DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/21/2026 has been entered.
Previous Rejections
Applicant’s arguments, filed 03/23/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 § 112 – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims 1, 10 and 19 recite an average particle diameter of “25 to 45 nm”. There does not appear support in the originally filed disclosure for an average particle diameter of “25 to 45 nm”.
The originally filed claim 1 supports a particle diameter of 20 to 50 nm, however the individual endpoints of 25 nm and 45 nm do not appear supported. The Examiner notes that the originally filed Example 4 disclosed a particle size of 35 nm, which falls within the presently claimed range, however, one example does not provide support for the disclosure as a whole. See paragraphs [0121, 0139] where the particle sizes are more broadly defined, and for which sizes the Applicant has support for the disclosure as a whole (e.g., 20-50 nm; 80-20 nm; 60-140 nm).
Response to Arguments
Applicant's arguments filed 03/23/2026 have been fully considered but they are not persuasive.
Applicant argued support for the newly claimed 25 to 45 nm particle diameter limitation.
The Examiner disagrees. Please see the above new matter discussion.
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) 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/178343 A1, with an English translation provided by Harashima et al (US 2017/0273905 A1, herein after Harashima), in view of WO 2016/121942, with an English translation provided by Nakai et al (US 2018/0155304 A1, hereinafter Nakai) and further in view of Sato et al (Molecular Therapy, 24(4), 788-795, 2016).
Harashima taught a method for delivering an siRNA intracellularly into a cell comprising intracellularly administering the siRNA together with a lipid membrane structure [claim 4], wherein the lipid membrane structure encapsulated the siRNA [claim 5] and delivered the siRNA to a patient [claim 8]. The lipid membrane contained YSK12 (e.g., a pH-sensitive cationic lipid comprising a structure comprising two hydrocarbon chains and fatty acids bonded to the two hydrocarbon chains via ester bonds) [0084-0085]; cholesterol-based lipids [0053]; and, PEG-modified lipids [0030, 0059, 0068]. The pKa was about 7.8 to 8.2 [0049]. The particle diameter of the lipid membrane structure was about 50 nm [0079].
In order to realize efficient knockdown of a target gene in a cell, Harashima conducted various researches concerning means for efficiently delivering siRNA into cells. As a result, they found that if a lipid membrane structure such as MEND (multifunctional envelope-type nano device) is formed by using a lipid compound having two unsaturated bonds in two aliphatic acid chains and showing a high pKa due to extended carbon chains in the hydrophilic parts, extremely high endosomal escaping property thereof can be attained, and knockdown of a target gene with siRNA can be very efficiently performed with the lipid membrane structure prepared with a lipid composition containing such a lipid compound as mentioned therein the disclosure. These results were reported as a model of siRNA delivery, without limitation to the cell type [0024, 0057, 0077]
Harashima taught a particle diameter of 50 nm; though was not as specific as a diameter of 25 to 45 nm, as recited by claims 1, 10 and 19. Harashima was not specific protein expression in the liver, as recited by claims 1 and 19.
Nakai taught a cationic lipid (e.g., MEND devices prepared with cationic lipids taught [0157, 0192, 203, 207]) used as a nucleic acid (e.g., siRNA, at [0131]) delivery carrier, and a lipid membrane structure thereof encapsulating the lipid [abstract]. The particle size of the lipid membrane structure encapsulating the nucleic acid was 10 nm-300 nm. The particle size of the lipid membrane structure could be adjusted, as desired [0139].
Regarding the particle size, the differences in the claimed subject matter, and the prior art are about 50 nm, as taught by Harashima, and 10-300 nm as taught by Nakai; versus, 25 to 45 nm, as instantly recited by claims 1, 10 and 19.
Harashima was not silent as the diameter of the particle size. For example, Harashima taught particle sizes of about 50 nm. However, Harashima was not as specific as the sizes as claimed. Nevertheless, Nakai taught that this parameter was useful at 10-300 nm, a diameter that overlaps that which is instantly claimed. This parameter, and its property, is recognized to have different effects (greater or less sizing of the lipid membrane structure, adjusted as desired, as taught by Nakai, at [0139]) with changing sizes used. Thus, the general condition (the diameter) is known, and the size of the lipid membrane structure is recognized to be result effective. As such, result effective variables can be optimized by routine experimentation, and it would have been prima facie obvious to optimize the particle size of the lipid membrane present in the teachings of Harashima, as taught by Nakai et al. See MPEP 2144.05.
