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 with traverse of Group I, claims 1-4, 6-11, 14-15, 17-18, 24, and 27 in the reply filed on 13 February 2026 is acknowledged. The traversal is on the ground(s) that restriction between a product is proper only upon showing distinction, as of applicant’s response on 13 February 2026, page 6, second to last paragraph.
This is not found persuasive because the issue of distinctness is applicable only in regard to restrictions under 35 U.S.C. 121. In contrast, the restriction set forth in the office action mailed on 14 November 2025 was based upon lack of unity, which is relevant for restrictions under 35 U.S.C. 371. As such, applicant’s arguments are not persuasive because they do not address the issue of lack of unity, which is the basis for the applied restriction.
The requirement is still deemed proper and is therefore made FINAL.
Claims 19-21 and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 13 February 2026.
Claim Interpretation
The claims recite the phrase “amphiphilic copolymer.” This phrase does not appear to have been defined in the instant specification.
The examiner takes the position that the prior art is replete with examples in which a lipid is covalently bound to polyethylene glycol. Examples of such pegylated lipids include DSPE-PEG or DMG-PEG, wherein DSPE refers to distearoyl phosphatidylethanolamine and is a lipid, DMG refers to dimyristoyl glycerol, and is a lipid, and PEG refers to polyethylene glycol, and is a polymer. These are amphiphilic because the lipids are hydrophobic and the PEG is hydrophilic, and these are covalently bound together. Nevertheless, the examiner understands that pegylated lipids are not amphiphilic copolymers because the lipid portion of the pegylated lipid is a small molecule and not a polymer. As such, the examiner understands pegylated lipids to be derivatized homopolymers rather than copolymers, and do not read on the required amphiphilic copolymer.
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 to claim 6, the examiner understands a lipid molecule to be a lipid structure.
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 § 102(a)(1) – Anticipation
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 6-8, 11, and 24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lu et al. (Nanoscale Research Letters, Vol. 14:193, 2019, pages 1-9).
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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As to the required payload molecule of claim 1, Lu teaches siRNA, as of Lu, page 1, title and abstract.
As to the required lipid structure of claim 1, Lu teaches the presence of DOTAP, which is a cationic lipid, as of Lu, page 1, abstract. The examiner takes the position that the presence of DOTAP would have resulted in the formation of a lipid structure.
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 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 6, the examiner understands a lipid molecule to be a lipid structure; therefore, the requirement of a plurality of lipid structures is understood to read on a plurality of lipid molecules per particle. This appears to have been taught by Lu, page 4, figure 1b, reproduced above, as the structure includes multiple lipid molecules pare particle.
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 teaches DOTAP, which is understood to read on this claim requirement.
As to claim 11, Lu teaches that the mPEG-PCL has a molecular weight of 4000 Daltons, as of Lu, page 2, right column, “Materials” paragraph.
As to claim 24, the examiner understands the composition of Lu to have been a pharmaceutical composition. The examiner understands that water present in the aqueous phase surrounding the particle would have read on the pharmaceutically acceptable vehicle.
Claim(s) 1-4, 6-9, 14-18, 24, and 27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipation by Smith et al. (US 2020/0069599 A1).
Smith et al. (hereafter referred to as Smith) is drawn to formulations comprising lipid nanoparticles, as of Smith, title and abstract. Smith teaches the following, as of page 46, Example 2, reproduced in part below with annotation by the examiner.
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As to the requirement of a submicron particle, the examiner notes that the particle size of the above-composition would appear to be in the submicron range; see at least figure 10B which appears to teach particle sizes ranging from about 80 nm at minimum to about 180 nm at maximum. These are sub-micron sizes.
As to claim 1, the claim requires a payload material. The mRNA in the above example of Smith is a payload material.
As to claim 1, the claim requires a lipid structure. The lipids in the above example of Smith, which are MC3, cholesterol, DSPC, and PEGylated lipid would have been expected to have formed a lipid structure.
As to claim 1, the claim requires an amphiphilic copolymer. The Poloxamer 188 of the above example would have been understood to have read on this limitation. The examiner notes that the term “poloxamer” refers to triblock copolymers which comprise a block of polypropylene oxide in the middle and two blocks of polyethylene oxide at each end. The term “amphiphilic” refers to a polymer with both a hydrophobic portion and a hydrophilic portion. In the case of poloxamers, the polypropylene oxide is the hydrophobic portion and the polyethylene oxides are the hydrophilic portions. As such, the poloxamer of Smith would have read on the required amphiphilic copolymer.
As to claim 1, the claim requires that the payload molecule and lipid structure is surrounded by an outer layer comprising the amphiphilic copolymer. Smith teaches the following, as of paragraph 0556, reproduced below.
