DETAILED ACTION
Status of the Claims
Claims 45-63 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The U.S. effective filing date has been determined to be 08/17/2015, the filing date of the U.S. Provisional Application No. 62/206,211.
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Information Disclosure Statement
The information disclosure statement submitted on 05/01/2023 was filed before the mailing date of the first office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Objections
Claim 45 is objected to because of the following informalities: Claim 45 has been amended to insert “and a surface modifying agent on a surface of the particle” wherein the word “and” has been inserted but not properly indicated as such. 37 C.F.R 1.121(c)(2) makes clear that: (2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of "currently amended," or "withdrawn" if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as "withdrawn— currently amended.". Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 45-63 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.
Claim 45 is rejected as being indefinite because the claim recites “wherein the pH of the composition is greater than the pka of the ionizable molecule and the pka of the ionizable molecule is greater than or equal to about 6” in lines 12-13 because it is unclear what exactly “the composition” is added amendment. Particularly, the claims encompass “a plurality of particles comprising mRNA” with an aqueous interior and delivery vehicle such as water (instant Specification, p. 13, lines 21-23; p. 38, lines 18-19). Therefore the claim is considered ambiguous as it is unclear what “the pH of the composition” should be considered. Appropriate clarification is required. Claims 46-63 inherit this limitation and do nothing to clarify, and are therefore rejected for eth same reason.
Applicant is referred to Ex parte Miyazaki (BPAI 11/19/2008) (Horner, APJ) (precedential). A five member expanded panel of the Board held that "if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 USC 112, second paragraph, as indefinite." Miyazaki, slip op. at 11-12.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 45-63 are rejected under 35 U.S.C. 103 as being unpatentable over GUILD (US 2013/0195967; published August, 2013) in view of de Fougerolles (US 2013/0236974; published September, 2013); Maier et al. (“Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics,” 2013; Molecular Therapy Vol. 21, No. 8, pp 1570-1578.); LEE (US 2011/0038941; February, 2011) and MANOHARAN US 2012/0027803; published February, 2012)
Applicants Claims
Applicant claims a composition comprising: a plurality of particles comprising mRNA comprising greater than or equal to 100 nucleotides and less than or equal to 10,000 nucleotides in length and an ionizable molecule,
wherein an average cross-sectional dimension of the particles in the composition is less than or equal to about 150 nm, a coefficient of variation of a cross-sectional dimension of the particles in the composition is less than or equal to about 20%, and a weight percentage of mRNA in the particles is greater than or equal to about 50% and less than or equal to about 99%, and
wherein the composition is formed by (ia) changing a pH of a suspension comprising a plurality of particles form a first pH to a second pH, wherein the second pH is greater than the pka of the ionizable molecule, wherein the pka of the ionizable molecule is greater than or equal to about 6, or (ib) changing an average zeta potential of a suspension comprising the plurality of particles, from a first zeta potential to a second zeta potential, wherein the second zeta potential is less than the first zeta potential, and subsequently, (ii) filtering the suspension (instant claim 1).
Claim interpretation: With regard to the process steps of claims 1, and 53-62, “Even though product-by process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113.
Regarding the cationic lipid species of instant claim 50, the instant specification discloses that: In some embodiments, the ionizable molecule is a cationic lipid such as 2,2-dilinoley-4-dimethylaminoethy-[1,3]-di-oxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethyl-aminobutyrate (DLin-MC3-DMA), or di((Z)-non-2-en-1-yl)9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319).” Noting the synonyms Dlin-KC2-DMA, Dlin-MC3-DMA, and L319 for the species, respectively.
Determination of the scope
and content of the prior art (MPEP 2141.01)
GUILD teaches liver specific delivery of messenger RNA (title, see whole document), and particularly “Disclosed herein are compositions and methods of modulating the expression of gene or the production of a protein by transfecting target cells with nucleic acids. The compositions disclosed herein demonstrate a high transfection efficacy and are capable of ameliorating diseases associated with protein or enzyme deficiencies.” (abstract).
GUILD teaches that: “In a preferred embodiment, the nucleic acids (e.g., mRNA) provided herein are formulated in a lipid or liposomal transfer vehicle to facilitate delivery to the target cells and/or to stabilize the nucleic acids contained therein. Contemplated transfer vehicles may comprise one or more cationic lipids, non-cationic lipids, and/or PEG-modified lipids. For example, the transfer vehicle may comprise a mixture of the lipids CHOL, DOPE, IThinDMA and DMG-PEG-2000.” [emphasis added]([0012])(instant claim 45, “a plurality of particles comprising mRNA […] and an ionizable molecule”; instant claims 47-49, 50-51). GUILD teaches that the cationic lipid may be: “2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane” ([0058])(instant claim 50).
