DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed 12/16/2025, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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) 1-6, 8-11,13, 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Valiante et al (US 2019/0351040 A1).
Valiante taught methods of treating brain cancer in humans [0582, 0597] comprising administering nanoparticles [0591, 0648-0649]. In some embodiments, the compositions were administered twice (e.g., Day 0 and Day 21; Day 0 and Day 14; Day 0 and Day 28) [1362-1363] (e.g., reads on every two weeks for an initial treatment period of about four weeks), followed by a booster dosage, wherein the booster was given after the earlier administration of the nanoparticles (e.g., reads on subsequent treatment period), and the time of administration between the earlier administration and the booster was once a month for 1 year [0592]. The zeta potential of the nanoparticles was about 50 mV [1332] (e.g., reads on positive surface charge).
As per Valiante, nanoparticle compositions are typically sized on the order of micrometers or smaller and can include a lipid bilayer; nanoparticle compositions include, for example, lipid nanoparticles (LNPs), liposomes, and lipoplexes. In some embodiments, nanoparticle compositions were vesicles including one or more lipid bilayers. In certain embodiments, a nanoparticle composition included two or more concentric bilayers separated by aqueous compartments (e.g., reads on a core) [1303-1304]. At ¶ [0094], Valiante taught that the disclosure was drawn to an mRNA cancer vaccine of one or more mRNA (e.g., reads on at least two nucleic acid layers; see also claim 1).
In some embodiments, the vaccine further comprised a cationic lipid nanoparticle [0103]. As a non-limiting example, a polynucleotide of the disclosure was formulated in a lipid nanoparticle comprising an ionizable lipid (e.g., a cationic lipid) [0453, 1315]. In some embodiments, the RNA vaccines were personalized, and based on mutation-derived neoepitopes to maximize specificity against a patient’s specific tumor (e.g., reads on nucleic acid derived from a cancer cell) [0166 and 0232].
In some embodiments, the RNA (e.g., mRNA) vaccine compositions were administered at dosage levels sufficient to deliver 0.0001 mg/kg to 100 mg/kg, 0.001 mg/kg to 0.05 mg/kg, 0.005 mg/kg to 0.05 mg/kg, 0.001 mg/kg to 0.005 mg/kg, 0.05 mg/kg to 0.5 mg/kg, 0.01 mg/kg to 50 mg/kg, 0.1 mg/kg to 40 mg/kg, 0.5 mg/kg to 30 mg/kg, 0.01 mg/kg to 10 mg/kg, 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 25 mg/kg, of subject body weight [1360]. Encapsulation was taught [0666]; liposomal material was taught [0666; also previously discussed; e.g., reads on the instant claim 9].
Claim 1 is rendered prima facie obvious over the teachings of Valiante, because it is prima facie obvious to combine prior art elements according to known methods, in order to yield predictable results. In the instant case, all the claimed elements (e.g., nanoparticles comprising a positive surface charge and an interior comprising a core and at least two nucleic acid layers, each positioned between a cationic lipid bilayer, wherein the nucleic acids are derived from a cancer cell) were known in the prior art (e.g., Valiante) and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results (e.g., a mRNA vaccine) to one of ordinary skill in the art. MPEP 2143.A.
The instant claim 1 recites at least two nucleic acid layers; a dose comprising about 0.00050 mg/kg to about 1.5 mg/kg of nucleic acid; dose of nanoparticles every two weeks, followed by a dose one a month.
The instant claim 2 recites at least three nucleic acid layers.
The instant claim 3 recites five or more nucleic acid layers.
The instant claim 4 recites a zeta potential of about 40 to about 60 mV.
The instant claim 5 recites a zeta potential of about 50 mV.
The instant claim 9 recites a nucleic acid dose of about 0.008 mg/kg to about 1.5 mg/kg of liposome material.
The instant claim 10 recites a nucleic acid dose of about 0.000625 mg/kg to about 0.08 mg/kg of nucleic acid.
The instant claim 11 recites a dose of about 0.000625 mg/kg of mRNA, about 0.00125 mg/kg mRNA, about 0.0025 mg/kg mRNA, about 0.005 mg/kg mRNA, about 0.01 mg/kg mRNA, about 0.02 mg/kg mRNA, about 0.04 mg/kg mRNA, or about 0.08 mg/kg mRNA.
Valiante taught one or more mRNA at dosage levels sufficient to deliver 0.0001 mg/kg to 100 mg/kg, 0.001 mg/kg to 0.05 mg/kg, 0.005 mg/kg to 0.05 mg/kg, 0.001 mg/kg to 0.005 mg/kg, 0.05 mg/kg to 0.5 mg/kg, 0.01 mg/kg to 50 mg/kg, 0.1 mg/kg to 40 mg/kg, 0.5 mg/kg to 30 mg/kg, 0.01 mg/kg to 10 mg/kg, 0.1 mg/kg to 10 mg/kg, or 1 mg/kg to 25 mg/kg; administering nanoparticles at a dosage of every two weeks, followed by a booster dosage, wherein the booster was given after the earlier administration of the nanoparticles, and the time of administration between the initial administration and the booster was 1 month. The zeta potential of the nanoparticles was about 50 mV.
