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
Claims 1, 3-6, and 9-12 are pending and being examined on the merit.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/13/2026 has been entered.
New Rejections Necessitated by Claim Amendments
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, 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 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.
Claims 1, 3, 4, and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Barati et al (“Nanoliposomes carrying HER2/neu-derived peptide AE36 with CpG-ODN exhibit therapeutic and prophylactic activities in a mice TUBO model of breast cancer”, Immunology Letters, October 2017, 190:108-117), hereinafter Barati, and further in view of Razazan et al (“Conjugated nanoliposome with the HER2/neu-derived peptide GP2 as an effective vaccine against breast cancer in mice xenograft model”, PLoS ONE, October 2017, 12(10): e0185099, pp 1-22), hereinafter Razazan.
Regarding instant claims 1, 3, 4, and 9-10, Barati teaches a nanoliposomal vaccine formulation for the prophylaxis and treatment of HER2-overexpressing breast cancer, in which the HER2/neu-derived peptide AE36, Ac-GVGSPYVSRLLGICL-NH2, is formulated together with a CpG oligodeoxynucleotide (CpG-ODN) adjuvant in liposomes composed of the cationic lipid N-[1-(2, 3-Dioleoyloxy) propyl]-N, N, N-trimethylammonium methyl-sulfate (DOTAP), the phospholipid dioleoylphosphatidylethanolamine (DOPE), and cholesterol (page 108, Abstract; page 109, left column, second paragraph and §2. Materials and Methods; page 114, right column, third paragraph-page 115, left column, first paragraph; Table 1). Barati also /JULIE WU/ teaches that upon addition of CpG to the liposomes, the charge of the particles decreased due to the negative charge of the CpG molecules, which electrostatically attach to the liposome surface and neutralize the positive charge of the cationic lipid, DOTAP (page 115, left column, second paragraph). Barati further discloses that the formulation induced CD8+ and CD4+ responses, stimulated cytokine production, and exhibited therapeutic and prophylactic antitumor activity in the TUBO murine model (page 112, §3.5; page 113-114, §3.7-3.8; Figs. 4, 5, 7, and 8).
However, Barati does not teach that the phospholipid comprises a DSPE-PEG derivative, wherein the tumor-associated peptide antigen is conjugated to the DSPE-PEG derivative and oriented on the surface of the lipid nanoparticle.
The deficiency is resolved by Razazan.
Razazan teaches a liposomal vaccine composed of DMPC, DMPG, cholesterol, and DOPE containing MPL adjuvant, with the HER2/neu-derived GP2 peptide conjugated to the surface of liposomes in order to increase the CTL response and cellular immunity in a murine TUBO xenograft cancer model (page 1, Abstract; page 2, second paragraph). Razazan accomplishes this surface conjugation by covalently linking the GP2 peptide to maleimide-mPEG2000-DSPE, which is a DSPE-PEG derivative, and post-inserting the resulting peptide-PEG-DSPE conjugate into the preformed liposomes (pages 3-4, §Conjugation of GP2 peptide to PEG2000-DSPE and Preparation of nanoliposomes). Razazan also teaches that linking antigen to liposome has higher efficiency in cell mediated immunity response compared to antigen encapsulation (page 2, last paragraph). Razazan further teaches that the resulting surface-conjugated formulation elicited elevated numbers of IFN-γ producing CD8+ cells and cytotoxic T lymphocyte (CTL) responses (pages 8-9, §Induction of CTL response…-Expression of IFNγ and IL-4; Figs. 2-5), reduced tumor size (page 9, §Therapeutic assays; Fig. 7), and prolonged survival relative to other formulations (page 9, §Prophylactic assays; Fig. 6).
Regarding instant claims 1, 3, 4, and 9-10, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the DOTAP/DOPE nanoliposomal peptide vaccine of Barati by incorporating the peptide-conjugated DSPE-PEG derivative taught by Razazan. This is obvious because, Barati teaches nanoliposomal vaccine formulation for the prophylaxis and treatment of HER2-overexpressing breast cancer, in which the HER2/neu-derived peptide AE36 is formulated together with a CpG-ODN adjuvant in liposomes composed of DOTAP, DOPE, and cholesterol, and Razazan teaches conjugating a peptide to the surface of liposomes by covalently linking the peptide to maleimide-mPEG2000-DSPE, because covalent linking of an antigen to a liposome has been reported to produce a higher cell-mediated immune response than encapsulation of the antigen. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant vaccine composition for treating cancer comprising a lipid nanoparticle, wherein the instant lipid nanoparticle comprises a tumor-associated peptide antigen, a DSPE-PEG derivative, DOTAP, and a CpG oligonucleotide wherein:
The tumor-associated peptide antigen is conjugated to the DSPE-PEG derivative and oriented on the surface of the lipid nanoparticle; and
The CpG oligonucleotide is bound by electrostatic interaction to the cationic lipid.
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Barati et al (“Nanoliposomes carrying HER2/neu-derived peptide AE36 with CpG-ODN exhibit therapeutic and prophylactic activities in a mice TUBO model of breast cancer”, Immunology Letters, October 2017, 190:108-117), hereinafter Barati, and Razazan et al (“Conjugated nanoliposome with the HER2/neu-derived peptide GP2 as an effective vaccine against breast cancer in mice xenograft model”, PLoS ONE, October 2017, 12(10): e0185099, pp 1-22), hereinafter Razazan, as applied to claim 1 above, and further in view of Lee et al (Theranostics, 2016, vol. 6, p. 192-203, IDS entered on 5/2/22; hereinafter Lee).
