DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed 12/19/2025, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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, 3, 8, 12-14, 16, 18-19, 21 are rejected under 35 U.S.C. 103 as being unpatentable over Deng et al (US 2018/0256480 A1), in view of Hernando et al (US 2014/0050803 A1).
Deng taught core-shell particles (nanoparticles, NP) having a hydrophobic core and a shell formed of hyperbranched polymers (HP). The HP, which were polyglycerols (HPG), were covalently bound to the one or more materials (polylactic acid, PLA) that formed the core, or were coated thereon the NP [abstract; claims 1-4]. The HPG was covalently bound to the PLA such that the hydrophilic HPG was oriented towards the outside of the particles, and the hydrophobic PLA was oriented to form the core [0012]. The NPs further encapsulated materials to induce an immunological response (e.g., reads on an immunostimulant therein) [0143-0144, 0361]. Effective amounts and therapeutically effective amounts were taught [claims 1 and 23; ¶s 0030, 0042, 0192, 0240-0241, 0243, 0258, 0261]. Therapeutically effective amounts for the treatment of melanoma by topical application to the skin of individuals in need thereof, was taught [¶s 0030, 0158, 0217, 0258, title; and, claims 1 and 23]. Additionally, Deng was directed to targeted administration in the treatment of melanoma [0030].
Deng was formulated for topical application in the treatment of melanoma, and did not teach intratumoral administration, as recited in claims 1, 13 and 19.
Nevertheless, Hernando taught that suitable administration routes of a pharmaceutical composition for the treatment of melanoma include, but are not limited to, topical. Hernando additionally taught intratumoral administration, wherein injecting directly into a tumor provides a desired effect [0275].
Since Deng generally taught targeted administration in the treatment of melanoma, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Deng, intratumoral administration, as taught by Hernando. The ordinarily skilled artisan would have been so motivated, because Hernando taught that suitable administration routes in the treatment of melanoma are not limited to topical, and that intratumoral administration provides a desired effect [0275].
Claim 14 is rendered prima facie obvious because Deng taught 100 nm [0057].
The instant claim 14 recites a diameter from about 5 nm to about 100 nm. Deng taught a diameter of 100 nm. 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.
Claims 16 and 18 are rendered prima facie obvious because Deng taught that the HP coating can be modified by attaching PEG to the surface of the coating. For example, HPG-coated particles can be modified by covalently attaching PEG to the surface. This can be achieved by converting the vicinyl diol groups to aldehydes and then reacting the aldehydes with functional groups on PEG, such as aliphatic amines, aromatic amines, hydrazines and thiols. The linker has end groups such as aliphatic amines, aromatic amines, hydrazines, thiols and O-substituted oxyamines [0159].
The instant claim 21 recites “wherein the nanoparticles are produced by sodium cholate-assisted emulsion”. The limitation of preparing the nanoparticles by sodium cholate-assisted emulsion is a product-by-process limitation. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.
Even though the product-by-process claims are limited by and defined by the process, the determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, then the claim is unpatentable even though the prior art product was made by a different process. In the instant case, Deng’s core-shell NPs having a hydrophobic core and a shell formed of hyperbranched polymers (HP, polyglycerols or HPG), where the HP were covalently bound to polylactic acid (PLA) that formed the core, or were coated thereon the NP. DENG’s HPG were covalently bound to the PLA such that the hydrophilic HPG was oriented towards the outside of the particles, and the hydrophobic PLA was oriented to form the core. Deng reads on the claimed nanoparticles formed of hyperbranched polyglycerol covalently bound to polylactic acid, presenting hyperbranched polyglycerol molecules on the surface of the nanoparticles. As such, the patentability of the instant formulation does not depend on its method of production, and the Applicant’s limitation regarding the nanoparticle production by sodium cholate-assisted emulsion is not patentable, in view of Deng et al. MPEP 2113.
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive. Declaration under 37 C.F.R. 1.132 of Dr. Michael Girardi has been fully considered.
Applicant and Declarant argued unexpected findings over Deng. Applicant and Declarant cited the instant Examples 4 (Figures 8A-8C) and 6-7 (Figures 10A-E, Figure 11; Figures 12-16).
The Examiner responds that the cited data demonstrates that the instant formulation accumulates in tumor draining lymph nodes, thereby enhancing the immunostimulatory potency of encapsulated MPLA, in order to remodel the tumor microenvironment, and delay tumor growth. These results appear unexpected over the closest prior art, Deng in view of Hernando [as cited].
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 instant claim 1 does not limit the immunostimulant or the tumor, and only requires an “immunostimulant” and a “tumor”. And, for both limitations, the data is not considered to be commensurate in scope.
The immunostimulant and tumor tested were MPLA and melanoma. However, it is unclear whether the effect (e.g., accumulation in tumor draining lymph nodes, to enhance the immunostimulatory potency, remodel tumor microenvironment, and delay tumor growth) would be present with other immunostimulants and tumors. It is noted that the instant claims 3 and 20 limit the immunostimulant and tumor, and are considered commensurate in scope, in this respect.
Claims 2, 4, 15, 17, 20, 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Deng et al (US 2018/0256480 A1), in view of Hernando et al (US 2014/0050803 A1) and further in view of Zhang et al (US 2013/0337066 A1).
The 35 U.S.C. 103 rejection over Deng was previously discussed.
As discussed, Deng generally taught materials encapsulated within the nanoparticles to induce an immunological response.
Deng, however, was not specific monophosphoryl lipid A, as recited in claims 2, 20, 22, 24.
Nevertheless, Zhang taught nanoparticles loaded with monophosphoryl lipid A, in order to allow the immune system to mount a strong response, in the treatment of a wide array of cancers [Example 3, especially at ¶s 0386 and 0391].
