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 .
Amendments
In the reply filed 7/30/2025, Applicant has amended Claims 64 and 84, and added new claims, Claims 86-96.
Claims 77-81 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable
Claims 64-76, and 82-96 are under consideration.
Withdrawn Objections to Specification
The prior objection to the specification as failing to include a cross reference to related applications is withdrawn in light of Applicant’s amended specification filed 7/30/2025.
The prior objection to the specification as not providing a Sequence Listing part of the disclosure and no CRF is withdrawn in light of Applicant’s amended specification filed 7/30/2025.
Withdrawn Objection to Drawings
The prior objection to Figure 14 of the specification as not conforming to sequence rules is withdrawn in light of Applicant’s amended specification disclosing SEQ ID NOs filed 7/30/2025.
Withdrawn Claim Rejections - 35 USC § 112(a)
The prior rejection of Claim 84 under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling is withdrawn in light of Applicant’s amended specification and claimed SEQ ID NOs.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 64-70, 82-86 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al., (US Patent 10,227,386, filed 9/29/2011, patented 3/12/2019, see IDS filed 3/22/2024) in view of Tasciotti et al. (US2019/0117572, filed 3/07/2018)
In regard to claim 64, Duncan teaches compositions and methods of making nucleic acid cargo-proteolipid vesicles comprising a purified FAST membrane protein (col 15, last two para., to col 18, 3rd para., col 20, last para., col 21, 2nd para., Examples 12-17, see also claims 1 and 2 of Duncan). Specifically, Duncan teaches the FAST membrane protein is purified (col 31, Example 14), and describes the p14 constructs as histidine tagged (col 28, 2nd para.), which allows affinity purification of the recombinant proteins. Finally, Duncan teaches the purified recombinant proteins are provided in an aqueous detergent suspension (col 17, 2nd para) prior to mixing with the liposomal components. Note that Applicant’s specification does not provides a special definition for the term “purified”, and neither the specification nor the claim prohibit the presence of a detergent in the aqueous suspension comprising the purified recombinant FAST protein.
In regard to the lipid formulation of claim 64, Duncan teaches making lipid vesicles comprising ionizable lipids (e.g, DC-Chol), helper lipids (e.g., DOPE), and PEGylated lipids (e.g, PE-PEG2000) (col 16, 2nd -5th para., see also Tables 1 & 2).
However, although Duncan teaches the method steps of providing the nucleic acid in an aqueous buffer (e.g., see Example 12), as well as providing the purified recombinant FAST protein in the aqueous buffer (e.g., see Example 14), they are silent with respect to making the nucleic acid cargo-proteolipid vesicles by formulating the nucleic acid cargo and the FAST protein in an aqueous solution and then mixing with the lipids in an organic solution
In regard to instant claims, Tasciotti teaches making proteolipid vesicles for the delivery of nucleic acid cargo by formulating a short transmembrane protein in an aqueous solution and then mixing with lipids in an organic solution of ethanol (Abstract, Example 1, see Claims 1-20 of Tasciotti). Specifically in regard to claim 64, Tasciotti teaches the steps of dissolving the lipids in ethanol to generate the organic phase, and suspending the small transmembrane proteins in an aqueous buffer, followed by mixing the two phases in a microfluidic mixer at a 2:1 ratio, flowing the proteolipid vesicles in a flow channel, purification by dialysis and ultracentrifugation (see [0157] of Example 1).
In regard to the purity of the membrane proteins, Tasciotti discloses that the membrane proteins were extracted from cells and incorporated within the lipid bilayer of nanovesicles using the microfluidic mixer [0153-0156].
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of preparing nucleic acid cargo-proteolipid vesicles as suggested by Duncan et al. and substitute the method steps of Tasciotti with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Tasciotti because the two-phase mixing steps result in loading efficiencies of over 60% of the transmembrane protein into the proteoliposome (Example 1, [0187], see also Claim 5 of Tasciotti).
In regard to claim 65 and 66, as stated supra, Tasciotti teaches the method step of ultracentrifugation [0157, 0162], which would exchange the mixed phase comprising ethanol for a buffer, concentrate the proteolipid vesicles, and remove unincorporated membrane proteins.
In regard to claim 67, as stated supra, Tasciotti teaches the step of dialysis using a filter in order to remove unincorporated lipids from the proteolipid vesicles [0162].