With the combined teachings of Harashima and Nakai, the ordinarily skilled artisan would have had a reasonable expectation of success in arriving at the claimed range of the average particle diameter.
The combined teachings of Harashima and Nakai did not teach protein expression in the liver.
Sato taught, as a sophisticated siRNA delivery system, a MEND synthesized with pH-sensitive cationic lipids (e.g., YSK13 or YSK15), and with pKa values ranging from 5.70 to 7.25 [page 788, right 3rd paragraph; page 789, left column, last paragraph], for specific and efficient delivery of siRNA to hepatocytes and liver sinusoidal endothelial cells, in order to analyze their functions in vivo directly, and for gene silencing in the liver [abstract and Introduction at the 2nd and 3rd paragraphs].
Since Harashima generally taught, as a model of efficient siRNA delivery without limitation to cell type, MEND vesicles synthesized with pH-cationic lipids, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Harashima, protein expression in the liver, as taught by Sato. The ordinarily skilled artisan would have been motivated to include a sophisticated and efficient delivery of siRNA to hepatocytes and liver sinusoidal endothelial cells, in order to analyze their functions in vivo directly, and for gene silencing in the liver, as taught by Sato at the abstract and introduction.
The combined teachings of Harashima and Sato read on claims 1, 3-10, 12-17 and 19-21.
The instant claims 1, 10 and 19 recite a pKa of 4.5 to 8.2; diameter of 25 to 45 nm.
The instant claims 9 and 18 recite a pKa of 5.85 to 6.95.
Harashima taught a pKa of 7.8 to 8.2; Nakai taught a diameter of 10 to 300 nm; Sato taught a pKa of 5.70 to 7.25. 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.
As to claims 2 and 11, the claims require 60 to 70 mol % pH-sensitive cationic lipids. Harashima taught 85 mol % pH-sensitive cationic lipid (YSK12) [0035-0036]. The ordinarily skilled artisan would have been motivated to have modified this to have been 60 to 70 mol %. Where 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 MPEP 2144.05(II)(A). In this case, the general conditions of administration of siRNA with lipid membranes containing pH-sensitive cationic lipids have been taught by the prior art (Harashima: YSK12; and, Sato: YSK13 or YSK15); as such, it would not have been inventive for the skilled artisan to have discovered the optimum mole % of pH-sensitive cationic lipid via routine experimentation.
Response to Arguments
Applicant’s arguments with respect to the instant claim(s) have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Nonstatutory Double Patenting
A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending U.S. Application No. 19/099,090.
Although the claims at issue are not identical, they are not patentably distinct from each other because the species recited in the claims of the issued patent and copending claims (lipid membrane structure for the delivery of siRNA into cells) fall within the genus (lipid membrane structure) recited in the claims of the instant application, and thus read on the instant claims.
Claims 1-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending U.S. Application No. 18/247,612, in view of WO 2015/178343 A1, with an English translation provided by Harashima et al (US 2017/0273905 A1, herein after Harashima), in view of WO 2016/121942, with an English translation provided by Nakai et al (US 2018/0155304 A1, hereinafter Nakai).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims require cholesterol-based lipids, PEG-modified lipids, a pKa of 4.5-8.2 and a lipid membrane structure of 25 to 45 nm, each of which are not required of the copending claims. Additionally, the instant claims require pH-sensitive cationic lipids that comprise a structure comprising two hydrocarbon chains and fatty acids bonded to the hydrocarbon chains via ester bonds, which are not required by the copending claims.
Harashima taught a method for delivering an siRNA intracellularly into a cell comprising intracellularly administering the siRNA together with a lipid membrane structure [claim 4], wherein the lipid membrane structure encapsulated the siRNA [claim 5] and delivered the siRNA to a patient [claim 8]. The lipid membrane contained YSK12 (e.g., a pH-sensitive cationic lipid that comprises a structure comprising two hydrocarbon chains and fatty acids bonded to the hydrocarbon chains via ester bonds) [0084-0085]; cholesterol-based lipids [0053]; and, PEG-modified lipids [0030, 0059, 0068]. The pKa was about 7.8 to 8.2 [0049]. The particle diameter was about 50 nm to 400 nm [0079].
It would have been prima facie obvious to one of ordinary skill in the art to include the teachings of Harashima within the copending claims. The ordinary skilled artisan would have been motivated to include a method for the delivery of siRNA, as taught by Harashima.
