecule.
As to claim 4, the siRNA of Lu reads on the required RNA.
As to claim 7, the skilled artisan would have understood the particle of Lu to have been a lipid nanoparticle because it is in the nanoparticle size range (see e.g. Lu, page 4, figure 1c) and comprises lipids.
As to claim 8, Lu appears to teach the amount of DOTAP used as of page 2, right column, top paragraph. While Lu teaches mPEG-PCL, which is an amphiphilic copolymer, it is unclear whether Lu teaches the amount of amphiphilic copolymer used. Regardless, 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, Lu teaches the general conditions of a particle comprising an amphiphilic copolymer (mPEG-PCL) and a cationic lipid (DOTAP). As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ratios of these ingredients via routine experimentation. The examiner notes here that after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process; see MPEP 2144.05(II)(B), end of last paragraph in section.
As to claim 10, Lu teaches the presence of siRNA payload molecule and mPEG-PCL; however, it is unclear from the teachings of Lu as to the relative amounts of each ingredient. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, there does not appear to be evidence of criticality. 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 lipid nanoparticle comprising payload (i.e. siRNA, as of Lu) and amphiphilic copolymer (e.g. mPEG-PCL, as of Lu) 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 these ingredients via routine experimentation.
As to claim 11, the optimization rationale provided by the examiner regarding claim 1 would appear to apply to claim 11. The examiner notes that although none of the actual examples of He comprise between 65% and 72% of PCL, the examples of He do appear to overlap with this. 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 30, both Lu and He teach a di-block copolymer of PEG and PCL. Because of the lack of a third block, the examiner understands the copolymers of Lu and He to consist of one hydrophilic portion and one hydrophobic portion. The examiner notes that the “m” prefix regard “mPEG” taught by Lu is understood to teach a methoxy end group and is not a separate hydrophilic portion.
As to claim 31, Lu indicates that the micelles have excellent stability, as of Lu, page 7, left column, bottom paragraph. As this stability appears to have been measured at room temperature, the skilled artisan would have expected that the composition of Lu, whether by itself or in view of He, would have had the required stability.
Claim(s) 1-4, 7-11, 14-15, 17-18, 24, and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (Nanoscale Research Letters, Vol. 14:193, 2019, pages 1-9) in view of He et al. (Biomacromolecules, Vol. 5, 2004, pages 2042-2047), the combination further in view of Ciaramella et al. (US 2019/0000959 A1).
Lu is drawn to a composition comprising mPEG-PCL, a cationic lipid, and a nucleic acid payload. He is cited to show the required ratio of hydrophilic (PEG) block and hydrophobic (PCL) block. See the rejection above over Lu in view of He.
Neither Lu nor He appear to teach the stabilizing molecule required by claim 14.
Ciaramella et al. (hereafter referred to as Ciaramella) is primarily drawn to nucleic acid vaccines comprising polynucleotide molecules, as of Ciaramella, title and abstract. With that being said, Ciaramella teaches lipid nanoparticles generally, as of paragraph 0013; Ciaramella also teaches siRNA as an alternative to mRNA, as of Ciaramella, paragraph 0096. Ciaramella teaches the inclusion of sucrose or trehalose as a cryoprotectant, as of Ciaramella, paragraph 1099. Ciaramella teaches pentablock copolymers containing a PCL block and a PEG block, as of Ciaramella, paragraphs 0932 and 1039.
Ciaramella is not anticipatory because although the broad disclosure of Ciaramella teaches block copolymers, the examples of Ciaramella do not include a block copolymer. The examiner notes that the PEG-modified lipids of Ciaramella, page 204, claim 1 are not understood to read on the required amphiphilic copolymer; see the “Claim Interpretation” section above.
It would have been prima facie obvious for one of ordinary skill in the art to have combined the cryoprotectant of Ciaramella with the composition of Lu. Lu is drawn to a composition for delivery of a nucleic acid active agent. Ciaramella is also drawn to a composition for the delivery of a nucleic acid active agent, and teaches a cryoprotectant in order to allow for freeze drying of the composition and storage of the composition. As such, the skilled artisan would have been motivated to have added a cryoprotectant to the composition of Lu in order to have predictably enabled freeze drying and thereby to have predictably improved storage with a reasonable expectation of success.