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The skilled artisan would have expected that the poloxamer would have been at least partially on the outside of the particle in view of the above-reproduced text, thereby reading on the claim scope.
As to claim 2, Smith teaches maximum diameters of about 80-180 nm as of figure 10B.
As to claim 3, the mRNA of Smith reads on the required biomolecule.
As to claim 4, the mRNA of Smith reads on the requirement of this claim.
As to claim 6, Smith teaches lipid nanoparticles, as of the reference title.
As to claim 7, Smith teaches lipid nanoparticles, as of the reference title.
As to claim 8, Smith teaches MC3 in the above example, which reads on the required cationic or ionizable lipid.
As to claim 9, Smith teaches a N:P ratio of about 5:1 to about 8:1 in paragraph 0439.
As to claim 14, the sucrose of Smith reads on the required stabilizing molecule.
As to claim 15, the skilled artisan would have understood sucrose to have been water-soluble. As such, the sucrose would have been present in the aqueous spaces at the inside of the lipid nanoparticle and would thereby have been surrounded by the amphiphilic copolymer.
As to claim 17, the skilled artisan would have understood sucrose to have been water-soluble. As such, the sucrose would have been present in the water external to the particle.
As to claim 18, the skilled artisan would have understood sucrose to have read on the required carbohydrate that is a disaccharide.
As to claim 24, the composition of Smith is a pharmaceutical composition, as of at least paragraph 0079 of Smith.
As to claim 27, Smith teaches a vaccine as of paragraph 0570.
Claim(s) 1-4, 6-8, 10-11, 14-15, 17-18 and 24 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by 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 lipid structure is surrounded by the outer layer comprising an amphiphilic copolymer. This appear 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 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 6, the above-reproduced composition of Choi contains a plurality of lipid molecules, which is understood to read on the required plurality of lipid structures.
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.
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.
The examiner additionally notes the following regarding Choi. First, according to MPEP 904.03, third paragraph, 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 notes here that the composition of Choi appears to have been made from very similar materials as compared with the composition of Lu et al. (Nanoscale Research Letters, Vol. 14:193, 2019, pages 1-9), over which the claims have been rejected above. Nevertheless, looking at the drawings in Choi and Lu, it appears that the internal structure of the composition of Choi appears to be very different from the internal structure of the composition of Lu. As such, the examiner takes the position that the teachings of Choi and Lu are quite different from each other; as such, the above-applied rejection over Choi does not appear to be duplicative of the rejection over Lu.
Note Regarding Reference Date: Choi was published on 18 March 2021. This is less than a year earlier than the earliest effective filing date of the instant application, which is 14 June 2021. As such, Choi is prior art under AIA 35 U.S.C. 102(a)(1) and 102(a)(2).
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, 6-11, 14-15, 17-18, 24 and 27 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 Ciaramella et al. (US 2019/0000959 A1).
Lu is drawn to a particle comprising RNA payload, cationic lipid, and mPEG-PCL for delivery of said RNA payload. See the above rejection over Lu by itself.
Lu is understood not to teach a stabilizing molecule other than the RNA payload, cationic lipid, and mPEG-PCL.
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. Ciaramella also teaches block copolymers comprising PEG and PCL, as of Ciaramella, paragraphs 0932 and 1039.
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) more external than 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 6, the examiner understands a lipid molecule to be a lipid structure; therefore, the requirement of a plurality of lipid structures is understood to read on a plurality of lipid molecules per particle. This appears to have been taught by Lu, page 4, figure 1b, reproduced above, as the structure includes multiple lipid molecules pare particle.
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 teaches DOTAP, which is understood to read on this claim requirement.
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, Lu teaches that the mPEG-PCL has a molecular weight of 4000 Daltons, as of Lu, page 2, right column, “Materials” paragraph.
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 27, Ciaramella teaches a vaccine as of the title and abstract.
Claim(s) 1-4, 6-8, 10, 24, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (US 2021/0330597 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.
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 6, Xu teaches a plurality of PBAE structures in the above-reproduced figure. The skilled artisan would have been motivated to have modified these structures with lipids; as such, the skilled artisan would have been motivated to have included a plurality of lipid structures in the composition of Xu.
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 a cationic lipid in paragraph 0121.
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 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 24, Xu teaches a pharmaceutical composition, as of paragraph 0071.
As to claim 27, Xu teaches a mRNA vaccine as of paragraph 0119.
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.
Claim(s) 1-4, 6-11, 14-15, 17-18, 24, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (US 2020/0069599 A1) as evidenced by Almeida et al. (Journal of Polymer Research, Vol. 25:31, 2018, pages 1-14) and as evidenced by Schoenmaker et al. (International Journal of Pharmaceutics, Vol. 601, 120586, pages 1-13).