In regard to claim 68, as stated supra, Tasciotti teaches the ratio of 2:1, which is about 3:1.
In regard to claim 69, both Duncan and Tasciotti teach the steps of combining the lipids to form combined lipids, while Duncan teaches the steps of further dehydrating the combine lipids; and rehydrating the lipids (see Example 12 of Duncan), which would have been obvious to generate a homogenous mixture of lipids in the organic phase.
In regard to claim 70, as stated supra, Tasciotti teaches the organic phase comprises ethanol.
In regard to claims 82 and 83, Duncan teaches the p14endop15 peptide (col 19, last para., col 20, 5th para., col 23, 2nd para., Examples 1 & 2, see Figs. 2-5), which comprises the fragments of the p14 ectodomain and the p15 endodomain.
In regard to claim 84, as stated supra, Duncan teaches the p14endop15 peptide, which comprises the 38 residue p14 ectodomain of SEQ ID NO:2, a p15 transmembrane domain, and the 97 residue p15 endodomain of SEQ ID NO:10 (see amino acid sequence in Fig. 1A of Duncan).
In regard to claim 85, Duncan teaches the nuclei acid is DNA (col 16, 4th para., col 20, 5th para.).
In regard to claim 86, Duncan teaches the nuclei acid is RNA such as an siRNA (col 4, last two para., col 5, 1st three para.).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 7/30/2025 are acknowledged.
Applicant argues that the primary reference of Duncan teaches a different production method for nucleic acid cargo-proteolipid vesicles comprising reconstituting the ionizable lipids in an aqueous buffer with the nucleic acids and then providing the FAST membrane proteins to the aqueous buffer. Duncan does not disclose mixing ionizable lipids in an organic buffer with the nucleic acids and purified FAST membrane proteins in an aqueous buffer.
Applicant argues that although the secondary reference of Tasciotti teaches production method for cargo-proteolipid vesicles comprising mixing lipids in an organic buffer with leukocyte membrane proteins in an aqueous buffer, Tasciotti does not teach ionizable lipids nor purified recombinant FAST membrane proteins.
Thus, Applicant asserts that there would not have been a reasonable expectation of success in using the mixing method of Tasciotti to make the nucleic acid cargo-proteolipid vesicles of Duncan. This assertion is based on 1) the mixing method of Tasciotti does not teach purified membrane proteins, and one of ordinary skill would have expected a purified FAST membrane protein to precipitated in the aqueous solution, and 2) the mixing method of Tasciotti does not use the claimed combination of ionizable lipid, helper lipid, and PEGylated lipid and instead uses helper lipids with cholesterol, which can greatly affect liposomal properties, and there is no evidence that the purified proteins and combination of lipids from Duncan would have worked in the production method of Tasciotti.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's arguments, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In instant case Duncan teaches the recombinant “purified” FAST protein was reconstituted into liposomes by mixing an aqueous detergent-suspended FAST protein with liposomes (Example 14), thereby demonstrating that the recombinant FAST protein was indeed purified and readily soluble in an aqueous media comprising detergent. As stated above, Applicant’s specification does not provides a special definition for the term “purified”, and neither the specification nor the claim prohibit the presence of a detergent in the aqueous suspension comprising the purified recombinant FAST protein. Furthermore, Tasciotti discloses that the membrane proteins were “extracted” from cells and incorporated within the lipid bilayer of nanovesicles using the microfluidic mixer, thereby supporting the fact that membrane protein extracts in an aqueous solution could have been successfully mixed with an organic solution comprising the liposomal lipids to make cargo-proteolipid vesicles. Tasciotti goes on to explain that the NA (NanoAssemblr) manufacturing protocols did not affect the function of key membrane proteins [0198], which evidences that similar results could have been achieved with FAST membrane protein extracts of Duncan.
Furthermore, in instant case the primary reference of Duncan teaches the cargo-proteolipid vesicles are to comprise ionizable lipids (e.g, DC-Chol), helper lipids (e.g., DOPE), and PEGylated lipids (e.g, PE-PEG2000), which were readily soluble in organic solvents and when rehydrated with an aqueous buffer naturally formed liposomes (Example 12). Note that although Duncan is silent to presence of cholesterol, instantly rejected claims are extremely broad to the nature of the lipid composition and Claim 64 recites the transition phrase “comprising” that does not exclude the presence of cholesterol. In addition, while the secondary reference of Tasciotti is limited to the use of helper lipids (e.g., DOPC) and cholesterol, they do disclose that the NanoAssemblr technology was well known for making liposomes in the prior art and reference the work of Kastner et al. (Reference #16 of Tasciotti) [0152]. Importantly, in order to complete the art of record and to rebut Applicant's arguments, Applicant is directed to the reference of Kastner et al., (Int J. Pharmaceuti, 2014, 477:361-368), which demonstrates that well before the time of invention it was known that other lipids such as the cationic lipid DOTAP, as well as other helper lipids such as DOPE, in the absence of cholesterol, have been used in the NanoAssemblr system to successfully make cargo vesicles (p. 362, last para.).
