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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 3/27/2026 has been entered. Applicant indicates on the Request for Continued Examination (RCE) Transmittal, that the response of 3/27/2026 be considered.
Claim status
Applicant has amended Claims 64 and 84, and canceled claims 82-83.
Claims 64-81, and 84-96 are pending.
Claims 64-76, and 84-96 are under consideration.
Election/Restrictions
Applicant’s election of the following species in the reply filed on 12/16/2024 without travers has been acknowledged.
P14endop15 as the FAST polypeptide.
The ionizable lipid DODAP formulations.
Claims 77-81 directed to the cation lipid formulations have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic claim.
Withdrawn 35 USC § 103
The prior rejection of Claims 64-70, 84-86 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 (US2019/0117572, filed 3/07/2018) is withdrawn in order to incorporate the prior art of Rudzinski et al. (J. Urology, 2019, 21:S4, see IDS filed 3/27/2026).
The prior rejection of Claims 71-73, and 75 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 (US 6,287,591, patented 9/11/2001) is withdrawn
The prior rejection of 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) is withdrawn
The prior rejection of Claims 71-72, 87-88, and 94-96 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) is withdrawn
The prior rejection of Claims 89-90 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) is withdrawn
The prior rejection of Claims 91-93 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) is withdrawn
New 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 64-72, 84-88 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 Rudzinski et al. (J. Urology, 2019, 21:S4, see IDS filed 3/27/2026), De Beer (US 10,561,610, filed 1/20/2015, prior art of record), and Tasciotti et al. (US2019/0117572, filed 3/07/2018, prior art of record)
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 1-3 of Duncan). Specifically, Duncan teaches the FAST membrane protein is the p14end15 peptide (col 19, last para., col 20, 5th para., col 23, 2nd para., Examples 1 & 2, see Figs. 2-5, see again claims 1 & 2, and excerpt from Fig. 2 is below), which comprises the fragments of the p14 ectodomain and the p15 endodomain and exhibits enhanced activity over the parent FAST proteins.
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In addition, Duncan teaches the FAST membrane proteins are purified (col 31, Example 14), and describes histidine tagged constructs (col 28, 2nd para.), which allows affinity purification of the recombinant proteins. Thus, Duncan reasonably suggests making a nucleic acid cargo-proteolipid vesicle with a purified recombinant FAST protein comprising a p14 ectodomain and p15 endodomain.
In regard to the aqueous phase of making a nucleic acid cargo-proteolipid vesicle of claim 64, Duncan teaches the purified recombinant FAST proteins are provided in an aqueous detergent suspension (col 17, 2nd para, see Example 14) 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. Furthermore, Duncan teaches the method steps of providing the nucleic acid in an aqueous buffer (e.g., see Example 12).
In regard to the organic phase of making a nucleic acid cargo-proteolipid vesicle 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 et al. teach the lipid vesicles can be prepared by a number of different methods, which will be known to a person skilled in the art (col 16, lines 37-39), 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.
Nevertheless, a co-inventor of Duncan et al., in Rudzinski et al. had previously published a method of preparing a nucleic acid cargo-proteolipid vesicles comprising a FAST membrane protein using the Precision Nanosystems Nanoassembler system.
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 comprising a FAST membrane protein vesicles as taught by Duncan et al. and choose a method using the Precision Nanosystems Nanoassembler system as taught by Rudzinksi with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, it is standard practice to analyze the scientific publications of patent inventors who are also registered as authors of scientific publications, as these boundary crossing between the science and technology spheres reflect a degree of cooperation between representatives of the technological and scientific activity spheres. It goes without saying that, once non-patent references have been identified, science intensity can be disentangled in a more substantive manner. Furthermore, Rudinski teaches using the Precision Nanosystems Nanoassembler system successfully made nucleic acid cargo-proteolipid vesicles encapsulating siRNAs that yielded significant reductions in the target genes (up to about 85% inhibition compared to scrambled siRNA), which appeared to be superior to the methods of making siRNA cargo-proteiolipid vesicles of Duncan wherein only about 20% inhibition of target gene was shown (Example 17, see Fig. 23).
