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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 5, 2024 has been considered by the examiner.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Paragraph [0001] of the instant published application, USPgPub 2025/0235524, incorporates the following unpublished U.S. applications: 63/293,652 and 63/408,465. Paragraph [0157] incorporates the following publication: Kore et al. Bioorganic & Medicinal Chemistry 2013 21:4570-4574. Paragraphs [0176 and 0234] incorporate the following foreign applications: WO1993007883 and International Patent Application No. PCT/US2017/058619, respectively. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 2, 3, and 5 are objected to because of the following informalities: Acronyms should be spelled out prior to first use. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 3, 5, 20, and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2, 3, and 5 encompass derivatives of: cationic lipids, neutral lipids, and polymer-conjugated lipids, listed in each claim respectively. There is no definition or discussion of the intended scope or type of any of these derivatives provided in the instant specification. Since any of the listed cationic-, neutral-, and polymer-conjugated- lipids, comprise a chemical union of two or more elements, the instant derivatives and scope of intended derivatives are indeterminate and indefinite.
Instant claim 20 recites, “the first lipid nanoparticle has a diameter size when in the presence of the second lipid nanoparticle that is less than the diameter size of a lipid nanoparticle in the absence of the second lipid nanoparticle, as measured under identical conditions.” It cannot be determined whether “less than the diameter size” is referring to the first or second lipid nanoparticle. Is it intended that the diameter size of the first lipid nanoparticle (comprising RNA) is different when in the presence or absence of the second (empty) lipid nanoparticle? There is no explanation provided in the instant disclosure for the intended phenomenon. In the interest of compact prosecution, the claim is interpreted as the empty lipid nanoparticle having a lesser diameter than the first lipid nanoparticles comprising cargo. This courtesy does not preempt the requirement for a clarifying amendment.
Instant claim 21 recites, “the first lipid nanoparticle has a polydispersion index when in the presence of the second lipid nanoparticle that is less than the polydispersion index of a lipid nanoparticle in the absence of the second lipid nanoparticle.” It cannot be determined whether “less than the polydispersion index” is referring to the first or second lipid nanoparticle. Is it intended that the polydispersion index of the first lipid nanoparticle (comprising RNA) is different when in the presence or absence of the second (empty) lipid nanoparticle? There is no explanation provided in the instant disclosure for the intended phenomenon. In the interest of compact prosecution, the claim is interpreted as the empty lipid nanoparticle having a lesser polydispersion index than the first lipid nanoparticles comprising cargo. This courtesy does not preempt the requirement for a clarifying amendment.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2, 3, and 5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 2, 3, and 5 encompass derivatives of listed: cationic lipids, neutral lipids, and polymer-conjugated lipids, in each claim respectively. There is no definition or discussion of the intended scope or type of any of these derivatives provided in the instant specification. Since any of the listed cationic-, neutral-, and polymer-conjugated- lipids, comprise a chemical union of two or more elements, the instant derivatives and scope of intended derivatives are indeterminate and indefinite.
The instant disclosure does not satisfy the essential or critical feature(s) required for adequate written description for derivates of the following cationic lipids recited in instant claim 2: ALC-0315, SM-102, DLinDMA, DLin-MC3-DMA, DLin-KC2-DMA, A9, C12-200, and/or L5; or the following neutral lipids recited in instant claim 3: DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and/or SM; or the following polymer-conjugated lipids recited in instant claim 5: PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG- DMPE, PEG-DPPC, and/or PEG-DSPE. There is no sufficient number of species within the claimed genus of listed cationic-, neutral-, and polymer-conjugated- lipids that would indicate a characteristic structure for any of the derivative classes claimed that would permit a person skilled in the art to clearly recognize that applicant had possession of the genus embraced by the claimed invention. In the instant case, there is no minimal structure that is required to be maintained to achieve the desired and required function of the derivatives of each genus type claimed. In addition, there is no means available for one skilled in the art to readily identify derivatives encompassed by the instant claims. Therefore, the claimed derivatives are not adequately described in sufficient terms to satisfy the written description requirement.