As to the required amphiphilic copolymer of claim 1, Lu teaches mPEG-PCL, as of the above-reproduced picture. The abbreviation “mPEG” refers to methoxy-polyethylene glycol and is the hydrophilic polymer block of the amphiphilic copolymer. The abbreviation “PCL” refers to polycaprolactone, and is the hydrophobic polymer block of the amphiphilic copolymer.
As to claims 1-2, the claim requires a submicron particle, which claim 2 further limits to a particle sized with a largest maximum dimension of less than 1 μm. Lu teaches the following particle sizes, as of page 4, Table 1.
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The particle sizes shown in the above-reproduced table, of about 68-145 nm, are within the claim scope.
As to claim 3, Lu teaches siRNA as the payload; this reads on the required biomolecule.
As to claim 4, the siRNA of Lu reads on the required RNA.
As to claim 7, the skilled artisan would have understood the particle of Lu to have been a lipid nanoparticle because it is in the nanoparticle size range (see e.g. Lu, page 4, figure 1c) and comprises lipids.
As to claim 8, Lu appears to teach the amount of DOTAP used as of page 2, right column, top paragraph. While Lu teaches mPEG-PCL, which is an amphiphilic copolymer, it is unclear whether Lu teaches the amount of amphiphilic copolymer used. Regardless, 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, Lu teaches the general conditions of a particle comprising an amphiphilic copolymer (mPEG-PCL) and a cationic lipid (DOTAP). As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ratios of these ingredients via routine experimentation. The examiner notes here that after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process; see MPEP 2144.05(II)(B), end of last paragraph in section.
As to claim 9, Ciaramella teaches a N:P ratio of between 20:1 and 1:1, as of paragraph 0749.
As to claim 10, Lu teaches the presence of siRNA payload molecule and mPEG-PCL; however, it is unclear from the teachings of Lu as to the relative amounts of each ingredient. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, there does not appear to be evidence of criticality. 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 lipid nanoparticle comprising payload (i.e. siRNA, as of Lu) and amphiphilic copolymer (e.g. mPEG-PCL, as of Lu) 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 these ingredients via routine experimentation.
As to claim 11, the optimization rationale provided by the examiner regarding claim 1 would appear to apply to claim 11. The examiner notes that although none of the actual examples of He comprise between 65% and 72% of PCL, the examples of He do appear to overlap with this. 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 14, Ciaramella teaches sucrose and trehalose, as of Ciaramella, paragraph 1099.
As to claim 15, Ciaramella appears to be silent as to the amount of cryoprotectant used. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, there does not appear to be evidence of criticality of the cryoprotectant amount. 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 lipid nanoparticle comprising cryoprotecatnt 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 the cryoprotectant via routine experimentation.
As to claim 17, the skilled artisan would have understood sucrose and trehalose, as of Ciaramella, to have been water-soluble molecules. As such, had sucrose and trehalose been combined with the composition of Lu, said sucrose and trehalose would have been disposed in the aqueous phase surrounding the particle. This would have head on the requirement that the stabilizing molecule be disposed outside the outer layer comprising the amphiphilic copolymer.
As to claim 18, the sucrose and trehalose of Ciaramella would have read on the required carbohydrate and/or polyol.
As to claim 24, Ciaramella teaches a pharmaceutical composition, as of paragraph 0010, as well as a pharmaceutically acceptable excipient and delivery vehicle, as of Ciaramella, paragraph 0970.
As to claim 30, both Lu and He teach a di-block copolymer of PEG and PCL. Because of the lack of a third block, the examiner understands the copolymers of Lu and He to consist of one hydrophilic portion and one hydrophobic portion. The examiner notes that the “m” prefix regard “mPEG” taught by Lu is understood to teach a methoxy end group and is not a separate hydrophilic portion.
As to claim 31, Lu indicates that the micelles have excellent stability, as of Lu, page 7, left column, bottom paragraph. As this stability appears to have been measured at room temperature, the skilled artisan would have expected that the composition of Lu, whether by itself or in view of He, would have had the required stability. Ciaramella also teaches storage stability in lyophilized form, as of paragraph 1100.
Claim(s) 1-4, 7-8, 10-11, 14-15, 17-18, 24, and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (US 2021/0077406 A1).
Choi et al. (hereafter referred to as Choi) is drawn to a composition for delivering an anionic drug with the following structure, as of Choi, title, abstract, and figure in abstract, reproduced below.
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Choi teaches the following compositions, as of page 7, Table 3, reproduced below.
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As to claim 1, the claim requires a payload. The anionic drug meets this limitation.