Smith et al. (hereafter referred to as Smith) is drawn to formulations comprising lipid nanoparticles, as of Smith, title and abstract. Smith teaches the following, as of page 46, Example 2, paragraph 0554, reproduced in the anticipation rejection above, which comprises at least mRNA, lipids including MC3, DSPC, and cholesterol, sucrose, and poloxamer 188.
As to the requirement of a submicron particle, the examiner notes that the particle size of the above-composition would appear to be in the submicron range; see at least figure 10B which appears to teach particle sizes ranging from about 80 nm at minimum to about 180 nm at maximum. These are sub-micron sizes.
As to claim 1, the claim requires a payload material. The mRNA in the above example of Smith is a payload material.
As to claim 1, the claim requires a lipid structure. The lipids in the above example of Smith, which are MC3, cholesterol, DSPC, and PEGylated lipid would have been expected to have formed a lipid structure.
As to claim 1, the claim requires an amphiphilic copolymer. The Poloxamer 188 of the above example would have been understood to have read on this limitation. The examiner notes that the term “poloxamer” refers to triblock copolymers which comprise a block of polypropylene oxide in the middle and two blocks of polyethylene oxide at each end. The term “amphiphilic” refers to a polymer with both a hydrophobic portion and a hydrophilic portion. In the case of poloxamers, the polypropylene oxide is the hydrophobic portion and the polyethylene oxides are the hydrophilic portions. As such, the poloxamer of Smith would have read on the required amphiphilic copolymer. Additionally evidence in support of this position is provided by Almeida , page 1, abstract.
As to claim 1, the claim requires that the payload molecule and lipid structure is surrounded by an outer layer comprising the amphiphilic copolymer. The examiner understands Smith, paragraph 0556 (which was reproduced in the above anticipation rejection) to teach that the poloxamer would have been at least partially on the outside of the particle, thereby reading on the claim scope.
As to claim 1, for the purposes of this rejection, purely en arguendo and in regard to this ground of rejection only, the examiner understands that Smith teaches all of the required elements, but not in the same embodiment. As such, while the prior art teaches all of the claimed components, the prior art is not anticipatory insofar as these components must be selected from various lists/locations in the prior art reference. It would have been prima facie obvious; however, to have selected the recited components from various lists/locations in the prior art reference and to have combined them together. This is because such a modification would have represented nothing more than the predictable use of prior art components according to their established functions. Combining separate prior art components (from a single prior art reference) according to known methods to yield predictable results is prima facie obvious. See MPEP 2143, Exemplary Rationale A.
As to claim 2, Smith teaches maximum diameters of about 80-180 nm as of figure 10B.
As to claim 3, the mRNA of Smith reads on the required biomolecule.
As to claim 4, the mRNA of Smith reads on the requirement of this claim.
As to claim 6, Smith teaches lipid nanoparticles, as of the reference title.
As to claim 7, Smith teaches lipid nanoparticles, as of the reference title.
As to claim 8, Smith teaches MC3 in the above example, which reads on the required cationic or ionizable lipid.
As to claim 9, Smith teaches a N:P ratio of about 5:1 to about 8:1 in paragraph 0439.
As to claim 10, the weight ratio of the poloxamer (i.e. amphiphilic copolymer) and the mRNA is unclear based upon the teachings of the table on paragraph 0554. Nevertheless, Smith teaches a specific amount of mRNA in paragraph 0554, and provides motivation for the skilled artisan to have optimized the amount of poloxamer P188 in paragraphs 0558-0559 in order to have acted as a steric stabilizer, or for optimization of improved storage (as of paragraph 0561) or to have optimized tangential flow filtration (as of paragraph 0560). As such, the skilled artisan would have been motivated to have optimized the ratio of mRNA payload to poloxamer P188. 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 particle comprising mRNA, lipid structure, and poloxamer, which is an amphiphilic polymer, has been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have determined the optimum or workable ranges of mRNA to amphiphilic polymer ratio via routine experimentation.
As to claim 11, Smith teaches poloxamer 188. Almeida teaches the following table of poloxamers, as of page 3, relevant table reproduced below with annotation by the examiner regarding the data related to poloxamer P188.
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The above-reproduced data appears to indicate that poloxamer P188 has a molecular weight of 8400 Daltons, which is within the claim scope.
As to claim 14, the sucrose of Smith reads on the required stabilizing molecule.