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.
Valiente reads on claims 1-5 and 8-11.
The Examiner notes that Valiente was not explicit that the nucleic acids were positioned between the cationic lipids; however, the ordinarily skilled artisan would recognize that mRNA are negatively charged, and that cationic lipids are positively charged, meaning that the nucleic acids are necessarily positioned between the cationic lipids, based on the attraction of the charges.
Claim 6 is rendered prima facie obvious because Valiente taught the ratio between the lipid and the polynucleotide (e.g., mRNA) from about 10:1 to about 60:1 [1298-1300].
The instant claim 6 recites a nucleic acid to lipid ratio of about 1 to about 5 to about 1 to about 20. Valiente taught a mRNA to cationic lipid ratio from about 10:1 to about 60:1. A prima facie case of obviousness exists because of overlap, as previously discussed.
Claim 12 is rendered prima facie obvious because Valiente taught that the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations), over the course of four weeks or more [1361].
The instant claim 12 recites an initial treatment period of 3 doses over 4 weeks, and a subsequent treatment period over the course of about 12 months.
Valiente taught multiple administrations of the initial treatment over the course of 4 weeks of more, followed by a booster administration over the course of 1 year. A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 16 is rendered prima facie obvious because Valiante taught glioblastoma [0597].
Claim 19 is rendered prima facie obvious because Valiante taught, though did not require, neutral lipids.
Response to Arguments
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant argued that the Examiner did not establish that Valiante teaches or suggests a nanoparticle as defined by the claims.
The Examiner disagrees. For purposes of argument only, and not as a basis of rejection, the Examiner responds that Valiante’s nanoparticles are lipoplexes. See Valiante at ¶s [1303-1304]. For argument only, the Examiner cites Fotin-Mleczek (US 2019/0040378A1) to evidence that lipoplexes are cationic lipid bilayers sandwiched between nucleic acid (e.g., RNA) layers [Fotin-Mleczek at ¶ 0549].
Applicant argued that Valiante does not disclose the claimed dosing.
The Examiner disagrees. As discussed in the body of the rejection, Valiante taught administration twice (e.g., Day 0 and Day 21; Day 0 and Day 14; Day 0 and Day 28) (e.g., reads on every two weeks for an initial treatment period of about four weeks), followed by a booster dosage, wherein the booster was given after the earlier administration of the nanoparticles (e.g., reads on subsequent treatment period), and the time of administration between the earlier administration and the booster is once a month for 1 year.
Applicant argued that Valiante’s ¶ [1361] describes split dosing and does not describe dosages that may be delivered over the course of four weeks or more.
The Examiner disagrees. Valiante’s ¶ [1361] discloses split dosing regimens “in some embodiments”, which were not relied upon in the rejection. Valiante’s ¶ [1361] also states that the desired dosage may be delivered every four weeks or every two weeks, for a period of up to 12 months. See ¶s [1361 and 0592].
Applicant argued that Valiante offered a vast genus of potential options for administration regimens.
The Examiner is not persuaded by the Applicant’s argument because the list of administrations [0583 and 0592] in Valiante is at most 24 lines long, and even with Valiante’s doses [0097], the list is at most 30 lines long. Valiante’s list presents a “finite number of identified, predictable solutions,” expressly including at least one combination of dosage and administration encompassed by the claims. The Applicant has failed to provide a persuasive reason why it would not have been with the skill of the ordinarily skilled artisan to try the limited number of dosages and administrations, which would allow for administering nanoparticles every two weeks for an initial period of four weeks, followed by once a month for a period of twelve months, as described in Valiante.
Regarding new claim 19, the Applicant argued that Valiante’s ¶s [0697] and [1217] consistently teach neutral lipids, with an emphasis on cholesterol and neutral phospholipids.
The Examiner disagrees. Valiante’s ¶ [0697] discussed that the lipid nanoparticles comprised structural lipids and phospholipids. At ¶ [1217], the structural lipids were not limited to cholesterol, and included ursolic acid, which is not neutral. Valiante discussed phospholipids at ¶s [1144 and 1148], including phosphatidylglycerol and phophatidylserine, which are not neutral.
Claim(s) 7 is are rejected under 35 U.S.C. 103 as being unpatentable over Valiante et al (US 2019/0351040 A1), in view of Molnár et al (US 20200069786 A1).
The 35 U.S.C. 103 rejection over Valiante was previously discussed.
Although Valiante taught mRNA formulated in a lipid nanoparticle, generally comprising cationic lipids, Valiante was not specific DOTAP, as recited in claim 7.
Molnár taught mRNA vaccines prepared in cationic lipid nanoparticles, for example comprising DOTAP [0213]. 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 DOTAP for incorporation into a nanoparticle, based on its recognized suitability for its intended use as a vesicle-forming lipid, as taught by Molnár.
Response to Arguments
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant argued that Molnár does not cure the deficiencies of Valiante.
The Examiner disagrees that Valiante is deficient.
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Valiante et al (US 2019/0351040 A1), in view of Alphandéry et al (US 2022/0233723 A1).
