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 .
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-5, 7-9, 16-20, 53, and 54 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wild (US 2018/111830 A1), as evidenced by Bumcrot (US 20140288154 A1).
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Regarding claim 1, Wild discloses a microfluidic chip (figure 4A) comprising:
at least one lipid insertion channel (308) configured to direct a flow of a lipid solution containing a quantity of oligonucleotides (para. [0096]-[0097], [0219]);
one or more buffer channels (304) configured to direct a flow of a buffer solution (para. [0094]-[0095], [0112]);
an inlet junction (312) positioned at the intersection of the lipid insertion and the buffer channel;
a mixing channel (314) in fluid communication with said inlet junction and configured to direct a flow of the lipid solution and the buffer solution to an outlet channel (para. [0098]), wherein said mixing channel includes one or more hairpin or a meander channel (See hairpin 314 of Fig. 4A is both a hairpin and serpentine/meandering channel) turns in fluid communication with said inlet junction and configured to direct a flow of the lipid solution and the buffer solution to an outlet channel; and
a receiving container configure to collect said LNPs (318).
The claim limitation of “…configured to direct a flow of a lipid/buffer solution” for the lipid insertion channel, buffer channel, and mixing channel is a recitation of intended use as the lipid solution and buffer solution are articles the claimed device works upon. Furthermore, the limitation of “wherein said lipid solution, as it is passes through said mixing channel, forms a plurality of lipid nanoparticles (LNPs) encapsulating the oligonucleotides” is also a intended use limitation. Manner of operating an apparatus does not differentiate apparatus claim from the prior art. A claim containing a “recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus” if the prior art apparatus teaches all the structural limitations of the claim (MPEP 2114, II). A recitation of intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Moreover, Wild discloses the inlet channel 308 is configured to direct a flow of a lipid solution (para. [0096]-[0097]) containing a quantity of oligonucleotides (para. [0219]); the inlet channel 304 is configured to direct a flow of a buffer solution (para. [0094]-[0095], [0112]); the second region 314 is configured to direct a flow of a lipid and buffer solution to an outlet channel (para. [0098]); and wherein said lipid solution as it is passes through said mixing channel (a second region 314 adapted for mixing the contents of the first and second streams to provide a third stream comprising a mixed solution; para. [0098]), forms a plurality of lipid nano-particles (LNPs) (The lipid nanoparticles so formed are conducted from the second (mixing) region by microchannel 316 to outlet 318. Para. [0098]) encapsulating the oligonucleotides (para. [0219]).
Regarding claims 2 and 3, Wild discloses the claimed invention as discussed above in claim 1. The claim recites the composition of lipid solution, yet the lipid solution is not recited as part of the claimed apparatus. Wild discloses the microfluidic device is capable of generating siRNA lipid nanoparticles (para. [0152]). Evidential reference Bumcrot discloses the use of a lipid solution comprising at least one cationic lipid/DDAB (Table 26, column “Lipid (mol%)”; para. [0185]-[0186]), at least one neutral lipid/DSPC (Table 26, column “DSPC (mol%)”, at least one sterol/CHOL (Table 26, column “Chol (mol%)”, and at least one co-surfactant/PEG-DMG (Table 26, column “PEG (mol%)”) (para. [0365]-[0366]) in order to obtain RNA products within a lipid nanoparticles.
Regarding claim 4, Wild discloses the claimed invention as discussed above in claim 3. Furthermore, evidential reference Bumcrot discloses components of lipid solution (a lipid particle that consists of or consists essentially of a cationic lipid of formula A, a neutral lipid, a sterol, a PEG of PEG-modified lipid; para. [0365]) have a molar ratio of:
DDAB approximately 50% (…in a molar ratio of about 35-65% of cationic lipid of formula A… para.[0365]);
DSPC approximately 10% (…3-12% of the neutral lipid…para.[0365]);
CHOL is approximately 15-45% (…15-45% of the sterol…para.[0365]); and
PEG-DMG is approximately 1% (…and 0.5-10% of the PEG or PEG-modified lipid, para.[0365]) (In particular embodiments, the molar lipid ratio is approximately 60/7.5/31/1.5 or 57.5/7.5/31.5/3.5 (mol % LIPID A/DSPC/Chol/PEG-DMG). Para. [0365]).
Regarding claim 5, Wild discloses the claimed invention as discussed above in claim 1. The limitation regarding the lipid solution containing a quantity of oligonucleotides is an intended use recitation as discussed above in claim 1 since the lipid solution is not positively recited as part of the claimed device. Furthermore, Wild discloses the quantity of oligonucleotides comprise a quantity of RNA oligonucleotides (para. [0219]).
Regarding claims 7-9, Wild discloses the claimed invention as discussed above in claim 1. Wild discloses the meander channel comprises a plurality of meander channels/plurality of hairpin turns, wherein said plurality of meander channel comprises at least one meander segment (See plurality of hairpin turns in Figure 4A; hairpin turn/serpentine is a subset of meandering segment).
