DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed 05/01/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 - Obviousness
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.
Claim(s) 1, 13, 15, 120-121, 123, 124-125, 126-133 and 139 are rejected under 35 U.S.C. 103 as being unpatentable over John et al (WO 2019/094679 A1), in view of Fahmy et al (US 2015/0064265A1), further in view of KR 2010/0031320A and further in view of Tzianabos et al (US 2011/0052673 A1).
John taught synthetic exosomes (SEs), provided for the delivery of various therapeutic molecules to the central nervous system including, but not limited to the brain. The SEs described therein were effective to transport large molecules across the blood brain barrier (BBB), and effectively deliver the molecule to the central nervous system [0167]. The exosomes comprised liposomes [0065] ranging in size up to about 500 nm [claim 64], and further comprised a lipid bilayer [0212], phospholipids generally [claim 38], cholesterol [0010] and a non-ionic detergent [0011]. Additional phospholipids as taught were DHP [0228]; DMPC [claim 43]; and DOTAP [claim 39]. John did not teach, as a required entity, a lipid bilayer that contained an alcohol. Further, John taught that the delivery vesicles contained an enzyme, generally, as a therapeutic agent [claim 1; ¶ 0006]. SEs of various charge concentrations (zeta potentials) were created through the use of different combinations of charged phospholipid components [0228].
Although John taught phospholipids, generally, John did not teach DHPC and DHPG. John generally taught enzymes, however, John was not specific IDUA.
Fahmy taught 1,2-diheptanoyl-SN-glycero-3-phosphocholine (e.g., DHPC) as a suitable phospholipid in the manufacture of the lipid bilayer of liposomes [0095-0097]. The molar ratio of a mixture of one or more phospholipids and one or more additional lipids or sterols ranged from about 1:1 to about 6:1 [0102]. Fahmy taught small organic molecules as therapeutic agents [0083].
Since John generally taught phospholipids, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of John, DHPC, as taught by Fahmy. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. In the instant case, it is prima facie obvious to select DHPC for incorporation into a liposome, based on its recognized suitability for its intended use as a bilayer-forming lipid, as taught by Fahmy at [0095-0097].
The combination of John and Fahmy did not teach DHPG, as instantly elected.
Nevertheless, KR 2010/0031320A taught liposomes [title and abstract], comprising, as a liposome forming lipid [page 8, line 4], 1,2-Dihexanoyl- sn -Glycero-3- [Phospho- rac- (1-Glycerol)] (e.g., DHPG) [page 8, 11th line from bottom].
Since John generally taught phospholipids, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of John, DHPG, as taught by KR 2010/0031320A. In the instant case, it is prima facie obvious to select DHPG for incorporation into a liposome, based on its recognized suitability for its intended use as a liposome-forming lipid, as taught by KR 2010/0031320A at [page 8, 11th line from bottom].
The combined teachings of John, Fahmy and KR 2010/0031320A did not teach IDUA as a therapeutic moiety.
However, Tzianabos taught liposomes comprising, as a therapeutic moiety, alpha iduronidase (e.g., IDUA) [claims 17-18].
Since John generally taught enzymes as therapeutic agents, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of John, alpha iduronidase, as taught by Tzianabos. In the instant case, it is prima facie obvious to select alpha iduronidase for incorporation into a liposome, based on its recognized suitability for its intended use as a therapeutic enzyme, as taught by Tzianabos at claims 17-18.
Claim 1 is rendered prima facie obvious because Fahmy taught, as previously discussed, that the molar ratio of a mixture of one or more phospholipids and one or more additional lipids or sterols ranged from about 1:1 to about 6:1 [Fahmy at ¶ 0102]. Additionally, John’s teachings of a surfactant were previously discussed. And, John taught a zeta potential of -12 mV [see Table 3]. Furthermore, Fahmy’s and KR 2010/0031320A’s teachings of DHPC and DHPG were previously described. The motivation to combine John with each of Fahmy and KR 2010/0031320A, was previously discussed.
