DETAILED ACTION
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 .
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.
Claim(s) 1, 5-8, 10-11, 13-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (International Journal of Molecular Medicine, 2019, cited in IDS) in view of Baumhof et al., (WO 2018/078053, cited in IDS).
Huang et al. teaches a method of using Keap1 mRNA to enhance sensitivity to Axitinib, “a second generation vascular endothelial growth factor receptor inhibitor”, which “selectively acts on multiple targets, blocking the proliferation of tumor cells by blocking specific targets” (p. 2044, right column, 1st full paragraph).
“A total of five randomly selected patients with RCC [renal cell carcinoma], five RCC cell lines and normal renal tubular cells were examined to detect the protein and mRNA expressions of Keap1” (Abstract).
Huang et al. further teaches, “Overexpressing Keap1 enhances cell sensitivity to Axitinib” (p. 2049, right column, last paragraph), which resulted in a decreased cell viability in a cancer cell line compared to control (p. 2051, left column, 1st paragraph). Said cell line in Huang et al. was called “ACHN” and was transfected via mRNA with “overexpressing Keap1 (p. 2045, right column, 2nd paragraph). The prior art further taught, “Overexpressing Keap1 significantly decreased the expression of Nrf2” (p. 2049, right column, 2nd paragraph). Note: Huang et al. believes Nrf2 expression to be responsible for Axitinib resistance (see p. 2052, last paragraph).
Regarding claims 14-19, these claims further define the nucleotide sequence for the KEAP1 protein. Since Huang et al. teaches Keap1 it would have been expected to have an open reading frame as per claims 14-19 since this is necessary translation of the nucleotide sequence. Further the BTB domain of Keap1 is necessary for protein homodimerization. The peptide linkers are there for structural flexibility and spatial orientation required to position bound substrates like NRF2. Accordingly, the claimed aspects regarding KEAP1 would have been expected or obviously associated with KEAP1 and therefore would have been reasonably been present and/or taken into consideration when using Keap1 for mRNA expression, especially since decreasing expression of Nrf2 is a property of Keap1. In other words, the Keap1 of Huang is reasonably expected to possess the same properties as the Keap1 of claims 14-19.
Accordingly, it would have been obvious to treat a disease by administering to a patient in need thereof a first therapeutic agent, i.e. Keap 1 mRNA, and a second therapeutic agent, i.e. Axitinib, as per claim 20, in view of Huang et al.
Huang et al. does not teach a pharmaceutical composition comprising mRNA expressing KEAP1.
Baumhof et al. teaches, “mRNA comprising lipid nanoparticles and their medical uses” (Abstract). The mRNA lipid nanoparticles are taught to be used “in the prophylaxis or treatment of infectious diseases, tumour or cancer diseases, allergies or autoimmune diseases” (p. 1, lines 3-8).
Lipid nanoparticles are taught to comprise “cationic lipids with other lipid components, such as neutral lipids, cholesterol, PEG, PEGylated lipids, and oligonucleotides” for the purpose of blocking “degradation of the RNAs in plasma and facilitate the cellular uptake of the oligonucleotides” (p. 2, lines 23-26).
Cationic lipids include “DLinDMA” (p. 109, line 19), as per claim 4.
The prior art teaches a specific embodiment of a lipid nanoparticle has a “particle size” of “70-90 nm diameter as determined by quasi-elastic light scattering using a Malvern Zetasizer Nano (Malvern, UK)” (p. 177, lines 31-33). Moreover, “the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm . . .” (p. 108, lines 16-22)
The mRNA sequence has “5’-CAP structure”; a “Poly-A-tail/sequence” of “up to about 400 adenosine nucleotides, e.g. from about 25 to about 400” (p. 12, lines 32-33); a “3’-untranslated region (3’-UTR)” (p. 13, line 9); and a “5’untranslated region (5’UTR)” (p. 13, lines 27).
Regarding claims 5-7, Baumhof et al. teaches “CAP1” (p. 12, line 2) as a 5’-CAP structure; an “α-globin” for the 3’UTR (p. 93, line 12).
Regarding claim 8, Baumhof et al. teaches, “An effective binding of the ribosomes to the ribosome binding site (Kozak sequence: SEQ ID NO: 224307 OR SEQ IDNO: 224307 or SEQ ID NO: 224308, the AUG forms the start codon) in turn has the effect of efficient translation of the mRNA” (p. 80, lines 24-25)
The lipids are taught to comprise a linker insofar as Baumhof et al. teaches, “Such a lipid-modified mRNA as defined herein typically further comprises at least one linker covalently linked with that mRNA, and at least one lipid covalently linked with the respective linker” (p. 77, lines 24-25).