However, in regard to using the Precision Nanosystems Nanoassembler system as taught by Rudzinksi to make a nucleic acid cargo-proteolipid vesicles, the disclosure of Rudzinksi does teach the steps of formulating the nucleic acid cargo and the FAST protein in an aqueous solution and then using the Nanoassembr to mix the aqueous solution with the lipids in an organic solution.
Nevertheless, these were well-known steps for making nucleic acid cargo-lipid vesicles using the Precision Nanosystems Nanoassembler system.
For example, De Beer teaches a method for forming nucleic acid cargo-lipid vesicles comprising the Precision Nanosystems Nanoassembler system, wherein the nucleic acids (e.g., siRNA) are in the aqueous solution and the lipid composition (e.g., ionizable lipid, helper lipid, and PEG-lipid) are in the organic solution, which were mixed at a 3:1 (Aq:Et) ratio by the device to form a mixed phase vesicle (Example 1C, col 35). Importantly, De Beer teaches due to the controlled synthesis conditions with the two-phase mixing steps using the Nanoassemblr results in loading efficiencies of over 90% of the nucleic acid into the vesicles (col 38, 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 using the Precision Nanosystems Nanoassembler system as suggested by Duncan in view of Rudzinski, and follow the enabling disclosure of De Beer of providing an aqueous phase with the nucleic acids and an organic phase with the ionizable lipid, helper lipid, and PEGylated lipid, and then mixing with the Nanoassembler to make a mixed phase comprising the nucleic acid cargo-proteolipid vesicle with a reasonable expectation of success.
Furthermore, in regard to the steps for making proteolipid vesicles using the Precision Nanosystems Nanoassembler system were also well-known in the prior art.
For example, Tasciotti teaches a method for forming proteolipid vesicles comprising the Precision Nanosystems Nanoassembler system, wherein small membrane proteins are in the aqueous solution and the lipid composition are in the organic solution of ethanol, which were mixed by the device to form a mixed phase vesicle ([0157] of Example 1, see Fig. 1A). Importantly, Tasciotti teaches the two-phase mixing steps with the Nanoassemblr result in loading efficiencies of over 60% of the transmembrane protein into the proteoliposome (Example 1, [0187], see also Claim 5 of Tasciotti).
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 using the Precision Nanosystems Nanoassembler system as suggested by Duncan in view of Rudzinski, and follow the enabling disclosure of Tasciotti of providing an aqueous phase with the membrane proteins and an organic phase with the lipids, and then mixing with the Nanoassembler to make a mixed phase comprising the nucleic acid cargo-proteolipid vesicle with a reasonable expectation of success.
[AltContent: textbox ([img-media_image2.png])] Thus, in summary with regard to claim 64, Duncan et al., teach a nucleic acid cargo-proteolipid vesicles comprising nucleic acids, a p14endp15 FAST protein, and a mixture of ionizable, helper, and PEGylated lipids, that can be prepared by a number of different methods, which will be known to a person skilled in the art, while the inventors prior art of Rudzinski et al. generally disclose a nucleic acid cargo-proteolipid vesicles comprising nucleic acids, a FAST protein, and liposomal lipids using the Precision Nanosystems Nanoassembler system, while De Beer provides an enabling disclosure for using the Precision Nanosystems Nanoassembler system to make nucleic acid cargo-lipid vesicles wherein the nucleic acid is provided in the aqueous solution and the lipids are provide in the organic solution, and Tasciotti provides an enabling disclosure for using the Precision Nanosystems Nanoassembler system to make proteolipid vesicles wherein the protein is provided in the aqueous solution and the lipids are provide in the organic solution. Therefore, a combination of these references make predictably obvious the method of providing the nucleic acid and p14end15 FAST membrane protein in the aqueous solution and the mixture of lipids in the aqueous solution to make the nucleic acid cargo-proteolipid vesicles of Duncan in view of Rudniski (see modified Fig. 1 from Tasciotti adjacent).