The instant claim 1 recites a 3:2:1 molar ratio of DHPG:DHPC:CH; the instant claims 129-130 recite a 2:2:1 molar ratio of DHPG:DHPC:CH and a zeta potential of about -20 mV or lower. The instant claim 139 recites a small organic molecule as therapeutic moiety; a 2:4:1 molar ratio of DMPC:DOTAP:CH, wherein the zeta potential is 20 mV or greater.
Fahmy taught that the molar ratio of a mixture of one or more phospholipids and one or more additional lipids or sterols ranged from about 1:1 to about 6:1. Fahmy taught small organic molecules as therapeutic agents. John taught a zeta potential of -12 mV; additionally, where the zeta potential could be created and varied, based upon the combination of charged phospholipids. A prima facie case of obviousness exists, as discussed above.
John, in view of Fahmy, KR 2010/0031320A and Tzianabos, reads on claims 1, 123,127-132 and 139.
Claims 13 and 120-121 are rendered prima facie obvious because John taught that the surfactant detergent ranged from about 5%, or from about 10% up to about 25%, or up to about 20%. In certain embodiments the surfactant/detergent was about 15% by weight [0223].
The instant claim 13 recites a surfactant range from about 1 % up to about 18 %.
The instant claim 120 recites a surfactant range from about 3 % to about 15 %.
The instant claim 121 recites a surfactant range from about 5 % up to about 13 %.
John taught that the surfactant detergent ranged from about 5%, or from about 10% up to about 25%, or up to about 20%. In certain embodiments the surfactant/detergent was about 15% by weight. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists. MPEP 2144.05 A.
Claim 15 is rendered prima facie obvious because John taught Span 80 [claims 55-56].
Claims 124-125 are rendered prima facie obvious because Fahmy taught, as suitable, cholesterol or derivatives thereof (the genus of which reads the recited species). The motivation to Fahmy with John was previously described.
Claim 126 is rendered prima facie obvious because John taught an average 150 nm diameter [claim 66].
The instant claim 126 recites a diameter that does not exceed 200 nm. John taught an average 150 nm diameter. A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 133 is rendered prima facie obvious because John taught, as a therapeutic molecule, sAPPa [0167].
Claim 138 is rendered prima facie obvious because John taught an enzyme for enzyme replacement therapy [0046].
Response to Arguments
Applicant's arguments filed 05/01/2026 have been fully considered but they are not persuasive.
Applicant argued an unexpected technical effect over the combined cited prior art, said effect due to the lipids and ratios recited in the instant claims 1, 129-131 and 139. Applicant argued approximately -10 fold or -15 fold higher levels of IDUA, compared with free IDUA (brain levels and plasma levels) with the claimed exosome.
The Examiner acknowledges the evidence relating to this unexpected result [instant Specification, Examples 2-3, Table 7 and Figure 5]. The data show that for encapsulation of IUDA with a lipid mixture of 2:2:1 (DHPG:DHPC:CH), with Span-80 concentration of 10% w/w, and with an obtained negative zeta potential, the particles showed a 10 fold increase in brain levels of IUDA, compared to free IUDA; or, a 15 fold enrichment of IUDA in the brain relative to plasma, compared with free IUDA [Table 8]. The effect (increased brain and plasma levels of IDUA protein), by the lipid combination, non-ionic surfactant concentration, molar ratio and zeta potential, is not recognized by the prior art, and thus this effect is unexpected.
However, once unexpectedness has been established, the probative value of the evidence as compared to the invention as claimed must be determined, i.e., claims must be “commensurate in scope” with the showing. See MPEP 716.02(d). In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. And this is not considered to be the case with the instant claims.
