DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, HK polymer of formula I and RD (SEQ ID NO: 8) for each of R1-R4 in the reply filed on November 13 2025 is acknowledged. In light of the prior art, the species election of the HK polymer has been expanded to include RB. Claims 1-15, 20, 34-35 and 47-48 are pending in the application. Claims 3-4, 9-15, 34-35 and 47-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 13 2025. Accordingly, claims 1-2, 5-8 and 20 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/US20/66878 (12/23/2020) which claims benefit of 62/952,727 (12/23/2019) as reflected in the filing receipt issued on June 26 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 21 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5-8 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (USPGPUB No. 20080171025, cited on PTO Form 1449) in view of Mockey et al. (Cancer Gene Therapy, 2007).
Applicant Claims
The instant application claims a method for inducing cellular uptake of a mRNA molecule in vivo, comprising: administering a HK polyplex, comprising a mRNA molecule bound to a HK polymer, to a mammal. As elected the HK polymer is formula I.
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The instant application claims a method for inducing cellular uptake of a mRNA molecule in vivo, comprising: administering a HK associated lipid particle, comprising a HK polymer, a lipid moiety, and a mRNA molecule, to a mammal.
The instant application claims a method for inducing cellular uptake of a mRNA molecule, comprising targeting a mammalian cell with a HK associated lipid particle under conditions permitting uptake by the cell of the HK associated lipid particle, wherein the HK associated lipid particle comprises a mRNA molecule wherein the HK polymer is of formula I and a lipid moiety wherein the lipid moiety is one or more of a liposome, micelle, fatty acyl group and cholesterol.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Mixson is directed to highly branched HK peptides as effective carriers of siRNA. A specific branched polymer taught is:
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(Fig. 1; paragraph 0051). It is taught that polymers with 4 branches, the repeating pattern of HHK (e.g. H3K4b) appears to augment uptake of siRNA more effectively than other repeating patterns (paragraph 0051). Claimed is a method of treating a patient comprising administering to the patient a therapeutically effective amount of a transfection complex wherein the transfection complex comprises siRNA and a transport polymer (claim 25). The disease could be cancer (claim 28). Therapeutic uses are suitable for use with an animal (e.g. a human ) (paragraph 0036). The term amino acid includes D-amino acids (paragraph 0024). Compositions include transfection complexes which contain the HK polymer, siRNA and a lipid. Lipids include liposomes, micelles or cholesterol (paragraph 0069, 0074-0078). In vivo therapies include local injection or intravenous (i.e. systemic) (paragraph 0030; 0064). Ratio of transport polymer to siRNA is about 0.5:1 to about 24:1 (wt:wt) (claim 17).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While the Mixson teaches delivering a nucleic acid with the HK polymer and treating cancer, Mixson does not expressly teach a mRNA. However, this deficiency is cured by Mockey et al.
Mockey et al. is directed to mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipoplexes. Systemic injections of MART1 mRNA formulated with polyethylene glycol (PEG) ylated histidine-rich polylysine and histidylated liposomes delayed significantly the growth of B16 melanoma (page 803, left column last complete paragraph). It is taught that the mRNA is complexed with the PEG-HpK (page 805, right column, first paragraph). Lipids are also taught (page 804). RNA/polymer ratio of 1:3 (wt:wt) is taught (page 804, left column, third complete paragraph).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mixson and Mockey et al. and utilize the HK polymer of Mixson with a MART1 mRNA and administer to a patient in order to treat cancer. One skilled in the art would have complexed the mRNA with the HK polymer of Mixson in order to deliver the mRNA. One skilled in the art would have been motivated to administer to a patient with cancer as Mixson expressly teaches this method. Since Mockey et al. teaches the use of the mRNA with a HK polymer, there is a reasonable expectation of success.
Regarding the claimed HK polymer, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mixson and Mockey et al. and utilize H3K4B as Mixson teaches that it can augment uptake more effectively than other repeating patterns. H3K4B reads on instantly claimed Formula I and RB.
Regarding the claimed “for inducing cellular uptake of a mRNA molecule”, this is the intended use of the instant claims. A recitation of the intended use of the claimed invention, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02 and MPEP 2145. Furthermore, Mixson teaches that the HK polymer can augment uptake suggesting the intended use.