Regarding the limitation “comprising mRNA comprising greater than or equal to 100 nucleotides and less than or equal to 10,000 nucleotides in length,” GUILD teaches mRNA species SEQ ID Nos. 1-3, having lengths of 1672, 157, and 100, respectively (MPEP §2131.03-I).
Regarding the claimed size “an average cross-sectional diameter of the particles in the composition is less than or equal to about 150 nm,” GUILD teaches that: “Generally, the size of the transfer vehicle is within the range of about 25 to 250 nm, preferably less than about 250 nm, 175 nm, 150 nm, 125 nm, 100 nm, 75 nm, 50 nm, 25 nm or 10 nm.” ([0071]). And discloses particles with an average size equal to 68.0 nm ([0120]). GUILD claims “the liposome comprises cationic or non-cationic lipid, cholesterol-based lipid and PEG-modified lipid and has a size less than about 100 nm.” (claim 1)( MPEP §2131.03-I & §2144.05-I).
Regarding the PEG-lipid constituent, GUILD teaches that: “Contemplated PEG-modified lipids include, but is not limited to, a polyethylene glycol chain of up to S kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length. The addition of such components may prevent complex aggregation and may also provide a means for increasing circulation lifetime and increasing the delivery of the lipid-nucleic acid composition to the target tissues, […].” [emphasis added]([0062]). As such, the PEG-lipid is regarded as “a surface modifying agent on a surface of the particles.” wherein one of ordinary skill would recognized that the PEG is on the surface as it “may prevent complex aggregation.” (instant claim 1, “a surface modifying agent on a surface of the particles”).
GUILD discloses that: “Aliquots of 50 mg/mL ethanolic solutions of an imidazole cholesterol ester lipid (ICE), DOPE and DMG PEG-2000 were mixed and diluted with ethanol to a final volume of 3 mL. The molar ratio of the prepared ICE:DOPE: DMG-PEG-2000 transfer vehicle was 70:25:5. Separately, an aqueous buffered solution (10 mM citrate/150 mM NaCl, pH 4.5) of FFL mRNA was prepared from a 1 mg/mL stock. The lipid solution was injected rapidly into the aqueous mRNA solution and shaken to yield a final suspension in 20% ethanol. The resulting nanoparticulate suspension was filtered, diafiltrated with lxPBS (pH 7.4), concentrated and stored at 2-8° C.” ([0120]).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of GUILD is that GUILD does not expressly teach “a coefficient of variation of a cross-sectional dimension of the particles in the composition is less than or equal to about 20%”.
de Fougerolles teaches that: “The present disclosure provides, inter alia, formulation compositions comprising modified nucleic acid molecules which may encode a protein, a protein precursor, or a partially or fully processed form of the protein or a protein precursor. The formulation composition may further include a modified nucleic acid molecule and a delivery agent. The present invention further provides nucleic acids useful for encoding polypeptides capable of modulating a cell's function and/or activity.” (abstract, see whole document).
de Fougerolles teaches that: “the formulation comprising the modified mRNA is a nanoparticle which may comprise at least one lipid. The lipid may be selected from, but is not limited to, DLin-DMA, DLin-K-DMA, 98Nl2-5, Cl2-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG and PEGylated lipids. In another aspect, the lipid may be a cationic lipid such as, but not limited to, DLin-DMA, DLin-D-DMA, DLin-MC3-DMA, DLin-KC2-DMA and DODMA.” ([0006]). de Fougerolles teaches that: “While a particle size of less than 150 nm may be desired for effective hepatocyte delivery due to the size of the endothelial fenestrae” ([0375]). And that: “the optimization size, polydispersity and the shelf-life of the vesicles for the intended application, and the batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products.” ([0378]).
de Fougerolles teaches that: “Formulations of DLin-KC2-DMA, Teta-5-Lap, DLin-DMA, DLin-K-DMA, Cl2-200, DLin-MC3-DMA at a lipid:mRNA ratio of 20: 1 were evaluated for particle size, polydispersity index and encapsulation efficiency for stability at room temperature.” and teaches the polydispersity index (PDI) is < 0.1 indicating highly monodisperse particles (Table 96), and therefore fairly suggesting a “a coefficient of variation of a cross-sectional dimension of the particles in the composition is less than or equal to about 20%” (or less than or equal to 15% - instant claim 58).
