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 .
Applicant’s amendment filed on 10/17/2025 has been entered.
Amended claims 1, 3, 6, 9-14 and 20 are pending in the present application, and they are examined on the merits herein.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Amended claims 9-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a modified rejection necessitated by Applicant’s amendment, particularly currently amended independent claim 1.
Claims 9-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: a cationic lipid, a phospholipid other than the cationic, a sterol, and a water-soluble polymer-modified lipid at the recited mass% per 100% mass% lipids constituting the lipid particle for each. This is because a single step of mixing a lipid-containing alcohol solution with an A-type CpG oligodeoxydeoxynucleotide-containing aqueous solution would not result in a lipid particle comprising an A-type CpG oligodeoxynucleotide, a cationic lipid as an amphipathic lipid, a phospholipid other than the cationic lipid as an amphipathic lipid, a sterol, and a water-soluble polymer-modified lipid at the recited mass% per 100% mass% lipids constituting the lipid particle for each in currently amended independent claim 1.
Claim Rejections - 35 USC § 103
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.
Amended claims 1, 3, 6, 9-14 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Cullis et al (WO 2011/140627) in view of Renner et al (WO 2007/068747). This is a modified rejection necessitated by Applicant’s amendment.
The instant claims are directed to a lipid particle comprising an A-type CpG oligodeoxynucleotide, a cationic lipid as an amphipathic lipid, a phospholipid other than the cationic lipid as an amphipathic lipid, a sterol, and a water-soluble polymer-modified lipid, wherein the lipid particle comprises an outer layer and an ion complex placed inside the outer layer, wherein the outer layer is a lipid monolayer membrane in which amphipathic lipids are arranged with hydrophilic parts facing outward, wherein the cationic lipid is at least one member selected from the group consisting of DOTAP and DOTMA, wherein a content of the cationic lipid is 40-60 mass% per 100 mass% lipids constituting the lipid particle, wherein a content of the phospholipid is 10 to 30% mass% per 100% lipids constituting the lipid particle, where a content of the sterol is 20 to 40 mass% per 100 mass% lipids constituting the lipid particle, and wherein a content of the waster-soluble polymer-modified lipid is 0.2 to 10 mass% per 100 mass% lipids constituting the lipid particle; a medicament, a reagent, an immunostimulant and an anticancer agent comprising the same lipid nanoparticle; and a method for producing the same lipid particle, comprising the step of mixing a lipid-containing alcohol solution and an A-type CpG oligonucleotide-containing aqueous solution, preferably the step is performed in a reaction system using a microchannel.
Cullis et al already disclosed lipid particles comprising nucleic acids (e.g., DNA, RNA, plasmid, siRNA, miRNA, immune-stimulating oligonucleotides, antisense and ribozymes) for delivering to a cell in vitro or in vivo, wherein the lipid particle comprises: (a) one or more cationic lipids (e.g., DLin-KC2-DMA, DOTAP, DOTMA), (b) one or more neutral lipids (e.g., DSPC/distearoylphosphatidylcholine, DOPC/dioleoylphosphatidylcholine, DPPC/dipalmitoylphosphatidylcholine), (c) one or more PEG-lipids (e.g., PEG-c-DMA, PEG-CerC14, PEG-c-DOMG), (d) one or more sterols such as cholesterol, and (e) one or more nucleic acids, and wherein the lipid particle comprises a substantially solid core (see at least the Abstract; Summary of the Invention; particularly pages 11-16; page 33, lines 22-33; and Examples 1-5). Cullis et al also taught that the lipid particle has a diameter from about 15 to about 300 nm, preferably from about 15 to about 20 nm (page 23, lines 3-17). An exemplary LNP siRNA formulation consisting of DLin-KC2-DMA/DSPC/Chol/PEG-lipid (40/11.5/47.5/1; mol/mol) containing siRNA at a 0.06 siRNA/lipid (wt/wt), which corresponds to a negative charge (on the siRNA) to positive charge (on the fully protonated cationic lipid) N/P ratio of 4 (page 40, last paragraph; and Fig. 22A). Another exemplary LNP siRNA formulation is comprised of DLin-KC2-DMA, DSPC, cholesterol, and PEG-c-DMA at 40:11.5:38.5:10 mol/mol, respectively, with a siRNA/total lipid ratio of 0.06 (wt/wt) (page 37, first paragraph). Cullis et al stated specifically “An initial composition of DLin-KC2-DMA, DSPC, cholesterol, and PEG-c-DMA (40:11.5:38.5:10 mol/mol) was used with a siRNA/total lipid ratio of 0.06 (wt/wt). Additional cholesterol was used to compensate for the decreased amount of PEG-c-DMA. Titration of PEG-c-DMA to 2 mol% led to only minor increase in particle size using the microfluidic approach. Further decrease to 1 mol% PEG led to an increase in diameter from about 20 nm to about 40 nm (FIGURE 18A)” (page 37, lines 1-7). Cullis et al also taught a method for preparing the nucleic acid-lipid nanoparticles in a microfluidic process that utilizes relatively rapid mixing the nucleic acid in a first solvent (e.g., aqueous buffers such as citrate and acetate buffers) with lipid particle-forming