As to claim 15, the skilled artisan would have understood sucrose to have been water-soluble. As such, the sucrose would have been present in the aqueous spaces at the inside of the lipid nanoparticle and would thereby have been surrounded by the amphiphilic copolymer. Evidence provided by Schoenmaker et al. indicates that there are water-soluble spaces in the middle of lipid nanoparticles, as of Schoenmaker, page 5, figure 3, reproduced below.
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The examiner notes that this figure in its original color shows light blue spaces that resemble locations where there is water. The skilled artisan would have expected sucrose to have been water soluble and therefore to have been in the water-containing spaces shown in Schoenmaker. The skilled artisan would have expected the lipid nanoparticle of Smith to have had a similar structure to that of Schoenmaker because both the lipid nanoparticle of Smith and that of Schoenmaker are lipid nanoparticles containing cationic lipids for the delivery of nucleic acid. As such, in view of the evidence provided by Schoenmaker, there would have been reason for the skilled artisan to have expected that the interior of the lipid nanoparticles would have contained water spaces that would have included solutes that are water-soluble such as sucrose.
As to claim 17, the skilled artisan would have understood sucrose to have been water-soluble. As such, the sucrose would have been present in the water external to the particle. Additionally, Smith teaches a sugar concentration of up to about 30%, as of Schoenmaker, paragraphs 0029-0030. In view of this, the skilled artisan would have been motivated to have optimized the amount of sugar to have been within the claimed range. 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). In this case, there is no evidence of the criticality of the sucrose concentration. 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 particle comprising mRNA, lipid structure, and poloxamer, which is an amphiphilic polymer, has been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have determined the optimum or workable ranges of mRNA to amphiphilic polymer ratio via routine experimentation.
As to claim 18, the skilled artisan would have understood sucrose to have read on the required carbohydrate that is a disaccharide.
As to claim 24, the composition of Smith is a pharmaceutical composition, as of at least paragraph 0079 of Smith.
As to claim 27, Smith teaches a vaccine as of paragraph 0570.
Claim(s) 1-3, 4-8, 10, 14-15, 17-18 and 24 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 in the anticipation rejection above. Choi teaches the following compositions, as of page 7, Table 3, reproduced in the anticipation rejection above.
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 lipid structure is surrounded by the outer layer comprising an amphiphilic copolymer. This appear 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, purely en arguendo and for the purposes of this ground of rejection only, the examiner understands Choi to teach all of the claimed requirements, but not necessarily in the same embodiment. While the prior art teaches all of the claimed components, the prior art is not anticipatory insofar as these components must be selected from various lists/locations in the prior art reference. It would have been prima facie obvious; however, to have selected the recited components from various lists/locations in the prior art reference and to have combined them together. This is because such a modification would have represented nothing more than the predictable use of prior art components according to their established functions. Combining separate prior art components (from a single prior art reference) according to known methods to yield predictable results is prima facie obvious. See MPEP 2143, Exemplary Rationale A.
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 6, the above-reproduced composition of Choi contains a plurality of lipid molecules, which is understood to read on the required plurality of lipid structures.
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.
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.
Additional Relevant Prior Art
As additional relevant prior art, the examiner cites Karve et al. (US 2021/0046192 A1). Karve et al. (hereafter referred to as Karve) is drawn to mRNA lipid nanoparticles, as of Karve, title and abstract. Karve teaches the following in paragraph 0004, relevant text reproduced below.
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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. Looking to the above-reproduced text, it appears that Karve et al. (US 2021/0046192 A1) is similar to Smith et al. (US 2020/0069599 A1), in that both references are drawn to a composition comprising a nucleic acid such as mRNA as the payload, a lipid nanoparticle, and poloxamer as the amphiphilic block copolymer. As such, in view of the provisions of MPEP 904.03, the examiner has not rejected the instant claims over Karve et al. (US 2021/0046192 A1) as it would appear to be substantially repetitive of the applied rejection over Smith et al. (US 2020/0069599 A1).
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6-11, 14-15, 17-18, 24, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7, 10, 12-13, 15, 19, 22, 25, 29, 33-35, 37, 42-43, 47, 50, and 52 of copending Application No. 18/707,877 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a sub-micron particle comprising a payload, a lipid structure, and an amphiphilic copolymer in the outer layer.
The copending claims recite a lipid structure, a first payload, and amphiphilic polymer chains, as of copending claim 1.
The instant and copending claims differ because the copending claims do not appear to explicitly recite that the amphiphilic copolymer is the outer layer and surrounds the lipid structure and payload. Nevertheless, the subject matter of the copending claims is made from essentially the same material as that of the instant claims. As such, the skilled artisan would have expected the composition of the copending claims to have adopted the same structure as that of the instant claims because it was made by the same material. This would appear to result in a prima facie case of anticipatory-type non-statutory double patenting with respect to instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612