Regarding the amount of mRNA – “wherein a weight percentage of mRNA in the particles is greater than or equal to about 50% and less than or equal to about 99%” – de Fougeroles teaches that: “In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase "active ingredient" generally refers to modified nucleic acids and mmRNA to be delivered as described herein.” ([0357]). And that: “By way of example, the composition may comprise between 0.1 % and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% ( w /w) active ingredient.” ([0361]). And further that: “For example, the composition may comprise between 0.1 % and 99% (w/w) of the active ingredient.” ([0365]).
MANOHARAN teaches biodegradable lipids for delivery of active agents (title, see whole document), and particularly “a cationic lipid having one or more biodegradable groups located in the mid- or distal section of a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid.” (abstract).
MANOHARAN teaches that: “In certain embodiments, protonatable lipids (i.e., cationic lipids) have a pKa of the protonatable group in the range of about 4 to about 11. Typically, lipids will have a pKa of about 4 to about 7, e.g., between about 5 and 7, such as between about 5.5 and 6.8, when incorporated into lipid particles. Such lipids will be cationic at a lower pH formulation stage, while particles will be largely (though not completely) surface neutralized at physiological pH around pH 7.4. One of the benefits of a pKa in the range of between about 4 and 7 is that at least some nucleic acid associated with the outside surface of the particle will lose its electrostatic interaction at physiological pH and be removed by simple dialysis; thus greatly reducing the particle's susceptibility to clearance.” ([0278], also see [0337]). It would have been prima facie obvious to formulate a composition at around pH 7.4 (physiological pH) and to include cationic lipid such as DLin-MC3-DMA, and to adjust the pH to 7.4 above the pKa of the cationic lipid to remove the nucleic acid associated with the outside surface of the particle by simile dialysis (instant claim 45, “wherein the pH of the composition is greater than the pka of the ionizable molecule and the pka of the ionizable molecule is greater than or equal to about 6”).
Maier et al. teaches biodegradable lipids enabling rapid eliminated lipid nanoparticles for systemic deliver of RNA therapeutics (title, see whole document). Maier et al. particularly teaches that: “Based on prior studies, we have correlated certain structural features with activity and arrived at structure-activity relationships that guide the design of lipids with good in vivo efficacy. Namely, the lipid should comprise an amphipathic structure with a hydrophilic headgroup region containing an ionizable amine and long hydrophobic dialkyl chains capable of promoting the self-assembly of formulation components into stable nanoparticles encapsulating the siRNA. We found that the acid dissociation constant (pKa) of the ionizable amino group strongly correlated with in vivo efficacy, with a pKa optimum between 6.2 and 6.5. Furthermore, the lipid should adopt an overall “cone” shape in acidic environments when paired with anionic endosomal membrane lipids such as phosphatidylserine. Lipids that adopt such a “cone” shape ion pair are hypothesized to promote the formation of non-bilayer phases, such as the hexagonal HII phase, that are associated with membrane disruption events. The structure-activity data indicate that modifications, such as double bonds, which alter the relative orientation of the alkyl chains from cylindrical to cone shape, increase the spacing between the alkyl chains, thereby enhancing the ability of the lipid to induce non-bilayer structures. The highly potent lipid DLin-MC3-DMA (Figure 1) appears to fulfill these criteria and was therefore used as a basis in the design of novel, highly potent, rapidly eliminated lipids.” [emphasis added](p. 1571, col. 1, §Results-General lipid design principles, 1st paragraph)(instant claim 50, species dilinoleyl-methyl-4-dimethyl-aminobutyrate (DLin-MC3-DMA); instant claims 56-57, pka of ionizable molecule (cationic lipid)).
Maier et al. teaches that: “When considering the placement of the ester groups, we made note of the fact that the presence of the sp2-carbon of the ester would introduce a kink in the alkyl chain, similar to a double bond, thereby maintaining the spacing between the alkyl chains, which has been shown to be important for efficacy. Therefore, we rationalized that one of the double bonds of the linoleyl chain could be replaced with an ester group. For instance, replacing the 9,10-cis double bond with an ester (L319) places the degradable functionality centrally within the hydrocarbon chain, yielding hydrolysis products that would be predicted to be significantly more hydrophilic than the parent lipid (Figure 1).” (p. 1571, col. 2, last paragraph)(instant claim 50, species di((Z)-non-2-en-1-yl)9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate)(L319).