Regarding claim 2/20, both Mixson and Mockey et al. suggest the use of lipids with the HK polymer in order to deliver the siRNA or mRNA. Administration to a human necessarily is administration to a mammalian cell. Lipids include liposomes, micelles and cholesterol.
Regarding claim 5, both Mixson and Mockey et al. teach systemic administration.
Regarding claims 6-7, as set forth above H3K4B reads on instantly claimed Formula I and RB.
Regarding claim 8, Mixson teaches a ratio of polymer to siRNA is about 0.5:1 to about 24:1; Mockey et al. teaches a RNA/polymer ratio of 1:3 (wt:wt). Therefore, the prior art teaches a ratio which anticipates (i.e. 1:3) or overlaps (0.5:1 to 24:1). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Claims 1-2, 5-8 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (USPGPUB No. 20080171025, cited on PTO Form 1449) in view of Mockey et al. (Cancer Gene Therapy, 2007), Laurent et al. (Febs Letters, 1999) and Leng et al. (Biochem Biophys Res Commun., 2016).
Applicant Claims
This rejection is solely to address the elected species of RD.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Mixson and Mockey et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Mixson suggest H3K4B and generally teaches amino acids include D-amino acids, Mixson does not expressly teach H3K4B with D-lysine. However, this deficiency is cured by Laurent et al. and Leng et al.
Laurent et al. is directed to uptake by rat liver and intracellular fate of plasmid DNA complexes with poly-L-lysine or poly-D-lysine. It is taught that complexes of DNA with poly-L-lysine and poly-D-lysine are taken up to the same extent by the liver but the intracellular degradation of nucleic acid molecules is markedly quicker when poly-L-lysine is injected. Injected plasmid DNA is more stable in vivo when it is associated with poly-D-lysine (abstract; page 64, discussion).
Leng et al. is directed to silver adducts of four branched histidine rich peptides exhibit synergistic antifungal activity. Due to the potential breakdown from proteases, H3K4b was evaluated by varying the D- and L-amino acid content in the branches (abstract). A specific compound taught is H3k4b which is the same as instantly claimed RD (Table 1). The d-lysine H3k4b has less proteolysis then the H3K4b (section 4).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mixson, Mockey et al., Laurent et al. and Leng et al. and utilize the HK polymer of Mixson with a MART1 mRNA and administer to a patient in order to treat cancer. One skilled in the art would have complexed the mRNA with the HK polymer of Mixson in order to deliver the mRNA. One skilled in the art would have been motivated to administer to a patient with cancer as Mixson expressly teaches this method. Since Mockey et al. teaches the use of the mRNA with a HK polymer, there is a reasonable expectation of success.
Regarding the claimed HK polymer, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mixson, Mockey et al., Laurent et al. and Leng et al. and utilize H3K4B as Mixson teaches that it can augment uptake more effectively than other repeating patterns. One skilled in the art would have been motivated to replace the L-lysine residues with D-lysine in order to improve stability as taught by Laurent et al. and Leng et al. Since Leng et al. teaches the same structure as instantly claimed RD and suggests it is more stable enzymatically which is also supported by Laurent et al. who teaches that poly-D-lysine when complexed with DNA is more stable provides the motivation to one skilled in the art to replace one isomer of lysine with another with a reasonable expectation of success.
Regarding the claimed “for inducing cellular uptake of a mRNA molecule”, this is the intended use of the instant claims. A recitation of the intended use of the claimed invention, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02 and MPEP 2145. Furthermore, Mixson teaches that the HK polymer can augment uptake suggesting the intended use.
Regarding claim 2/20, both Mixson and Mockey et al. suggest the use of lipids with the HK polymer in order to deliver the siRNA or mRNA. Administration to a human necessarily is administration to a mammalian cell. Lipids include liposomes, micelles and cholesterol.
Regarding claim 5, both Mixson and Mockey et al. teach systemic administration.
Regarding claims 6-7, as set forth above H3K4B reads on instantly claimed Formula I and replacement of L-lysine with D-lysine results in RD.
Regarding claim 8, Mixson teaches a ratio of polymer to siRNA is about 0.5:1 to about 24:1; Mockey et al. teaches a RNA/polymer ratio of 1:3 (wt:wt). Therefore, the prior art teaches a ratio which anticipates (i.e. 1:3) or overlaps (0.5:1 to 24:1). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636