In regard to claim 65-67, De Beer teaches the step of buffer exchange of the mixed phase vesicles via extensive dialysis against PBS to remove the organic solute (i.e., ethanol) and allow the pH to adjust to 7.4. This is followed by concentrating the mixed phase vesicles by anion exchange spin column to remove unencapsulated nucleic acids (col 34, 3rd para., col 35, Section C). Notably, Tasciotti also teaches ultracentrifugation and dialysis steps using an Amicon filter [0157, 0162], which also would also exchange the mixed phase comprising ethanol for a buffer, concentrate the proteolipid vesicles, and remove unincorporated membrane proteins. Accordingly, it would have been obvious to conduct these buffer exchange, concentrating, and filtering steps in the method suggested by Duncan et al. so as to produce nucleic acid cargo-proteolipid vesicles in buffer at a physiological pH without unincorporated nucleic acids and membrane proteins.
In regard to claims 68 and 94, as stated supra, De Beer teaches the Nanoassembler is set at a ratio of 3:1 of aqueous phase to organic phase to make the nucleic acid cargo-lipid vesicles, while Tasciotti teaches the Nanoassembler is set at a ratio of 2:1 of aqueous phase to organic phase to make the proteolipid vesicles. Siince the DeBeer and Tasciotti identify each of the instant aqueous and organic phases as active ingredients in making a mixed phase vesicle, and each of the phases achieve a recognized result and are therefore considered to be result effective variables, it would have been within the purview of one of ordinary skill in the art to optimize the aqueous to organic phase ratios to achieve a 3:1 ratio or thereabout as a matter of routine experimentation. Generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
In regard to claim 69, Duncan, De Beer 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, both De Beer and Tasciotti teach the organic phase comprises ethanol, which would have been an obvious choice for the organic solvent because it is efficient as dissolving a variety of lipids (see col 17, 1st para. of Duncan).
In regard to claims 71-72, 87-88 and 95-96, although Duncan teaches the lipid mixture comprises an ionizable lipid (i.e., DC-Chol), they are silent to the ionizable lipid DODAP. Nevertheless, De Beer 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, De Beer 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 et al. and substitute the ionizable lipid for DODAP at 40 mol % in the organic phase to achieve an average of 83 nm vesicles with a PDI under 0.3 as taught by De Beer with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by De Beer because nucleic acid encapsulation efficiency of the nucleic acid was over 90% with the DODAP formulation (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.
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 3/27/2026 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 p14/15 FAST membrane proteins in an aqueous buffer, and does not address the issues of solubility, function, or incorporation into the vesicle membrane.
Applicant argues that although the secondary reference of Tasciotti teaches production method for cargo-proteolipid vesicles comprising mixing lipids in an organic buffer with a crude mixture of leukocyte membrane proteins in an aqueous buffer, Tasciotti does not teach ionizable lipids nor purified recombinant FAST membrane proteins, and provides little motivation to substitute the Nanoassembler based method based on loading efficiencies of 60% for transmembrane proteins.
Finally, Applicant argues that the claimed p14endop15 FAST protein achieved unexpected results. Specifically, Applicant has demonstrated such as in Figs. 2 & 18, that the p14endo15 had significantly higher activity than either the p14 or p15 FAST proteins.
Applicant's arguments have been fully considered and they are found partially persuasive and therefore the rejection of record have been withdrawn.
However, Duncan, Tassciotti and De Beer have been reapplied in view of Rudniski, who teaches that it would have been obvious to make a nucleic acid cargo-proteolipid vesicles using the Nanoassembr system.
Thus, Duncan et al., teach a nucleic acid cargo-proteolipid vesicles comprising nucleic acids, a p14endp15 FAST protein, and a mixture of ionizable, helper, and PEGylated lipids, that can be prepared by a number of different methods, which will be known to a person skilled in the art, while the inventors prior art of Rudzinski et al. generally disclose a nucleic acid cargo-proteolipid vesicles comprising nucleic acids, a FAST protein, and liposomal lipids using the Precision Nanosystems Nanoassembler system, while De Beer provides an enabling disclosure for using the Precision Nanosystems Nanoassembler system to make nucleic acid cargo-lipid vesicles wherein the nucleic acid is provided in the aqueous solution and the lipids are provide in the organic solution, and Tasciotti provides an enabling disclosure for using the Precision Nanosystems Nanoassembler system to make proteolipid vesicles wherein the protein is provided in the aqueous solution and the lipids are provide in the organic solution. Note that similar prior art by Zinger et al. (WO2021/091582, filed 11/09/2020, with priority to 62/933,363 filed 11/08/2019) teaches using a Nanoassemblr can make neurosomes comprising the steps of providing the membrane proteins in an aqueous solution and the lipids in an organic solution (see Fig. 1 of drawings of priority document), thereby indicating that a variety of membrane proteins can be used in this system to make proteolipids with a reasonable expectation of success. Therefore, a combination of these references make predictably obvious the method of providing the nucleic acid and p14endp15 FAST membrane protein in the aqueous solution and the mixture of lipids in the aqueous solution to make the nucleic acid cargo-proteolipid vesicles of Duncan in view of Rudniski.