Thus, contrary to Applicant’s assertions, it would have been predictably obvious to have practiced the method of preparing nucleic acid cargo-proteolipid vesicles comprising purified FAST membrane proteins and a combination of ionizable lipid, helper lipid, and PEG-lipid as suggested by Duncan et al. and substitute the method steps using the NanoAssemblr protocol of Tasciotti with a reasonable expectation of success.
Furthermore, any conclusions of unpredictability have to be made in the context of this particular method, i.e., making vesicles in vitro using the well-established NanoAssemblr system, which is a highly developed art. In instant case, the Federal Circuit would have found that the claims at issue would have been obvious because there was ample suggestion in the prior art that the claimed NanoAssemblr based method would have worked. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304. Note that Applicant’s disclosure indicates that it was the NanoAssemblr system that was used to make the cargo-proteolipid vesicles (p. 51, 1st para. of Applicant’s specification).
Finally, Arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements regarding the inoperability of the prior art NanoAssemblr based method of Tasciotti to be adapted to the purified FAST membrane proteins and ionizable lipid combination of Duncan are not evidence without a supporting declaration.
Claims 71-73, and 75 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al., (US Patent 10,227,386, filed 9/29/2011, patented 3/12/2019, see IDS filed 3/22/2024) in view of Tasciotti et al. (US2019/0117572, filed 3/07/2018), as applied claim 64, in further view of Semple et al. (US 6,287,591, patented 9/11/2001)
As discussed previously, Duncan et al. teaches methods of making nucleic acid cargo proteolipid vesicles comprising purified recombinant FAST membrane proteins, and ionizable lipids, helper lipids, and PEGylated lipids.
However, although Duncan teaches the liposomes comprise ionizable lipids, helper lipids such as DOPE, and PEGylated lipids, they are silent with respect to formulation of comprising the ionizable lipide DODAP, the helper lipid DOPE, and a PEGylated lipid, and at a molar ratio of about 66:30:4.
In regard to instant claims, Semple teaches methods of making lipid vesicle for the encapsulation of nucleic acids comprising the ionizable lipid such as DODAP, the neutral helper lipid such as DOPE, and a PEGylated lipid, wherein the molar ratio of the ionizable lipid, the neutral helper lipid, and PEGylated lipid is 20:25:10 (Abstract, Example 1, col 25, 2nd para., Example 2, 2nd para., see also Claim 27-35 of Semple).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of preparing nucleic acid cargo-proteolipid vesicles as suggested by Duncan et al. and substitute the formulation of ionizable lipid such as DODAP, the neutral helper lipid such as DOPE, and a PEGylated lipid, wherein the molar ratio of the ionizable lipid, the neutral helper lipid, and PEGylated lipid is 20:25:10 as taught by Semple with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Semple because nucleic acid encapsulation efficiency of the nucleic acid was over 90% with the DODAP formulation (Fig. 5), and the protonatable nature of the tertiary amine of DODAP allows unincorporated lipid to be more easily removed (col 10, Section III). In regard to the molar ratios of the taught formulation, Applicant has provided no special definition of the term “about”. Thus, the Examiner has interpreted the term to encompass an order of magnitude from the claimed molar ratio. Thus, the 20:25:10 molar ratio of Semple is encompassed by the broadly recited molar ratio of about 66:30:4.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 7/30/2025 are acknowledged and have been addressed supra.
Claims 74 and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al., (US Patent 10,227,386, filed 9/29/2011, patented 3/12/2019, see IDS filed 3/22/2024) in view of Tasciotti et al. (US2019/0117572, filed 3/07/2018), and Semple et al. (US 6,287,591, patented 9/11/2001), as applied to claims 64 and 75 in further view of Suzuki et al. (IJP, 2020, 588:119792, available 8/19/2020)
As discussed previously, Duncan et al. teaches methods of making nucleic acid cargo proteolipid vesicles comprising purified recombinant FAST membrane proteins and ionizable lipids, helper lipids, and PEGylated lipids.