materials in a second solvent (e.g., alcohols, aqueous ethanol 90%) in a microchannel of a microfluidic mixing device to form LNP containing OGN of 100 nm size or smaller and provide OGN encapsulation 100%; and that the LNP OGN systems can be scaled up (pages 23-25; page 39, last two lines continue to first paragraph on page 40). Cullis et al further stated “The present invention provides a method for preparing nucleic acid-lipid nanoparticles comprising the cationic lipid DLinKC2-DMA using a microfluidic mixing device, wherein the resulting nucleic acid-lipid nanoparticles exhibit smaller particle diameter and greater core density than nucleic acid-lipid nanoparticles of the same formulation produced by the conventional performed vesicle method” (Abstract). Fig. 27 below is a schematic representation of the solid core LNP siRNA system formed by microfluidic mixing, which comprise encapsulated siRNA residing in a distorted inverted micelle surrounded by cationic lipid, and the remaining lipid is organized in inverted micelles surrounding anionic counterions and also makes up the outermost monolayer (page 43, last two lines continue to first two lines on page 44). The outermost monolayer in Fig. 27 is apparently comprised predominantly of PEG-DSPC (amphipathic lipids).
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Cullis et al did not teach specifically at least that the above disclosed lipid nanoparticles comprising an A-type CpG oligodeoxynucleotide, even though they disclosed that the lipid nanoparticles comprising immune-stimulating oligonucleotides.
Before the effective filing date of the present application (07/19/2018), Renner et al already taught a composition comprising particles such as virus-like particles, nanoparticles, microparticles and liposomes which are packaged with an immunostimulatory nucleic acid (e.g., oligonucleotides capable of stimulating IFN-alpha production in cells such as A-type CpGs and C-type CpGs), that is useful in the treatment of hypersensitivity (see at least Abstract; page 2, lines 4-30; page 14, lines 21-24; page 15, line 34 continues to 25; page 21, line 17 continues to line 27 on page 23; page 32, lines 10-18; and page 45, lines 25-31). Renner et al stated “[n]anoparticles incorporating an ISS-NA like an unmethylated CpG-containing oligodeoxynucleotide are able to stimulate dendritic cells upon uptake, and these dendritic cells thereafter activated T-cells” (page 30, lines 30-32); and “[u]ptake of particles such as nanoparticles or VLPs packaged with ISS-NA, such as unmethylated CpG-containing oligonucleotide, by plasmacytoid dendritic cells or antigen present cells and thereby inhibit the allergen induced response. The same import involved mast cells in the suppressive action of unmethylated CpG-containing oligonucleotide on the allergic response” (page 31, lines 3-8). Renner et al further stated explicitly “In a preferred embodiment, the ISS-NA, preferably an unmethylated CpG-containing oligonucleotide, is packaged within a “stabilized antisense-lipid particle” containing preferably PEG-ceramide-C14, as described by Semple S.C. et al. Methods Enzymol. 2000; 313:322-41. In the performance of this method for the practice of the invention, the antisense oligonucleotide is replaced by an ISS-NA, and in particular an unmethylated CpG-containing oligonucleotide. These liposomes are prepared with cationic lipids that are only charged at subphysiological pH” (page 45, lines 25-31).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Cullis et al by also encapsulating an A-type CpG oligodeoxynucleotide in their disclosed lipid nanoparticle system, including at least in a LNP formulation comprised of DOTAP: DSPC:cholesterol:PEG-c-DMA at 40:11.5:38.5:10 mol/mol, respectively; or DOTMA:DSPC:cholesterol:PEG-c-DMA at 40:11.5:38.5:10 mol/mol, respectively; in light of the teachings of Renner et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Renner et al already taught at least to package or encapsulate A-type CpG oligodeoxynucleotide in a particle in various forms such as virus-like particles, nanoparticles, microparticles and liposomes for use in the treatment of hypersensitivity, including replacing an antisense oligonucleotide with an unmethylated CpG-containing oligonucleotide in a “stabilized antisense-lipid particle” of Semple S.C. et al. Methods Enzymol. 2000; 313:322-41. Please also note that the primary Cullis reference already taught lipid particles comprising nucleic acids (e.g., DNA, RNA, plasmid, siRNA, miRNA, immune-stimulating oligonucleotides, antisense and ribozymes) for delivering to a cell in vitro or in vivo; and an exemplary LNP siRNA formulation is comprised of DLin-KC2-DMA, DSPC, cholesterol, and PEG-c-DMA at 40:11.5:38.5:10 mol/mol, respectively; along with the specific teachings that a cationic lipid can be a DOTMA or DOTAP other than DLin-KC2-DMA.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Cullis et al and Renner et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified lipid particle and a method for producing the same modified lipid particle resulting from the combined teachings of Cullis et al and Renner et al as set forth above are indistinguishable and encompassed by the presently claimed inventions.