Regarding the product-by process claims, particularly the filtration via tangential flow filtration and through a 0.2 micron filter (instant claims 59-62), LEE teaches lipid nanoparticle compositions (title, see whole document), and particularly oligonucleotide-lipid nanoparticles (abstract). LEE teaches that: “The method can include a solvent removal step which can be accomplished by using a tangential-flow diafiltration method to exchange the nanoparticles into an aqueous buffer and to adjust the oligonucleotide-lipid nanoparticles to a desired concentration.” ([0012], [0170]). And that: “After the formation of the oligonucleotide-lipid nanoparticles, the lipid nanoparticles can be sterilized by filtration, for example, through a 0.2 micron membrane.” ([0206]).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising a plurality of lipid nanoparticles for mRNA delivery including one or more cationic lipids, non-cationic lipids, and/or PEG-modified lipids, such as the cationic lipid species Dlin-KC2-DMA, as suggested by GUILD, for delivery of mRNA, and to produce the lipid nanoparticles with a narrow size distribution, as suggested by de Fougerolles, and utilizing the cationic lipid species DLin-MC3-DMA and/or L319, as suggested by Maier et al. as having a pka in the range of 6.2-6.5 as being biodegradable to improve biocompatibility and/or to facilitate elimination, as suggested by Maier et al. (abstract), and further to utilize known methods of producing the same such as using tangential flow filtration to remover solvents, and a membrane filter having a mean pore size of less than or equal to 0.2 microns, as suggested by LEE, for sterile filtration; and further to provide a composition with a physiological pH for administration, and adjusting the pH from acidic (formulation pH) to higher physiological pH for administration, the formulation including a cationic lipid such as Dlin-KC2-DMA having an optimum pKa between 6.2 and 6.5, as suggested by Maier et al. and MANOHARAN.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention as the cited prior art clearly teaches methods of producing the described nanoparticles. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 10/17/2025 have been fully considered but they are not persuasive.
Applicant argues that “Without conceding the correctness of the rejection and solely in the interest of advancing prosecution, Applicant has amended claim 45 to recite that the pH of the composition is greater than the pKa of the ionizable molecule and the pKa of the ionizable molecule is greater than or equal to about 6. Applicant has also amended claim 45 to recite that the composition comprises a surface modifying agent on a surface of the particles. The combination of cited references do not teach or suggest each element of the claimed compositions. In particular, the cited references do not teach a composition comprising a plurality of particles comprising mRNA, an ionizable molecule, and a surface modifying agent on a surface of the particles, wherein the pH of the composition is greater than the pKa of the ionizable molecule and the pKa of the ionizable molecule is greater than or equal to about 6. The Examiner has also not pointed to a reference teaching "a weight percentage of mRNA in the particles is greater than or equal to about 50% and less than or equal to about 99%," as recited in the instant claims. The combination of cited references is therefore insufficient to establish a prima facie case of obviousness with respect to the amended claims.” (pp. 6-7, item A).
In response the examiner argues that the prior art clearly teaches PEG-lipids where PEG is on the surface therefore constituting “a surface modifying agent on the surface of the particles”. It is unclear what Applicant means “the pH of the composition” to mean but it is clearly obvious to select a cationic lipid known in the prior art for the very same usage, and to adjust the pH above the Pka, for example to provide a composition with a physiological pH. GUILD teaches that the cationic lipid may be: “2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane” ([0058])(instant claim 50), which has a pka of “greater than or equal to about 6” and therefore adjusting the pH to physiological pH of 7.4 would have been prima facie obvious. Regarding the amount of mRNA – “wherein a weight percentage of mRNA in the particles is greater than or equal to about 50% and less than or equal to about 99%” – de Fougeroles teaches that: “In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase "active ingredient" generally refers to modified nucleic acids and mmRNA to be delivered as described herein.” ([0357]). And that: “By way of example, the composition may comprise between 0.1 % and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w /w) active ingredient.” ([0361]). And further that: “For example, the composition may comprise between 0.1 % and 99% (w/w) of the active ingredient.” ([0365]). Alternatively, given that the ingredients and methods are consistent with the prior art it would have been prima facie obvious to optimize the amount of the mRNA (active ingredient), thus in the absence of evidence of unexpected properties associated with the full scope of the claims, it would have been obvious to the ordinary skilled artisan at the effective filing date of the instant invention to have identified optimal or workable ranges of the weight percentage of nucleic acid (active ingredient) in the lipid-nucleic acid particles by routine optimization using known methods.