Nakai taught a cationic lipid (e.g., MEND devices prepared with cationic lipids taught [0157, 0192, 203, 207]) used as a nucleic acid (e.g., siRNA, at [0131]) delivery carrier, and a lipid membrane structure thereof encapsulating the lipid [abstract]. The particle size of the lipid membrane structure encapsulating the nucleic acid was 10 nm-300 nm. The particle size of the lipid membrane structure can be appropriately adjusted accordingly, as desired [0139].
It would have been prima facie obvious to one of ordinary skill in the art to include, within the copending claims, lipid membranes sized 10-300 nm, as taught by Nakai. The ordinarily skilled artisan would have been motivated to include lipid membranes, sized and adjusted as desired, for the delivery of nucleic acids, as taught by Nakai [abstract, 0157, 0192, 203, 207].
Claims 1-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,182,987.
Claims 1-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending U.S. Application No. 18/851,300, in view of WO 2015/178343 A1, with an English translation provided by Harashima et al (US 2017/0273905 A1, herein after Harashima), in view of WO 2016/121942, with an English translation provided by Nakai et al (US 2018/0155304 A1, hereinafter Nakai) and further in view of Sato et al (Molecular Therapy, 24(4), 788-795, 2016).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims require cholesterol-based lipids, PEG-modified lipids, a pKa of 4.5-8.2, a lipid membrane structure of 25-45 nm, and delivery to the liver, each of which are not required of the copending claims. Additionally, the instant claims require pH-sensitive cationic lipids that comprise a structure comprising two hydrocarbon chains and fatty acids bonded to the hydrocarbon chains via ester bonds, which are not required by the copending or issued claims.
Harashima taught a method for delivering an siRNA intracellularly into a cell comprising intracellularly administering the siRNA together with a lipid membrane structure [claim 4], wherein the lipid membrane structure encapsulated the siRNA [claim 5] and delivered the siRNA to a patient [claim 8]. The lipid membrane contained YSK12 (e.g., a pH-sensitive cationic lipid that comprises a structure comprising two hydrocarbon chains and fatty acids bonded to the hydrocarbon chains via ester bonds) [0084-0085]; cholesterol-based lipids [0053]; and, PEG-modified lipids [0030, 0059, 0068]. The pKa was about 7.8 to 8.2 [0049]. The particle diameter was about 50 nm [0079].
Harashima, though, was not specific protein expression in the liver, or a particle diameter of 25 to 45 nm.
Nakai taught a cationic lipid (e.g., MEND devices prepared with cationic lipids taught [0157, 0192, 203, 207]) used as a nucleic acid (e.g., siRNA, at [0131]) delivery carrier, and a lipid membrane structure thereof encapsulating the lipid [abstract]. The particle size of the lipid membrane structure encapsulating the nucleic acid was 10 nm-300 nm. The particle size of the lipid membrane structure can be appropriately adjusted accordingly, as desired [0139].
Sato taught, as a sophisticated siRNA delivery system, a MEND synthesized with pH-sensitive cationic lipids (e.g., YSK13 or YSK15) and with pKa values ranging from 5.70 to 7.25 [page 788, right 3rd paragraph; page 789, left column, last paragraph], for specific and efficient delivery of siRNA to hepatocytes and liver sinusoidal endothelial cells, in order to analyze their functions in vivo directly, and for gene silencing in the liver [abstract and Introduction at the 2nd and 3rd paragraphs].
It would have been prima facie obvious to one of ordinary skill in the art to include, within the copending claims, lipid membranes sized 10-300 nm, as taught by Nakai. The ordinarily skilled artisan would have been motivated to include lipid membranes, sized and adjusted as desired, for the delivery of nucleic acids, as taught by Nakai [abstract, 0157, 0192, 203, 207].
It would have been prima facie obvious to one of ordinary skill in the art to include the teachings of Harashima within the copending claims. The ordinary skilled artisan would have been motivated to include a method for the delivery of siRNA, as taught by Harashima.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the copending claims, protein expression in the liver. The ordinarily skilled artisan would have been motivated to include a sophisticated and efficient delivery of siRNA to hepatocytes and liver sinusoidal endothelial cells, in order to analyze their functions in vivo directly, and for gene silencing in the liver, as taught by Sato.
Response to Arguments
Applicant’s arguments with respect to the instant claim(s) have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
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/CELESTE A RONEY/ Primary Examiner, Art Unit 1612