The delivery vesicle tested was encapsulation of IUDA with a lipid mixture of 2:2:1 (DHPG:DHPC:CH), a Span-80 concentration of 10% w/w, and with an obtained negative zeta potential. However, other phospholipids, molar ratios and concentrations of the non-ionic surfactant would be expected to interact differently, and it is unclear whether the effect would be present when there are different conditions (e.g., lipids, ratios, encapsulated moiety, surfactant concentrations and zeta potentials). Thus, the data show that the particular combination (e.g., IUDA, 2:2:1 (DHPG:DHPC:CH), 10 % Span-80 concentration, negative zeta potential) influences brain or plasma uptake, but the instant claims 1, 129 and 139 are not so limited. It is noted that the instant claims 130-131 are considered commensurate in scope in this respect. Additionally, the Examiner recommends further limiting the non-ionic surfactant concentration to 10 %, and further limiting the zeta potential to -20 mV or lower.
Claim 122 is rejected under 35 U.S.C. 103 as being unpatentable over John et al (WO 2019/094679 A1), in view of Fahmy et al (US 2015/0064265A1), further in view of KR 2010/0031320A, further in view of Tzianabos et al (US 2011/0052673 A1) and further in view of Nishimura et al (USP 12,514,929).
The 35 U.S.C. 103 rejection over John, Fahmy, KR 2010/0031320A and Tzianabos was previously described.
John generally described non-ionic detergents, as previously discussed; however, the combined teachings of the prior art were not specific sorbitan monooleate, as recited in claim 122.
Nishimura taught drug delivery vehicles (e.g., liposome with lipid bilayer, cholesterol, non-ionic detergent, 1st and 2nd phospholipids) for trans-blood brain barrier drug delivery [claim 1], comprising sorbitan monooleate as the non-ionic detergent [claims 7-8]. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. In the instant case, it is prima facie obvious to select sorbitan monooleate for incorporation into a drug vesicle for delivery across the blood brain barrier, based on its recognized suitability for its intended use as a non-ionic detergent, as taught by Nishimura, at claims 7-8.
Response to Arguments
The rejection over Nishimura is newly applied, and has not been traversed.
Claims 134-137 are rejected under 35 U.S.C. 103 as being unpatentable over John et al (WO 2019/094679 A1), in view of Park et al (Nature Neuroscience, 22, 2019, 524-528).
The 35 U.S.C. 103 rejection over John was previously described.
Additionally, John was drawn to the inhibition of BACE [see claim 8], in the treatment of Alzheimer’s disease [¶s 0002-0003, 0005, 0019, 0172, 0174].
John, though, did not teach components of a CRISPR/Cas system for the treatment of Alzheimer’s disease, as recited in claim 87.
Park taught that in vivo gene editing in post-mitotic neurons of the adult brain is a useful strategy for treating neurological diseases. Park developed CRISPR–Cas9 nanocomplexes to target Bace1 suppressed amyloid beta (Aβ)-associated pathologies, and cognitive deficits, in mouse models of Alzheimer’s disease. The CRISPR-Cas9 system was effective in the adult mouse brain, with minimal off-target effects [abstract].
Additionally, Park examined the effects of the Cas9-Bace1 nanocomplex in a second Alzheimer’s disease model. Consistent with previous results, Cas9-Bace1 nanocomplex treatment of these mice decreased the number of Bace1+ cells, reduced Aβ42 secretion, and ameliorated cognitive deficits relative to controls [page 528, 1st paragraph]. These results broaden the application of CRISPR–Cas9 systems to neurodegenerative diseases [abstract].
Since John generally taught the inhibition of BACE, in the treatment of Alzheimer’s disease, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of John, components of a CRISPR/Cas system for the treatment of Alzheimer’s disease, as taught by Park. The ordinarily skilled artisan would have been motivated, in the treatment of Alzheimer’s disease, to target Bace1 suppressed amyloid beta (Aβ)-associated pathologies and cognitive deficits; and, to decrease the number of Bace1+ cells, while reducing Aβ42 secretion, and ameliorating cognitive deficits, as taught by Park [abstract and page 528 at the 1st paragraph].
Response to Arguments
Applicant did not traverse the rejection over Park et al.
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 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.
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/CELESTE A RONEY/Primary Examiner, Art Unit 1612
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