However, although Duncan teaches PEGylated lipids such as PE-PEG2000 with a dipalmitoyl lipid groups, the are silent with respect to DMG-PEG2000 with dimyristoyl lipid groups.
Suzuki et al. teaches a method of preparing a nucleic acid cargo lipid vesicle comprising an ionizable lipid, a helper lipid, and a PEGylated lipid. In regard to instant claims, Suzuki teaches the PEGylated lipid is DMG-PEG (Abstract, p. 119792, Materials & Methods).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of preparing nucleic acid cargo-proteolipid vesicles as suggested by Duncan et al. and substitute the dipalmitoyl (C16) PEG of Duncan for the dimyristoyl (C14) PEG of Suzuki with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Suzuki because the DMG-PEG is less immunogenic (Abstract, Fig. 1), which would be beneficial for method steps encompassing administration of the formulation of Duncan to human patients (see col 17, 4th para. of Duncan).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 7/30/2025 are acknowledged and have been addressed supra.
New Claim Rejections - 35 USC § 103
as necessitated by the addition of new Claims 87-96
Claims 71-72, 87-88, and 94-96 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al., (US Patent 10,227,386, filed 9/29/2011, patented 3/12/2019, see IDS filed 3/22/2024) in view of Tasciotti et al. (US2019/0117572, filed 3/07/2018), as applied to claim 64, in further view of DeBeer (US 10,561,610, filed 1/20/2015)
As discussed previously, Duncan et al. teaches methods of making nucleic acid cargo proteolipid vesicles comprising purified recombinant FAST membrane proteins, and ionizable lipids, helper lipids, and PEGylated lipids.
However, although Duncan teaches the liposomes comprise ionizable lipids, helper lipids such as DOPE, and PEGylated lipids, they are silent with respect to organic phase comprising the ionizable lipide DODAP, where the ionizable lipide DODAP is at 42% of the total lipids, wherein the organic phase is combined with the aqueous phast at 3:1, wherein the proteolipid vesicle has a diameter of less than 80 nm and PDI of less than 0.3.
In regard to instant claims 71-72, 87-88, and 94-96, DeBeer teaches a method for forming nucleic acid cargo carrying lipid nanoparticles comprising the NanoAssemblr microfluidic system comprising an siRNA in an aqueous solution and lipid composition in an organic solution comprising an ionizable lipid, helper lipid, and PEG-lipid, which were mixed at a 3:1 (Aq:Et) ratio (Example 1C, col 35). In regard to the ionizable lipid, DeBeer teaches the ionizable lipid is DODAP, which results in over 90% encapsulation efficiency of the siRNA (col 37, Table 1). Moreover, in regard to the mol% of the ionizable lipid, DeBeer teaches the organic solutions comprise DODAP, cholesterol, DSPC, and PEG-lipid at a 40:40:18:2 molar ratio (Example 1, col 34). Finally, DeBeer teaches the DODAP lipid nanoparticles are on average 83 nm in diameter with a PDI of 0.27 (Table 1).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of preparing nucleic acid cargo-proteolipid vesicles comprising mixing an organic phase comprising an ionizable lipid, helper lipid and PEG-lipid with the aqueous phase as suggested by Duncan in view of Tasciotti and substitute the ionizable lipid for DODAP at 40 mol % in the organic phase that is diluted 1:3 with the aqueous phase to achieve an average of 83 nm vesicles with a PDI under 0.3 as taught by DuBeer with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by DuBeer because nucleic acid encapsulation efficiency of the nucleic acid was over 90% with the DODAP formulation when diluted at the 3:1 (Aq:Et) ratio (col 37, Table 1), and the protonatable nature of the tertiary amine of DODAP serves to promote endosomal or lysosomal release of the content that are encapsulated (col 25, 4th para., col 33, 2nd para. to col 34, 2nd para.). In addition, the 80 nm diameter appears to be a natural consequence of using this mol% of DODAP with encapsulated siRNA in the NanoAssemblr system. Importantly, this slightly exceeds the diameter minimum of 50 nm as taught by Duncan so as to hold sufficient siRNA (col 16, 5th para. of Duncan). Furthermore, in regard to the amount of 40% DODAP disclosed by De Beer compared to the 42% as claimed and the average diameter of 83 nm disclosed by De Beer compared to under 80 nm as claimed, MPEP 2144.05(I) states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close, and were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al., (US Patent 10,227,386, filed 9/29/2011, patented 3/12/2019, see IDS filed 3/22/2024) in view of Tasciotti et al. (US2019/0117572, filed 3/07/2018), and DeBeer (US 10,561,610, filed 1/20/2015) as applied to claim 64 and 72, in further view of Kamrud et al (US2018/0318218, filed 5/2/2018) and Belliveau et al. (Mol Ther-Nucleic Acids, 2012, 1, e37)
As discussed previously, Duncan et al. teaches methods of making nucleic acid cargo proteolipid vesicles comprising purified recombinant FAST membrane proteins, and ionizable lipids, helper lipids, and PEGylated lipids.