Since Deng generally taught materials incapsulated within nanoparticles in order to induce an immunological response in the treatment of cancer, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Deng, monophosphoryl lipid A, as taught by Zhang. The ordinarily skilled artisan would have been motivated to allow the immune system to mount a strong response, in the treatment of cancer, as taught by Zhang at Example 3. The ordinarily skilled artisan would recognize that monophosphoryl lipid A would load into Deng’s hydrophobic core.
Claim 15 is rendered prima facie obvious because Deng taught 100 nm [0057].
The instant claim 15 recites a diameter from about 5 nm to about 100 nm. Deng taught a diameter of 100 nm. A prima facie case of obviousness exists because of overlap, as discussed above.
Claims 17 and 23 are rendered prima facie obvious because Deng taught that the HP coating can be modified by attaching PEG to the surface of the coating. For example, HPG-coated particles can be modified by covalently attaching PEG to the surface. This can be achieved by converting the vicinyl diol groups to aldehydes and then reacting the aldehydes with functional groups on PEG, such as aliphatic amines, aromatic amines, hydrazines and thiols. The linker has end groups such as aliphatic amines, aromatic amines, hydrazines, thiols and O-substituted oxyamines [0159].
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive.
Applicant argued that Zhang does not cure the deficiencies of Deng.
The Examiner disagrees that Deng, in view of Hernando, is deficient.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Deng et al (US 2018/0256480 A1), in view of Hernando et al (US 2014/0050803 A1) and further in view of Bray et al (US 2014/0093568 A1).
The 35 U.S.C. 103 rejection over Deng was previously described.
Additionally, Deng generally taught chemotherapeutics, including cytotoxic drugs and combinations thereof [0130, 0173, 0260; claims 7, 23], in the treatment of melanoma [previously discussed].
However, Deng did not specifically teach BRAF and MEK inhibitors, as recited in claim 6.
Nevertheless, Bray taught combination therapies for treating a pathological condition, such as cancer, wherein a MEK inhibitor is combined with a BRAF inhibitor, thereby providing significant anti-tumor activity in patients having melanoma [0005].
Since Deng generally taught cytotoxic drugs, and combinations thereof, in the treatment of melanoma, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Deng, a MEK inhibitor combined with a BRAF inhibitor, as taught by Bray. The ordinarily skilled artisan would have been motivated to provide significant anti-tumor activity in patients having melanoma, as taught by Bray [0005].
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive.
Applicant argued that Bray does not cure the deficiencies of Deng.
The Examiner disagrees that Deng, in view of Hernando and Bray, is deficient.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Deng et al (US 2018/0256480 A1), in view of Hernando et al (US 2014/0050803 A1), further in view of Zhang et al (US 2013/0337066 A1) and further in view of Bray et al (US 2014/0093568 A1).
The 35 U.S.C. 103 rejection over Deng was previously described.
Additionally, Deng taught generally taught chemotherapeutics, including cytotoxic drugs and combinations thereof [0130, 0173, 0260; claims 7, 23], in the treatment of melanoma [previously discussed].
However, Deng did not specifically teach BRAF and MEK inhibitors, as recited in claim 7.
Nevertheless, Bray taught combination therapies for treating a pathological condition, such as cancer, wherein a MEK inhibitor is combined with a BRAF inhibitor, thereby providing significant anti-tumor activity in patients having melanoma [0005].
Since Deng generally taught cytotoxic drugs, and combinations thereof, in the treatment of melanoma, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Deng, a MEK inhibitor combined with a BRAF inhibitor, as taught by Bray. The ordinarily skilled artisan would have been motivated to provide significant anti-tumor activity in patients having melanoma, as taught by Bray [0005].
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive.
Applicant argued that Bray does not cure the deficiencies of Deng.
The Examiner disagrees that Deng, in view of Hernando and Bray, 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 1-4, 6-8 and 12-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,826,438, in view of Deng et al (US 2018/0256480 A1) and Hernando et al (US 2014/0050803 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims require an immunostimulant and formulation for intratumoral injection, which are not required of the issued claims.
Deng taught core-shell particles (nanoparticles, NP) having a hydrophobic core and a shell formed of hyperbranched polymers (HP). The HP, which were polyglycerols (HPG), were covalently bound to the one or more materials (polylactic acid, PLA) that formed the core, or were coated thereon the NP. The HPG was covalently bound the PLA such that the hydrophilic HPG was oriented towards the outside of the particles and the hydrophobic PLA was oriented to form the core. Therapeutically effective amounts for the treatment of melanoma by topical application to the skin of individuals in need thereof, was taught.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the issued claims, lipopolysaccharide (e.g., an immunostimulant) and effective amounts, as taught by Deng et al. The ordinarily skilled artisan would have been motivated to treat cancers, as taught by Deng.
Deng was directed to targeted administration in the treatment of melanoma.
However, Deng was formulated for topical application in the treatment of melanoma, and did not teach intratumoral administration.
Nevertheless, Hernando taught that suitable administration routes of a pharmaceutical composition for the treatment of melanoma include, but are not limited to, topical. Hernando additionally taught intratumoral administration, wherein injecting directly into a tumor provides a desired effect.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the issued claims, intratumoral administration, as taught by Hernando. The ordinarily skilled artisan would have been so motivated, because Hernando taught that suitable administration routes in the treatment of melanoma are not limited to topical, and that intratumoral administration provides a desired effect.
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive.
Applicant argued unexpected results over Deng.
The Examiner responds that the rejection over Deng is maintained (see both the Obviousness and Double Patenting rejections above). Evidence of unexpectedness was shown; however, the claims are not commensurate in scope with the showing. A terminal disclaimer is required to obviate the nonstatutory-type double patenting rejection.
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