In regard to Applicant’s arguments that the p14endop15 FAST protein in particular achieved unexpected results, Duncan has already demonstrated that the p14end15 construct is superior to the p14 parent construct (see Fig. 3 & 4). Thus, the fact that Applicant has seen the same effect when formulated with the Nanoassemblr system indicates that the invention worked as expected.
Claims 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 Rudzinski et al. (J. Urology, 2019, 21:S4, see IDS filed 3/27/2026), De Beer (US 10,561,610, filed 1/20/2015, prior art of record), and Tasciotti et al. (US2019/0117572, filed 3/07/2018, prior art of record), as applied claim 64, in further view of Semple et al. (US 6,287,591, patented 9/11/2001, prior art of record)
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 lipid, 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 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 Rudzinski et al. (J. Urology, 2019, 21:S4, see IDS filed 3/27/2026), DeBeer (US 10,561,610, filed 1/20/2015, prior art of record), Tasciotti et al. (US2019/0117572, filed 3/07/2018, prior art of record) and Semple et al. (US 6,287,591, patented 9/11/2001), as applied to claims 64, 72 and 75 in further view of Suzuki et al. (IJP, 2020, 588:119792, available 8/19/2020, prior art of record)
As discussed previously, Duncan et al. teaches methods of making nucleic acid cargo proteolipid vesicles comprising purified recombinant FAST membrane proteins and the ionizable lipid of DODAP, 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 3/27/2026 are acknowledged and have been addressed supra.
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 Rudzinski et al. (J. Urology, 2019, 21:S4, see IDS filed 3/27/2026), DeBeer (US 10,561,610, filed 1/20/2015, prior art of record), and Tasciotti et al. (US2019/0117572, filed 3/07/2018, prior art of record), as applied to claim 64 and 72, in further view of Kamrud et al (US2018/0318218, filed 5/2/2018, prior art of record) and Belliveau et al. (Mol Ther-Nucleic Acids, 2012, 1, e37, prior art of record)
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 De Beer 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 system of Rudinksi, De Beer and Tasciotti, De Beer 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.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 3/27/2026 are acknowledged and have been addressed supra.
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 Rudzinski et al. (J. Urology, 2019, 21:S4, see IDS filed 3/27/2026), DeBeer (US 10,561,610, filed 1/20/2015, prior art of record), and Tasciotti et al. (US2019/0117572, filed 3/07/2018, prior art of record), as applied to claim 64 in further view of Belliveau et al. (Mol Ther-Nucleic Acids, 2012, 1, e37, prior art of record)
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 De Beer 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, De Beer cites the prior art of Belliveau et al., (2012) (col 7, 3rd para.).
[AltContent: textbox ([img-media_image3.png])] Belliveau et al. teaches a method of preparing a siRNA cargo-lipid vesiclea comprising an ionizable lipid, a helper lipid, and a PEGylated lipid, using the Precision NanoSystems NanoAssemblr system (see Fig. 1a excerpt adjacent).
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.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 3/27/2026 are acknowledged and have been addressed supra.
Pertinent References
[AltContent: textbox ([img-media_image4.png])]The prior art made of record and not relied upon is considered pertinent to applicant's disclosure is the following: Zinger et al. (WO2021/091582, filed 11/09/2020, with priority to 62/933,363 filed 11/08/2019) teaches using a Nanoassemblr to make neurosomes comprising the steps of providing the membrane proteins in an aqueous solution and the lipids in an organic solution (Fig. 1 of drawings of priority document, adjacent).
Conclusion
No claims are allowed.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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