Regarding claim 10, the “lipid nanoparticles would provide optimal drug:lipid ratios, protect the nucleic acid from degradation and clearance in serum, be suitable for systemic or local delivery, and provide intracellular delivery of the nucleic acid” (p. 2, lines 28-30). That being said, it would have been obvious to optimize the ratio of lipid to polynucleotide, as per claim 10, to protect the nucleic acid from degradation and clearance in serum, be suitable for systemic or local delivery, and provide intracellular delivery of the nucleic acid. Accordingly, "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, quoting In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Suitable nucleotides include “N2-methyl-pseudouridine” (p. 77, lines 13-14), as per claim 11, and “2-thio-5-methyl-cytidine”, as per claim 13.
“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)” (see MPEP 2144.07).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to combine the Keap1 of Huang et al. with the lipid nanoparticles of Baumhof et al. since Huang et al. teaches transfection of cells with Keap1 via synthetic mRNA, and the lipid nanoparticles of Baumhof et al. are designed for containing/protecting mRNA for subsequent transfection of cells. The artisan would have been motivated to use the device of Baumhof et al. in the method of Huang based on its recognized suitability for its intended use in transfecting cells.
2) Claim(s) 2-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (International Journal of Molecular Medicine, 2019, cited in IDS) in view of Baumhof et al., (WO 2018/078053, cited in IDS) as applied to claim 1 above, and further in view of Maier et al., (Molecular Therapy, 2013).
The combination of Huang et al. and Baumhof et al., which is taught above, teaches cationic lipids such as DLinDMA, but differs from claims 2-4 insofar as it does not teach that the cationic lipids are biodegradable.
Maier et al. teaches biodegradable lipids for enabling rapidly eliminated lipid nanoparticles (Ti). “A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination” (Abstract).
Biodegradability can be added to lipids via ester linkages. Maier et al. teaches, “Taken together, these design criteria pointed use toward the incorporation of ester linkages into the hydrocarbon chain of the amino lipid, thereby preserving a headgroup-linker structure with demonstrated efficacy. Ester linkages were selected as biocleavable functionalities as they generally display good chemical stability at physiologic pH but can be hydrolyzed enzymatically by esterase or lipase activity present in tissues and intracellular compartments” (p. 1571, left col. last paragraph).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to use/or add biodegradable cationic lipids, e.g. incorporate ester linkages into cationic lipids, in the lipid nanoparticles of Huang et al. and Baumhof et al. for the advantage of improving biocompatibility and/or facilitating elimination, as taught by Maier et al. The artisan would have had a reasonable expectation with the combination insofar as Baumhof et al. teaches “at least one linker covalently linked with that mRNA, and at least one lipid covalently linked with the respective linker” (p. 77, lines 24-25).
3) Claim(s) 9 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (International Journal of Molecular Medicine, 2019, cited in IDS) in view of Baumhof et al., (WO 2018/078053, cited in IDS) as applied to claim 1 above, and further in view of Geldhof (US 2020/0315967).
The combination of Huang et al. and Baumhof et al., which is taught above, differs from claims 9 and 12 insofar as it does not teach a mean polydispersity index nor a 5-methoxy-uracil for the nanoparticles.
Geldhof teaches lipid nanoparticles and an apparatus for producing lipid nanoparticles (Abstract).
The lipid nanoparticles therein are taught to have “a mean diameter between 80 nm and 100 nm” and “a polydispersity index of 0.25 or less”, e.g. “0.03” (p. 1, para. [0004]).
The reference also teaches “5-methoxy-uracil” as an alternative uracil (p. 9, para. [0084]).
“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)” (see MPEP 2144.07).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to provide a polydispersity index between 0.02 and 0.2 and 5-methocy-uracil in the combination of Huang et al. and Baumhof et al., based on their suitability for their intended used in lipid nanoparticles as taught by Geldhof.
Conclusion
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER E WEBB whose telephone number is (571)270-3287 and fax number is (571) 270-4287. The examiner can normally be reached from Mon-Fri 7-3:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Walter E. Webb
/WALTER E WEBB/Primary Examiner, Art Unit 1612
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