As to claim 1, the claim requires a lipid structure. The above-reproduced figure comprises a cationic lipid.
As to claim 1, the claim requires an amphiphilic copolymer. This is taught in the above-reproduced figure.
As to claim 1, the claim requires that the amphiphilic copolymer comprises 40% to 70% by weight of the hydrophilic block, with the remaining 30% to 60% apparently being hydrophobic block. This overlaps with the claimed requirement at the endpoint of 40% hydrophobic block and the remaining 60% hydrophilic block. This overlap is sufficient to result 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 1, the claim requires that the lipid structure is surrounded by the outer layer comprising an amphiphilic copolymer. This appears to be taught in the above-reproduced figure because the most external part of the above-reproduced structure is the block of the amphiphilic block copolymer shown by a squiggly line.
As to claim 1, the claim requires a plurality of lipid nanostructures. The examiner notes that the single particle in the above-reproduced figure meets the requirement of a plurality. See the above section entitled “Claim Interpretation” for further explanation as to how the term “plurality” is interpreted.
As to claim 2, the claim requires that the particle have a largest maximum dimension of less than 1 micron. Choi appears to teach this in paragraph 0018.
As to claim 3, the above-reproduced figure teaches an anionic drug; this reads on the required biomolecule payload.
As to claim 4, Choi teaches DNA and RNA as of paragraph 0020.
As to claim 7, the composition of Choi is described as a nanoparticle in paragraph 0009, and comprises a lipid, so is understood to read on the required lipid nanoparticle.
As to claim 8, the dioTETA of Choi is understood to read on the required ionizable cationic lipid. The examiner understands Choi to teach ratios of amphiphilic copolymer to dioTETA of 1:18 as of Table 3, reproduced above. This appears to be within the claim scope.
As to claim 10, Choi teaches a ratio of 5 micrograms of siRNA to 1000 micrograms of polymer. This is ratio of amphiphilic copolymer to payload of 200:1, which is within the claim scope.
As to claim 11, Choi teaches the following, as of page 4, paragraph 0041, relevant text reproduced below.
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This appears to result in 30 to 60% hydrophobic block, which would appear to be within the claim scope.
As to claim 14, the sorbitol of Choi reads on the required stabilizing molecule.
As to claim 15, sorbitol is water-soluble; as such, the skilled artisan would have expected the sorbitol to have been in the interior aqueous space of the particle shown in the above-reproduced figure.
As to claim 17, sorbitol is water-soluble; as such, the skilled artisan would have expected sorbitol to have been present in the exterior aqueous space outside the particle, which reads on the requirement of outside the outer layer.
As to claim 18, the sorbitol of Choi reads on the polyol required by this claim.
As to claim 24, Choi teaches a pharmaceutical composition as of Choi, title and abstract.
As to claim 30, Choi teaches the following, as of the figure in the abstract.
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This appears to show an amphiphilic di-block copolymer consisting of a hydrophobic block and hydrophilic block. This is understood to meet the claimed requirements due to the lack of a third block.
As to claim 31, Choi teaches that the composition has excellent stability; as such, the skilled artisan would have expected the composition of Choi to have met the stability requirements of claim 31.
Claim(s) 1-4, 7-8, 10-11, 24, and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (US 2021/0330597 A1) in view of Zale et al. (US 2010/0068285 A1).
Xu et al. (hereafter referred to as Xu) is drawn to a particle encapsulating another particle for gene delivery, as of Xu, title and abstract. Xu teaches the following as of the figure in the abstract, which is reproduced below with additional annotation by the examiner.
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As to the required submicron particle, Xu teaches that the particle size of the entire particle is about 130 nm, as of Xu, paragraph 0019.
As to the required payload, the plasmid in the above-reproduced diagram is understood to read on the required payload.
As to the required lipid structure, the examiner notes that Xu teaches PBAE, as of the above-reproduced figure; this stands for poly(β-amino ester), as of Xu, paragraph 0009. Xu is not anticipatory because the poly(β-amino ester) of Xu does not necessarily comprise lipids. However, Xu suggests including lipids with the poly(β-amino ester), as of Xu, paragraph 0074. As such, the skilled artisan would have been motivated to have made the PBAE particles in the above-reproduced diagram into lipid particles for predictable delivery of the genetic payload with a reasonable expectation of success.