Please note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above modified 103 rejection in the Amendment filed on 10/17/2025 (pages 6-7) have been fully considered, but they are respectfully not found persuasive for the following reasons.
Once again, Applicant argued basically that the primary Cullis reference merely mentions DOTAP, DOTMA and even DODAP among a long list of cationic lipids, and discloses examples of lipid nanoparticles with siRNA with Dlin-KC2-DMA as the cationic lipid. In contrast, Applicant demonstrated results in Test Example 1 showing superior stability and performance of lipid nanoparticles with DOTMA and DOTAP in delivering an A-type CpG oligodeoxynucleotide for the induction of IFN-α that are surprising and unexpected. Specifically, Fig. 1 in Test Example 1 demonstrates the ability to promote IFN-α production was highest when DOTAP was used as a cationic lipid (#41), followed by DOTMA (#45), and then DODAP (#47); and when DODAP was used the stability was relatively low and cloudy aggregation occurred within 3 months of storage at 40C. Thus, in view of the “unexpected” results for the lipid particles recited in the as-amended claims, the obviousness rejection over Cullis in view of Renner should be withdrawn. Applicant also argued that the surprising and unexpected results in Test Example 1 are commensurate with the scope of the as-amended claims. Applicant argued that the claimed effects for the superiority of DOTAP and DOTMA include stability in addition to the ability to promote IFNα, and there is no evidence in the Examples of this application that stability is affected by the N/P ratio. In Test Example 1 of the present application, the N/P ratio is the same “3” in all cases where DOTAP, DOTMA and DODAP were used, and therefore it can be assumed that it is the type of cationic lipid, not the N/P ratio, which contributes to the ability to promote IFNα; and that even if the N/P ratio is changed to 1, DOTAP and DOTMA still remain advantageous. Applicant further argued that it is not necessary to limit the sequence of the A-type CpG oligonucleotide since D35 was used in Test Example 1 in all cases where DOTAP, DOTMA, and DODAP were used, thus it can be assumed that the type of cationic lipid is important; and that even if it is changed to CpG ODN with a different sequence, DOTAP and DOTMA still remain advantageous.
First, the primary Cullis reference teaches clearly a lipid particle comprising nucleic acids (e.g., DNA, RNA, plasmid, siRNA, miRNA, immune-stimulating oligonucleotides, antisense and ribozymes) for delivering to a cell in vitro or in vivo, wherein the lipid particle comprises: (a) a lipid particle comprises: (a) one or more cationic lipids (e.g., DLin-KC2-DMA, DOTAP, DOTMA, DODAP and others), (b) one or more neutral lipids (e.g., DSPC, DOPC, DPPC), (c) one or more PEG-lipids (e.g., PEG-c-DMA, PEG-CerC14, PEG-c-DOMG), (d) one or more sterols such as cholesterol, and (e) one or more nucleic acids, and wherein the lipid particle comprises a substantially solid core. An exemplary LNP siRNA formulation is comprised of DLin-KC2-DMA, DSPC, cholesterol, and PEG-c-DMA at 40:11.5:38.5:10 mol/mol, respectively. Thus, the teachings of Cullis et al are not necessarily limited only to examples, including a lipid nanoparticle comprising siRNA with Dlin-KC2-DMA as a cationic lipid. Additionally, it is not an issue that the Cullis reference does not teach the use of DOTAP and/or DOTMA as cationic lipids their disclosed lipid nanoparticle. Please refer to the above modified 103 rejection for details.