The combined teachings of Barati and Razazan are discussed above.
However, the combined teachings of Barati and Razazan do not teach a lipid nanoparticle wherein the cationic lipid is a cationic cholesterol derivative, wherein the cationic cholesterol is mono arginine-cholesterol (MA-Chol).
The deficiency is resolved by Lee.
Lee discloses small lipid nanoparticles for the systemic delivery of anionic nucleic acid payloads in cancer therapy (page 192, Abstract; page 193, left column, second paragraph). Lee also teaches that MA-Chol has several favorable attributes as a complexing agent, such as exhibiting much lower cytotoxicity than other cationic lipids, because other cationic lipids, e.g. DC-Chol, have a non-cleavable cationic head group linked to cholesterol whereas MA-Chol is comprised of the arginine linked to cholesterol via a cleavable ester bond, yielding two nontoxic endogenous compounds upon hydrolysis—arginine and cholesterol (page 196, “Design and Synthesis of a new cationic cholesterol derivative” section).
Regarding instant claims 5 and 6, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the MA-Chol cationic cholesterol derivative of Lee for the DOTAP of the said vaccine as taught by the combined teachings of Barati and Razazan. This is obvious because, the combined teachings of Barati and Razazan teach a vaccine composition comprising a lipid nanoparticle comprising a tumor-associated peptide antigen, a DSPE-PEG derivative, DOTAP, and a CpG oligonucleotide adjuvant, and Lee discloses that MA-Chol nanoparticles exhibited much lower toxicity than typical cationic cholesterol-based lipid nanoparticles. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the said instant lipid nanoparticle comprising a tumor-associated peptide antigen, a DSPE-PEG derivative, a CpG oligonucleotide, and MA-Chol.
Claim(s) 11-12 remained rejected under 35 U.S.C. 103 as being unpatentable over Barati et al (“Nanoliposomes carrying HER2/neu-derived peptide AE36 with CpG-ODN exhibit therapeutic and prophylactic activities in a mice TUBO model of breast cancer”, Immunology Letters, October 2017, 190:108-117), hereinafter Barati, Razazan et al (“Conjugated nanoliposome with the HER2/neu-derived peptide GP2 as an effective vaccine against breast cancer in mice xenograft model”, PLoS ONE, October 2017, 12(10): e0185099, pp 1-22), hereinafter Razazan, and Lee et al (Theranostics, 2016, vol. 6, p. 192-203, IDS entered on 5/2/22; hereinafter Lee) as applied to claim 1 above, and further in view of Zhao et al (“"The application of nanoparticle-based drug delivery systems in checkpoint blockade cancer immunotherapy", Journal of immunology research, 2018, thesis no. 3673295, pp. 1-13, IDS entered on 5/2/22), hereinafter Zhao, and Pravda (US7312243B1, Priority to August 29, 2004, PTO-892).
The combined teachings of Barati, Razazan, and Lee are discussed above.
Lee further teaches loading siRNA directed against kinesin spindle protein into nanoparticles and demonstrates that systemic administration of the resulting siRNA-loaded nanoparticles to prostate tumor-bearing mice produced preferential accumulation of the delivered siRNA at the tumor site and significant inhibition in tumor growth with low toxicity.
However, the combined teachings of Barati, Razazan, and Lee do not teach the formation of a kit and the combination of the nanoparticles with anti-PD-L1 or anti-PD-1 antibodies.
The deficiency is resolved by Zhao and Pravda.
Zhao discloses the combination therapy of nanoparticles and checkpoint blockade antibodies, such as anti-PD-1 and anti-PD-L1 antibodies (pages 2-9).
Pravda discloses the formation of kits for the ease of administration to a person (page 8, col. 7, lines 10-15 and page 10, col. 12, line 65-col. 13, line 25).
Regarding instant claims 11 and 12, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the lipid nanoparticle of Barati and Razazan to further comprise an anionic nucleic acid drug as taught by Lee, and to provide the said composition of Barati, Razazan and Lee in combination with anti-PD-1 and anti-PD-L1 antibodies in a kit with the expected benefit of treating cancer as taught by Zhao and Pravda. This is obvious because, the combined teachings of Barati and Razazan teach a vaccine composition comprising a lipid nanoparticle comprising a tumor-associated peptide antigen, a DSPE-PEG derivative, DOTAP, and a CpG oligonucleotide adjuvant, Lee teaches MA-Chol nanoparticles with markedly reduced cytotoxicity relative to conventional cationic lipids, successfully delivered together with anionic nucleic acid payloads to tumors in vivo, Zhao discloses the combination therapy of nanoparticles and checkpoint blockade antibodies, such as anti-PD-1 and anti-PD-L1 antibodies, and Pravda discloses formation of kits for the ease of administration to a person is known in the art. With respect to the kit comprising a first and second vaccine composition, this is within the purview of one skilled in the art. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant cancer vaccine kit comprising the lipid nanoparticle comprising a tumor-associated peptide antigen, a DSPE-PEG derivative, DOTAP, and a CpG oligonucleotide, wherein the cancer kit comprises a first vaccine composition comprising the lipid nanoparticle and an anionic drug, and a second vaccine composition comprising the lipid nanoparticle and an immune checkpoint inhibitor, an anti-PD-1 antibody.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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