As to claim 1, the claim requires that the outer layer comprise an amphiphilic copolymer. This is taught as of the above-reproduced figure in which PLGA-PEG is the amphiphilic copolymer.
Xu appears to be deficient because in Xu, paragraph 0072, the PLGA appears to be 80% and the PEG appears to be 20% by weight, which is not within the claimed ratio range.
Zale et al. (hereafter referred to as Zale) is drawn to drug loaded particles comprising a di-block copolymer, as of Zale, title and abstract. Zale teaches delivery of nucleic acids, as of Zale, at least paragraph 0066. Zale teaches the following, as of paragraph 0072, relevant text reproduced below.
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Although the above reproduced text relates to copolymers of polylactic acid (PLA) and polyethylene glycol (PEG), Zale also teaches poly(lactic-co-glycolic) acid copolymerized with PEG as an alternative, as of at least Zale, paragraphs 0049 and 0064.
Zale does not teach a cationic lipid.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the molecular weights of the PLGA and the PEG portions of the PLGA-PEG copolymer of Xu to have been in the range taught by Zale. Xu is drawn to a composition comprising a PLGA-PEG copolymer for delivery of nucleic acids. Zale teaches a range of molecular weights of PLA (or PLGA) and PEG to be used in a PLGA-PEG copolymer for administration of a drug. As such, the skilled artisan would have been motivated to have modified the molecular weights of the PLGA and PEG blocks of the PLGA-PEG block copolymer of Xu to have been in the range taught by Zale for predictable delivery of a nucleic acid active agent with a reasonable expectation of success.
As to claim 1, the claim requires that the amphiphilic copolymer comprise between 25% and 40% by weight of the hydrophilic portion and 60% to 75% by weight of the hydrophobic portion. Zale teaches a minimum molecular weight of the hydrophobic PLA portion of 15 kDa, and a maximum molecular weight of the hydrophilic PEG portion of 10 kDa, as of Zale, paragraph 0072. A PLA-PEG (or PLGA-PEG) copolymer with the PLA (or PLGA) having a molecular weight of 15 kDa and the PEG having a molecular weight of 10kDa would appear to comprise 60% (i.e. 15 divided by 15+10) hydrophobic PLA (or PLGA) and 40% (i.e. 10 divided by 15+10) of PEG. The examiner notes that Zale teaches embodiments having well over 75% hydrophobic PLA/PLGA and well under 25% PEG. Nevertheless, the molecular weight ranges of hydrophobic (PLA/PLGA) to hydrophilic (PEG) copolymers in Zale would appear to overlap with what is required by the instant claims, thereby resulting 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 2, Xu teaches that the particle size of the entire particle is about 130 nm, as of Xu, paragraph 0019. This is less than the required 1 micron.
As to claim 3, Xu teaches a plasmid as the bioactive agent in the above-reproduced figure.
As to claim 4, Xu teaches nucleic acid active agents such as mRNA and siRNA, as of Xu, paragraph 0057.
As to claim 7, were the skilled artisan to have modified the PBAE structure of Xu to have included lipids, the resultant structure would have been a lipid nanoparticle, as required by the instant claim.
As to claim 8, Xu teaches both a PLGA-PEG copolymer and cationic lipids. Xu does not appear to teach the ratio of these elements. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, there does not appear to be evidence of criticality of the ratio of PLGA-PEG amphiphilic copolymer and cationic lipid. 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 PLGA-PEG particle encapsulating smaller lipid particles has been taught by the Xu. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of the ratio of PLGA-PEG to payload nucleic acid via routine experimentation.
As to claims 10, this claim is drawn to the ratio of amphiphilic copolymer (i.e. PLGA-PEG in Xu) to payload (e.g. nucleic acid in the examples of Xu). Xu appears to be silent regarding this ratio. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, there does not appear to be evidence of criticality of the ratio of PLGA-PEG to nucleic acid. 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 PLGA-PEG particle encapsulating smaller lipid particles has been taught by the Xu. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of the ratio of PLGA-PEG to payload nucleic acid via routine experimentation.
As to claim 11, the rationale applied by the examiner under MPEP 2144.05(I & II) applies to claim 11 in the same manner that it applies to claim 1.
As to claim 24, Xu teaches a pharmaceutical composition, as of paragraph 0071.
As to claim 30, the polymer of both Xu and Zale appears to be a di-block copolymer. The examiner understands a PLGA-PEG copolymer to include one hydrophobic region of lactide and glycolide, and one hydrophilic region of polyethylene glycol. In view of the lack of the third block, this di-block copolymer is understood to read on the claimed requirements that the amphiphilic copolymer consist of one hydrophilic portion and one hydrophobic portion.