Second, please note that any “surprising/unexpected” result must be commensurate with the scope of the claims. In this instance, with respect to the results in Figure 1 of Test Example 1, it is noted that all the lipid nanoparticles comprise the A-type CpG oligonucleotide of SEQ ID NO: 1: G_G_TGCATCGATGCAGGGG_G, where the underline indicates that nucleosides on both sides of the underline are phosphorothioate-bonded to each other, while nucleosides that are not connected with the underline are phosphodiester-bonded to each other; and each of the tested lipid nanoparticles is composed of a cationic lipid (DOTAP, DOTMA or DODAP), DPPC, cholesterol and DSPE-PEG-2K at their respective mass% of 50:19.5:30:0.5, and the ratio (N/P) of the number of nitrogen atoms (N) in the lipids constituting the lipid particles to the number of phosphorus atoms in the A-type CpG oligonucleotide of SEQ ID NO: 1 is 3 (paragraphs [0093]-[0094]). In contrast, currently amended claims are much broader than the lipid particle used in Test Example 1 to demonstrate “surprising/unexpected” results. Currently amended claims are drawn to a lipid particle comprising any A-type CpG oligodeoxynucleotide, a cationic lipid as an amphipathic lipid, a phospholipid other than the cationic lipid as an amphipathic lipid, a sterol, and a water-soluble polymer-modified lipid, wherein the lipid particle comprises an outer layer and an ion complex placed inside the outer layer, wherein the outer layer is a lipid monolayer membrane in which amphipathic lipids are arranged with hydrophilic parts facing outward, wherein the cationic lipid is at least one member selected from the group consisting of DOTAP and DOTMA, wherein a content of the cationic lipid is 40-60 mass% per 100 mass% lipids constituting the lipid particle, wherein a content of the phospholipid is 10 to 30% mass% per 100% lipids constituting the lipid particle, where a content of the sterol is 20 to 40 mass% per 100 mass% lipids constituting the lipid particle, and wherein a content of the waster-soluble polymer-modified lipid is 0.2 to 10 mass% per 100 mass% lipids constituting the lipid particle.
Third, in Test Example 1 of the present application Applicant simply stated “The results are shown in Fig. 1. The ability to promote IFN-α production highest when DOTAP was used as a cationic lipid (#41), followed by when DOTMA was used (#45) and when DODAP was used (#47). When DODAP was used, the stability was relatively low, and cloudy aggregation occurred within 3 months of storage at 40C” (paragraph [0095]). So basically, the results in Test Example 1 are for the 3 tested cationic lipids DOTAP, DOTMA and DODAP; with DOTAP when used promotes the highest IFN-α production and DODAP when used results in low stability relatively to DOTAP and DOTMA. Regardless of the different results generated by these 3 cationic lipids, the primary Cullis reference already taught explicitly the use of DOTAP and DOTMA as cationic lipids in lipid nanoparticles. Additionally, just because the N/P ratio is the same “3” in all cases where DOTAP, DOTMA and DODAP were used in Test Example 1, one cannot assume that the N/P ratio (the ratio of the number of nitrogen atoms (N) in the lipids constituting the lipid particles to the number of phosphorus atoms (P) in the nucleic acid in the lipid particles) does not contribute to the ability to promote IFN-α because Test Example 2 of the present application demonstrated clearly that the ability to promote IFN-α was significantly decreased when the N/P ratio was 1 instead of 3 using lipid nanoparticles containing DOTAP (see paragraph [0098]; and Figure 2). Applicant also stated clearly “[w]hen the N/P ratio was 1, the particle size was relatively large and was micro-scale” (last sentence of paragraph [0098]). As such, the sequence and/or nature of an A-type CpG in a lipid nanoparticle may affect the amount of induced IFN-α and/or the size/stability of the lipid nanoparticle.
Fourth, just because the same D35 was used in Test Example 1 in all cases where DOTAP, DOTMA and DODAP were used, one cannot assume that the type of cationic lipid is the sole factor determining in the induction of IFN-α, particularly the highest IFN-α production for DOTAP, because Test Example 2 of the present application demonstrated clearly that the ability to promote IFN-α was significantly decreased when the N/P ratio was 1 instead of 3 using lipid nanoparticles containing DOTAP (see paragraph [0098]; and Figure 2). Please note that N/P ratio is the ratio of the number of nitrogen atoms (N) in the lipids constituting the lipid particles to the number of phosphorus atoms (P) in the nucleic acid in the lipid particles.
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 Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s acting SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
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