The 35 U.S.C. 103 rejection over Valiante was previously described.
Valiante was silent the concentration of the nanoparticles, as recited in claim 14.
Alphandéry taught RNA based nanoparticles [0490] for the treatment of cancer [0748], wherein the nanoparticles were administered at a concentration that was lower than 1020, 1010, 10, 10−1, 10−5 or 10−10 ; or, larger than 10−20, 10−10, 10−1, 1, 5, 10, 103, 105 or 1010, mg of nanoparticles, per mL [0403-0404].
Since Valiante generally taught RNA nanoparticles for the general treatment of cancer, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Valiante, nanoparticles at a concentration as taught by Alphandéry. The ordinarily skilled artisan would have been motivated to treat the cancer, as taught by Alphandéry at [0403-0404].
The instant claim 14 recites about 1010 nanoparticles per mL to about 1015 nanoparticles per mL to about.
Alphandéry taught a concentration that was lower than 1020, 1010, 10, 10−1, 10−5 or 10−10 ; or, larger than 10−20, 10−10, 10−1, 1, 5, 10, 103, 105 or 1010, mg of nanoparticles, per mL. A prima facie case of obviousness exists because of overlap, as discussed above.
Response to Arguments
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant argued that Alphandéry does not cure the deficiencies of Valiante.
The Examiner disagrees that Valiante is deficient.
Claim(s) 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Valiante et al (US 2019/0351040 A1), in view of Brito et al (US 2016/0317458 A1).
The 35 U.S.C. 103 rejection over Valiante was previously discussed.
Although Valiante taught treating humans, Valiante was silent the ages, as recited in claims 17-18.
Brito taught lipids and lipid compositions for the delivery of active agents, at the title. Lipid nanoparticles were taught at [0013]; cationic lipids were taught at [0001]; one or more nucleic acids, including mRNA was taught at [0371]; the treatment of cancer was taught at [0399]. At ¶s [0598-0600], Brito taught vaccine administration to human patients, both adults and children, aged from less than 1 year old to ≥ 65 years old, in order to assess safety, dosage, immunogenicity, etc., and to induce systemic and/or mucosal immunity, furthermore, to elicit an enhanced systemic and/or mucosal immunity.
Since Valiante generally taught administering vaccines to humans, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Valiante, adult and pediatric subjects, as taught by Brito. The ordinarily skilled artisan would have been motivated to assess, within the said population, safety, dosage, immunogenicity, etc., as taught by Brito at [0598-0600].
Response to Arguments
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant argued that Brito does not cure the deficiencies of Valiante.
The Examiner disagrees that Valiante is deficient.
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 1-12, 14 and 16-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-11, 13-20, 26-28, 59-61 of copending Application No. 17/800,687, in view of Valiante et al (US 2019/0351040 A1), and further in view of Brito et al (US 2016/0317458 A1).
Claims 1-12, 14 and 16-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7-15, 17-19, 23, 25-31, 40, 43, 45-46, 49-50, 52-53 and 56-58 of copending Application No. 17/626,674, in view of Valiante et al (US 2019/0351040 A1), and further in view of Brito et al (US 2016/0317458 A1).
Claims 1-12, 14 and 16-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 13-19, 21, 27-28, 30-31, 37, 43, 63, 80, 84, 91, 93-94 and 100 of copending Application No. 17/797,810, in view of Valiante et al (US 2019/0351040 A1), and further in view of Brito et al (US 2016/0317458 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims require treating a brain tumor in humans by administering the nanoparticles for an initial treatment period of two weeks in a four week period followed by a subsequent treatment period of once a month for twelve months, wherein the humans are both adults and pediatric, and these limitations are not recited by the copending claims.
Valiante taught methods of treating brain cancer in humans comprising administering nanoparticles. In some embodiments, the compositions were administered twice, followed by a booster dosage, wherein the booster is given after the earlier administration of the nanoparticles, and the time of administration between the earlier administration and the booster is once a month for 1 year.
Although Valiante taught treating humans, Valiante was silent the ages.
Brito taught lipids and lipid compositions for the delivery of active agents. Brito taught vaccine administration to human patients, both adults and children, aged from less than 1 year old to ≥ 65 years old, in order to assess safety, dosage, immunogenicity, etc., and to induce systemic and/or mucosal immunity, furthermore, to elicit an enhanced systemic and/or mucosal immunity.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the recitation of the copending claims, a treatment schedule, as taught by Valiante. The ordinarily skilled artisan would have been motivated to treat cancer, as taught by Valiante.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the recitation of the copending claims, adult and pediatric subjects, as taught by Brito. The ordinarily skilled artisan would have been motivated to assess, within the said population, safety, dosage, immunogenicity, etc., as taught by Brito et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant argued that the Examiner did not establish a prima case of obviousness because the reference applications do not recite everything required of the instant claims.
The Examiner disagrees, and responds that the claims were rejected in view of secondary references (please see the obviousness-type double patenting rejections). The rejections are maintained. Terminal disclaimers are required to obviate the rejections.
Conclusion
THIS ACTION IS MADE FINAL. 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