As to claim 31, the skilled artisan would have expected that aggregation could have been decreased such as to have met the claimed requirements; see paragraph 0121 of Xu which teaches decreasing aggregation. As best understood by the examiner, this appears to refer to room temperature.
Note Regarding Reference Date: The instant application appears to have an earliest effective filing date of 14 June 2021 based upon a foreign priority claim. Xu was published in October 2021, and is therefore not prior art under AIA 35 U.S.C. 102(a)(1). However, Xu was filed prior to the effective filing date of the instant application and is prior art under AIA 35 U.S.C. 102(a)(2). There appear to be no common inventors or common assignee between Xu and the claimed invention; as such, the exceptions under AIA 35 U.S.C. 102(b)(2) do not appear to be applicable in this case.
Response to Arguments Regarding Prior Art Rejections
Applicant has presented arguments regarding the rejections previously presented by the examiner, as of applicant’s response on 9 September 2026. These arguments are addressed below.
In applicant’s response, page 8, applicant appears to argue that Lu does not teach the arrangement required by the instant claims. For example, applicant makes the following arguments.
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The examiner disagrees that figure 1b of Lu shows what is allegedly asserted here. The examiner notes that the figure, as originally presented in the Lu document, is presented in color. DOTAP is presented such that the two hydrophobic chains are colored purple, whereas the hydrophilic head is colored pink. The di-block copolymer mPEG-PCL is presented such that the mPEG portion is colored gray, and the PCL portion is colored light blue. The figure of Lu appears to show the gray and purple portions of mPEG-PCL and DOTAP on the inside, the pink portion of DOTAP relatively outside the purple portion of DOTAP, and the light blue portion of mPEG-PCL outside the pink portion of DOTAP. This would appear to show a distribution that is not homogeneous.
With that being said, the examiner agrees that Lu does not teach the required 25-40 wt% hydrophilic and 60-75 wt% hydrophobic proportions of the block copolymer. As such, the He reference was newly cited by the examiner to render obvious this limitation. The examiner’s new citation of this reference represents a newly applied rejection necessitated by amendment.
Applicant then cites the paragraph bridging pages 7-8 of Lu as allegedly teaching that the structure of Lu differs from the claimed structure in that the mPEG-PCL does not surround the payload molecule and the lipid components, as of applicant’s response, page 8, fourth to last and third to last paragraphs. The relevant paragraphs from Lu are reproduced below.
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That the positive charges of DOTAP are partially exposed would appear to mean that the positive charges of DOTAP are partially surrounded by the copolymer. This would appear to meet the claimed requirements. As best understood by the examiner, a case wherein the plurality of lipid structures are partially surrounded by an outer layer would appear to meet the requirements of the term “surrounded” on the second line of claim 1. Claims are to be given their broadest reasonable interpretation in light of the specification, as of MPEP 2111, and in this case, prior art that teaches that the lipids are partially surrounded is understood to meet this claimed requirement. As such, applicant’s arguments appear to insist that the term “surrounded” be interpreted more narrowly than its broadest reasonable interpretation, and this argument is not persuasive.
Regarding the combination of Lu and Ciaramella, applicant makes the following argument on page 10, relevant text reproduced below.
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This argument is not persuasive because the examiner’s main reason for citing Ciaramella is that it teaches cryoprotectants such as sucrose and trehalose. Ciaramella was not cited to teach a particular particle architecture, as that is already cited by Lu.
Regarding the Choi reference, applicant makes the following argument, as of page 9, second to last paragraph.
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In response, the examiner takes the position that this teaching of Choi, while insufficient to anticipate the claimed invention, is sufficient to result in a prima facie case of obviousness due to overlap of ranges. See MPEP 2144.05(I).
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This is not persuasive. While the instant claims require an outer shell, the instant claims do not require a discrete outer shell. As such, applicant appears to be arguing subject matter not actually recited by the instant claims. Additionally, even if, purely en arguendo, the claims did require a discrete outer shell, it is not clear to the examiner how the term “discrete” would be interpreted.
Applicant then argues that the shared 40/60 endpoint of Choi is insufficient to meet the claimed requirements, as of applicant’s response, page 11. This is not persuasive. The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain. See MPEP 2123(I). As such, the teaching of the 40/60 endpoint in Choi, overlapping with the claimed range, is sufficient to render the instant claims prima facie obvious. See MPEP 2144.05(I).