Applicant argues that a person of ordinary skill in the art would not have had a reasonable expectation of success in arriving at the claimed invention (p. 7, item b). Particularly that: “Guild and de Fougerolles do not teach or suggest a pKa of an ionizable molecule is greater than or equal to about 6, let alone that the pKa of the ionizable molecule is greater than or equal to about 6 and the pH of the composition is greater than the pKa of the ionizable molecule. The Examiner alleges that Maier teaches having a pKa in the range of 6.2-6.5. However, Maier teaches siRNA lipid nanoparticles comprising ionizable lipids. The section of Maier that discusses the pKa of the ionizable amino group, first states "the lipid should comprise an amphipathic structure with a hydrophilic headgroup region containing an ionizable amine and long hydrophobic dialkyl chains capable of promoting the self-assembly of formulation components into stable nanoparticles encapsulating the siRNA" (see Results section of Maier). Applicant submits that one of ordinary skill in the art would not have had a reasonable expectation that mRNA could be substituted for siRNA in Maier's lipid nanoparticles. mRNA (long single stranded) is structurally distinct from siRNA (short double stranded. Based on the different properties of mRNA and siRNA, one of ordinary skill in the art would not have expected that mRNA could effectively be substituted for siRNA in the Maier." Lee also fails to cure the deficiencies of the cited references. As such, a person of ordinary skill in the art, upon reading the cited references, would not have had any reasonable expectation of success of arriving at the instant compositions a plurality of particles comprising mRNA, wherein the mRNA have a length of at least 100 nucleotides and no greater than 10,000 nucleotides, wherein the property is altered during a distinct step, prior to filtration. Accordingly, Applicant respectfully argues a prima facie case of obviousness has not been established and thus, respectfully requests withdrawal of this rejection.” (paragraph bridging pp. 7-8).
In response the examiner argues that the pKa is a property of a molecule and if the molecule is the same the pKa is the same (MPEP 2112.01-II – "Products of identical chemical composition can not have mutually exclusive properties."). The examiner invites Applicant to provide a list of pKa values for “an ionizable molecule” within the context of the instant claims for the Official Record. The instant Application does not list such values. MANOHARAN (US 2011/0311582 Al) provides a list in Figure 3 indicating that Dlin-MC3-DMA has a pKa of 6.44 (also see p. 60, Example 15A for Determination of pKa of Formulated Lipids). Additionally, the prior art to which the invention pertains clearly list various nucleic acid useable in particles for delivery of nucleic acids such as mRNA. For example GUILD teaches “Disclosed herein are compositions that facilitate the delivery of nucleic acids to, and the subsequent transfection of, target cells. In particular, the compositions provided herein are useful for the treatment of diseases which result from the deficient production of proteins and/or enzymes.” ([0023]). And that: “As used herein, the term "nucleic acid" refers to genetic material (e.g., oligonucleotides or polynucleotides comprising DNA or RNA). In some embodiments, the nucleic acid of the compositions is RNA. Suitable RNA includes mRNA, siRNA, […].” ([0028]). Therefore, the nucleic acid species mRNA and siRNA would have been considered substitutable in the context of “compositions that facilitate the delivery of nucleic acids to, and the subsequent transfection of, target cells”.