Regarding claim 16, Wild discloses the claimed invention as discussed above in claim 1. The claim recites the particle size of LNP, yet the LNP is not recited as part of the claimed apparatus. Furthermore, Wild discloses the particle size of 10 to 100 nm, which overlaps with the claimed range of 82 and 420 nm (para. [0185]).
Regarding claim 17, Wild discloses the claimed invention as discussed above in claim 1. The claim recites the encapsulation efficiency of LNP, yet the LNP is not recited as part of the claimed apparatus. Furthermore, Wild discloses the encapsulation efficiency of 98% (Table 1, para. [0257]).
Regarding claims 18-19, Wild discloses the claimed invention as discussed above in claim 1. The claim recites the LNPs are lyophilized, and the lyophilized LNPs are reconstituted, yet the LNPs are not recited as part of the claimed invention. Furthermore, lyophilization, by definition, is a commonly process in pharmaceutical industry to increase the stability and shelf life by removing the water from formulation (in freeze-dried form), and reconstitution is process of rehydrating/restoring the LNPs (by adding a diluent).
Regarding claim 20, Wild discloses the claimed invention as discussed above in claim 1. Wild does not explicitly disclose the retention of encapsulated RNA. The claim recites the reconstituted LNPs have at least a 90% retention of encapsulated RNA, yet the LNPs is not recited as part of the claimed invention.
Regarding claims 53 and 54, Wild discloses a system for the production LNP (Figure 1) comprising:
Microfluidic mixing chip having (figure 4A):
at least one lipid insertion channel (308) configured to direct a flow of a lipid solution containing a quantity of oligonucleotides (para. [0096]-[0097], [0219]);
one or more buffer channels (304) (para. [0094]-[0095], [0112]);
an inlet junction (312);
a mixing channel (314) in fluid communication with said inlet junction, wherein said mixing channel includes at least one meander channel (channel between inlet junction and first hairpin) and one or more hairpin turns (See hairpin 314 of Fig. 4A is both a hairpin and serpentine channel).
The claim limitation of “…configured to direct a flow of a lipid” for the lipid insertion channel is directed to article the claimed device works upon. Furthermore, the limitation of “wherein said lipid solution includes at least one cationic lipid,/DDAB at least one neutral lipid/DSPC, at least one sterol/CHOL, and at least one co-surfactant/PEG-DMG” is also a intended use limitation. Manner of operating an apparatus does not differentiate apparatus claim from the prior art. A claim containing a “recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus” if the prior art apparatus teaches all the structural limitations of the claim (MPEP 2114, II). A recitation of intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Moreover, Wild discloses the inlet channel 308 is configured to direct a flow of a lipid solution (para. [0096]-[0097]) containing a quantity of oligonucleotides (para. [0219]), and Evidential reference Bumcrot discloses the use of a lipid solution comprising at least one cationic lipid/DDAB (Table 26, column “Lipid (mol%)”; para. [0185]-[0186]), at least one neutral lipid/DSPC (Table 26, column “DSPC (mol%)”, at least one sterol/CHOL (Table 26, column “Chol (mol%)”, and at least one co-surfactant/PEG-DMG (Table 26, column “PEG (mol%)”) (para. [0365]-[0366]) in order to obtain RNA products within a lipid nanoparticles.
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.
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.
Claim(s) 6 and 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wild.
Regarding claim 6, Wild teaches the claimed invention as discussed above in claim 1. Wild discloses the flow of fluid through the channels of said microfluidic chip comprises a volumetric throughput (Qtotal) between 1 mL/min to 40 mL/min (para. [0255]), which overlaps with the claimed range of 1000 and 8000
μ
L
/min. It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to have selected the overlapping portion of the ranges disclosed by the reference because selection of overlapping portion of ranges has been held to be a prima facie case of obviousness. See MPEP § 2144.05.I.
Regarding claims 10-13, Wild discloses the claimed invention as discussed above in claim 1. Wild does not explicitly discloses the onset length and distance between the inlet junction and first meander/hairpin turn, mixing channel length, and the distance between the plurality of hairpin turns are variable.
Wild discloses factors such as varying flow rates and surface tension are taken into consideration when varying specific dimensions of fluidic channels (differing flow ratios may be enabled by either differential pressure drops across the flow channels, differential channel impedances, or combination therein, applied to the inlet streams. Differential impedances of the channels through varying the channel heights, widths, lengths, or surface properties, may be used to achieve different flow rates. Para. [0083]).
As the flow rates and differential pressure drops are variables that can be modified, among others, by adjusting the channel dimensions, the varying the channel distance/lengths of claims 10-13 would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, the channel dimensions in Wild to obtain the desired balance between flow rates and differential pressure drops and channel lengths/dimensions (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223). “[W]here 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 In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.). “[W]here 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 In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
Conclusion
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/M.H./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758