Regarding Xu, applicant argues the following, as of page 10, relevant text reproduced below.
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This is not persuasive. Xu teaches that cationic lipids are useful for delivery of nucleic acids because they bind negatively charged nucleic acids via electrostatic interaction, as of paragraph 0008 of Xu. Xu also teaches that cationic lipids delivery siRNA, as of paragraph 0121 of Xu. As such, contrary to applicant’s arguments, Xu provides substantial explanation as to why the skilled artisan would have used cationic lipids.
Applicant then makes additional arguments referring to experiments from the specification, as of applicant’s response, page 11, bottom paragraph and onto page 12. Applicant relies upon figure 6, as of page 11, bottom paragraph. This figure is reproduced below.
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As an initial matter, it is not entirely clear to the examiner as to what was tested in this figure. Nevertheless, as best understood by the examiner, applicant appears to have compared the claimed invention with DOTAP (i.e. cationic lipid) by itself. This is not probative of non-obviousness. Applicant must compare the claimed invention to the closest subject matter to actually exist in the prior art. See MPEP 716.02(e). In this case, the subject matter taught by Lu, Xu, and Choi is closer to the claimed invention than a pure DOTAP membrane. This is because all of the cited references teach cationic lipid in combination with an amphiphilic copolymer, even if the amphiphilic copolymer of the prior art differs from the claimed amphiphilic copolymer. In contrast, the comparative example in figure 6 appears to disclose cationic lipid in the absence of an amphiphilic copolymer. This comparative example is therefore less similar to the claimed invention than the compositions of Lu, Xu, or Choi. As such, applicant has failed to compare the claimed invention to the closest subject matter to actually exist in the prior art in figure 6.
Moreover, applicant’s arguments on page 11 state the following.
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If, purely en arguendo, it is true that the particles disclosed by the instant specification do not have a homogenous membrane, this would appear to go against what applicant argues to have been the invention. In applicant’s response, page 9, last paragraph, applicant argues that the prior art fails to teach a discrete outer shell. This indicates that applicant believes that the particle of the invention has a discrete outer shell, apparently made of the amphiphilic copolymer. As best understood by the examiner, this would actually be a homogenous exterior. Therefore, to the extent that applicant is arguing on page 11 of applicant’s response that the particles of the invention lack a homogenous exterior, this appears to have been contradicted on page 9 of applicant’s response in which applicant argues that the particles do not have a homogeneous exterior. As such, applicant’s arguments related to the physical chemistry of the structure of the instant invention and/or recited structure are confusion and/or not clear, and are therefore not persuasive for this reason.
The examiner makes the following argument on page 11, top paragraph.
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The examiner notes that nothing indicated in the above-reproduced paragraph is actually recited by the claims. Claim 31 is drawn to stability at 25°C to 85°C. This is a more difficult benchmark to achieve than stability at 4°C. This is because stability is generally more difficult at higher temperatures; it is for that reason that food is put in the refrigerator (4°C) to improve the stability of food compared with room temperature (about 25°C). Secondly, nothing in claim 31 recites 21 day stability.
Applicant then cites the text “improved stability.” The term “improved” would appear to imply that comparative testing has been done comparing the claimed invention to subject matter outside the claim scope. However, looking to Example 11 and figures 18-19 cited therein, the examiner is unable to determine that comparative testing has been completed. While Figure 19 appears to show multiple formulations, it is the examiner’s best understanding that the multiple formulations shown by figure 19 appear to be multiple examples within the claim scope, not a comparison between a composition in the claim scope and a composition outside the claim scope. Direct and indirect comparative tests can be probative of non-obviousness. See MPEP 716.02(b)(III). However, the examiner is unable to determine that applicant actually conducted direct and indirect comparative tests to determine that the alleged improvement actually occurred.
Applicant then makes the following argument at the bottom of the first paragraph of page 12, relevant text reproduced below.
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As best understood by the examiner, trehalose is a stabilizer that stabilizes particles to temperature change. See Ciaramella et al. (US 2019/0000959 A1), paragraphs 1099 and 1100. As such, the improvement of stability in the presence of trehalose would appear to be an expected beneficial result. Such expected beneficial results are evidence of obviousness. See MPEP 716.02(c)(II).
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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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
Prosecution Insights