Applicant further argues that The claimed invention exhibits unexpected results. Particularly that: “For example, it has been discovered that the claimed compositions, which comprise, inter alia, a plurality of particles comprising mRNA, an ionizable molecule having a pKa greater than or equal to about 6 and the pH of the composition is greater than the pKa of the ionizable molecule, and are formed by (ia) changing a pH of a suspension comprising the plurality of particles from a first pH to a second pH, wherein the second pH is greater than the pKa of the ionizable molecule, wherein the pKa of the ionizable molecule is greater than or equal to about 6, or (ib) changing an average zeta potential of a suspension comprising the plurality of particles, from a first zeta potential to a second zeta potential, wherein the second zeta potential is less than the first zeta potential and subsequently, (ii) filtering the suspension, reduce and/or eliminate certain problems associated with filtration, such as fouling. The specification as-filed describes that "when the pH of the suspension was greater than the pKa of the ionizable lipid, the filtration time was reduced, a higher permeate flux was achieved throughout the filtration process, and the coefficient in variation of the resulting particles was reduced compared to a suspension having a pH less than the pKa of the ionizable lipid (control)" (see Example 3 and page 43, lines 11-14 of the specification as-filed). FIGs. 6A and 6B demonstrate that the suspension having a pH greater than the pKa of the ionizable lipid, wherein the pKa of the ionizable molecule is greater than or equal to about 6 (i.e., 6.3) had better filtration performance than the suspension having a pH less than the pKa of the ionizable lipid. Additionally, FIG. 7 A demonstrates that the average particle size of the particles in the suspension having a pH greater than the pKa of the ionizable lipid was smaller than the average particle size of the particles in the suspension having a pH less than the pKa of the ionizable lipid after filtration. FIG. 7B demonstrates that the suspension having a pH greater than the pKa of the ionizable lipid had a significantly lower polydispersity in average particle size than the suspension having a pH less than the pKa of the ionizable lipid. Example 2 further demonstrates that a nanoparticle composition having a pH greater than the pKa of the ionizable lipid, wherein the pKa of the ionizable molecule is greater than or equal to about 6 (i.e., 6.3) has a greater magnitude of average surface charge when the pH was altered to be greater than the pKa of the ionizable lipid, than the magnitude prior to changing the pH.” (pp. 8-9, item C).
In response the examiner argues that the instant claims are directed to compositions of matter and not methods (as in the allowed parent case – USPN 11,564,893). And while the instant claims include product-by-process limitations the examiner sees no data showing a structural distinction of the composition resulting from the recited process step(s). Additionally, the examiner notes that nucleic acids have long been known to be charged molecules, particularly negatively charged (anionic) and have therefore been combined with cationic molecules (positively charged) such as cationic lipids. MANOHARAN teaches that: “In certain embodiments, protonatable lipids (i.e., cationic lipids) have a pKa of the protonatable group in the range of about 4 to about 11. Typically, lipids will have a pKa of about 4 to about 7, e.g., between about 5 and 7, such as between about 5.5 and 6.8, when incorporated into lipid particles. Such lipids will be cationic at a lower pH formulation stage, while particles will be largely (though not completely) surface neutralized at physiological pH around pH 7.4. One of the benefits of a pKa in the range of between about 4 and 7 is that at least some nucleic acid associated with the outside surface of the particle will lose its electrostatic interaction at physiological pH and be removed by simple dialysis; thus greatly reducing the particle's susceptibility to clearance.” ([0278], also see [0337]). Thus it is pretty clear that these nucleic acid delivery particles are formulated at a lower pH (“a lower pH formulation stage”) and the pH is raised to a physiological pH for an injectable formulation, and such a process reduces non-encapsulated nucleic acid (“nucleic acid associated with the outside surface of the particle”) which can then more easily be removed by filtration (“removed by simple dialysis”). The examiner notes that dialysis and tangential flow filtration are both filtration techniques used for nano formulations. The examiner cites Dalwadi et al. (“Comparison of Diafiltration and Tangential Flow Filtration for Purification of Nanoparticle Suspensions,” 2005, Pharmaceutical Research, Vol. 22, No. 12, pp. 2152-2162) teaching the various techniques used for purification of nanoparticle formulations (see whole document, particularly the §Introduction). Therefore, “filtering the suspension, reduce and/or eliminate certain problems associated with filtration, such as fouling.” and “the filtration time was reduce” do not appear to be unexpected in the context of the prior art as MANOHARAN clearly teaches such a steps with the substantially identical result. Therefore the results do not appear to be unexpected in the context of the prior art to which the invention pertains.
Additionally, the claims are not limited to the Examples in such a way that the should be considered commensurate with the same (MPEP §716.02(d)).
Conclusion
Claims 45-63 are pending and have been examined on the merits. Claim 45 is objected to (Rule 1.121); claims 45-63 are rejected under 35 U.S.C. 112(b) and claims 45-63 are rejected under 35 U.S.C. 103. No claims allowed at this time.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: SCOTT (US 2006/0018971) is cited as teaching nucleic acid microspheres having a high loading – “Microspheres comprising between about 20 weight percent and about 100 weight percent of one or more nucleic acids, and having an average particle size of not greater than about 50 microns.” (see whole document, claim 1).
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 IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619