However, although Duncan in view of DeBeer suggest the liposomes comprise ionizable lipids such as DODAP, helper lipids, and PEGylated lipids, they are silent with respect to ionizable lipid DODAP at 60% of the total lipids.
Kamrud teaches methods of making nucleic acid cargo-proteolipid vesicles comprising providing a nucleic acid cargo and providing an organic phase comprising an ionizable lipid such as DODAP, a bulk lipid and a helper lipid, wherein the ionizable lipid is up to 60 mol % of the lipid component ([0109-112], p. 20, Table 1, see Claims 21-23 of Kamrud).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of preparing nucleic acid cargo-proteolipid vesicles comprising the ionizable lipid of DODAP as suggested by Duncan et al. and substitute 60% DODAP as taught by Kamrud with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so since it has been held that where the general conditions of a 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 233. In regard to the reasonable expectation of success of using 60 mol% of the ionizable lipid to make the cargo carrying vesicles according with the NanoAssemblr of Tasciotti and DeBeer, DeBeer cites the prior art of Belliveau et al., (2012), who is an inventor of the NanoAssemblr system, and teaches this system can successfully use 60 mol% of an ionizable lipid to make nucleic acid carrying vesicles (Fig. 6), and makes predictably obvious this higher mol % because it allowed lower siRNA dosages to inhibit the gene of interest (p. 4, last para., Fig. 6a).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 91-93 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al., (US Patent 10,227,386, filed 9/29/2011, patented 3/12/2019, see IDS filed 3/22/2024) in view of Tasciotti et al. (US2019/0117572, filed 3/07/2018) in view DeBeer (US 10,561,610, filed 1/20/2015), as applied to claim 64 in further view of Belliveau et al. (Mol Ther-Nucleic Acids, 2012, 1, e37)
As discussed previously, Duncan et al. suggest methods of making siRNA cargo proteolipid vesicles comprising purified FAST membrane proteins, and ionizable lipids, helper lipids, and PEGylated lipids.
Although Duncan teaches a mol ratio of siRNA to total lipid (Example 12), and DeBeer teaches a weight ratio of siRNA to total lipid (Example 1C), they are silent to a specific charge ratio of siRNA to ionizable lipid.
Nevertheless, DeBeer cites the prior art of Belliveau et al., (2012) (col 7, 3rd para.).
Belliveau et al. teaches a method of preparing a siRNA cargo lipid vesicle comprising an ionizable lipid, a helper lipid, and a PEGylated lipid, and are the inventors of the NanoAssemblr system from Precision NanoSystems.
In regard to instant claims 91-93, Belliveau teaches mixing the organic phase comprising an ionizable lipid with the aqueous phase comprising the siRNA cargo at a siRNA-to-cationic lipid at varying charge ratios with a charge ratio of near .21 (i.e., nearly 5:1 ionizable lipid: nucleic acid charge ratio) (p. 5, Fig. 4, see also Fig. 6b results).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of preparing siRNA cargo-proteolipid vesicles as suggested by Duncan et al. and choose a near 5:1 ionizable lipid to siRNA cargo charge ratio as taught by Belliveau with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Belliveau because this charge ratio yielded 100% encapsulation efficiency of the siRNA (p. 3, 4th para., see Fig. 4). Furthermore, in regard to the charge ratio of 0.21 disclosed by Belliveau compared to the 0.20 (i.e., 5:1) as claimed, MPEP 2144.05(I) states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close, and were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ARTHUR S LEONARD/Examiner, Art Unit 1631