Sarmah et al. (Small. 2025 Oct; 21 (43): e06812) review requisite structures of cationic-, neutral-, and PEG-polymer-conjugated- lipids and corresponding functions within lipid nanoparticle (NPL) architecture contributing to particle size, polydispersity, surface charge, morphology, cellular tropism, biodistribution, nucleic acid delivery, pharmacokinetics, clearance, therapeutic efficacy, and cytotoxicity. See section 2.1 discussing cationic lipid moieties; section 5.1 and Table 1 discussing neutral lipid moieties; Figure 2 and section 2.4, discussing PEG-Lipid Conjugates; and sections 8.1, 8.2, and 9 for discussions of minute changes to any of the LNP building blocks significantly affecting intended and/or inadvertent functions. Therefore, the precise lipid components within the multi-component LNP structure affects performance and function. In the instant case of the claimed derivatives, there is no teaching or indication of which kinds of types of materials or bonds within an individual LNP complex would result in the instant composition claimed.
The written description requirement ensures that an applicant invented the subject matter that is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure. See MPEP § 2163.
Only listed in instant claims 2, 3, and 5, but not the full breadth of the claims, meet the written description provision of 35 U.S.C. §112, first paragraph. The claimed subject matter is not sufficiently described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s) had possession of the genuses of cationic lipid derivatives, neutral lipid derivatives, and PEG-lipid derivatives claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 7-10, 13-16, and 19-23 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Karve et al. (USPgPub 2021/0275689).
Karve et al. anticipate a composition comprising a first lipid nanoparticle encapsulating a self-amplifying ribonucleic acid (RNA) encoding at least one immunogenic influenza viral antigen, see “’Remix’ formulation in Figure 9; paragraphs [0100, 0101, and 0309], as required by instant claims 1, 14, 15, and 19. Also in Figure 9, Karve et al. depict a second lipid nanoparticle that does not encapsulate a nucleic acid, see “Empty LNPs” (eLNP), required in instant claim 1.
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Each first and second lipid nanoparticle population of Karve et al. comprises an ionizable cationic lipid, selected from and encompassing: C12-200 and DLinDMA, which may be combined with MC3-, and DLinkC2DMA (derivative of DLin-KC2-DMA), in paragraph [0066], required in instant claims 2 and 7. Each first and second nanoparticle population of Karve et al. also comprises a neutral lipid, selected from DSPC, DPPC, DOPC, POPC, and DOPE in paragraph [0215], required in instant claims 3 and 7. Karve et al. teach cholesterol (steroid) is incorporated into the first and second LNP population in paragraphs [0032 and 0217-0219], recited in instant claims 1, 4, and 7. In paragraphs [0068 and 0220-0223], each first and second lipid nanoparticle population of Karve et al. also comprises a polymer (PEG)-conjugated lipid, required in instant claims 1 and 7, including DMG-PEG2K, which is at least a derivative of PEG-DMG, recited in instant claim 5. The loaded-LNP and eLMP composition of Karve et al. are in a liquid suspension or frozen, comprising about 5% to about 30% (w/v) of sucrose (cryoprotectant) in paragraph [0231], recited in instant claims 1 and 8-10. Paragraph [0137] of Karve et al. teach the RNA encoding the antigen comprises 1-methyl-pseudouridine, recited in instant claim 13. Paragraph [0025] of Karve et al. anticipate claim instant claim 16, stating the mRNA encapsulation percentage that is greater than about 80%, and that LNPs encapsulating the mRNA have a size that is at least about 5% (e.g., at least about 10%) larger in size than the preformed empty LNPs (interpretation of instant claim 20, discussed above). Paragraph [0276] of Karve et al. discusses the polydispersion index (PDI) of the loaded LNPs as less than the empty LNPs (interpretation of instant claim 21, discussed above). Also see claims 23, 24, 30, 38, 50, 75, and 82, 89, and 90 of Karve et al. Paragraphs [0126, 0127, 0231], and claims 99 and 100 of Karve et al. anticipate a method of producing a polypeptide of interest in a cell by administering the first, RNA-loaded LNPs and second eLNPs in storage buffer comprising sucrose (cryoprotectant), resulting “in an mRNA formulation with higher potency (peptide, polypeptide or protein expression) and higher efficacy (improvement of a biologically relevant endpoint) both in vitro and in vivo with potentially better tolerability as compared to the same mRNA formulation prepared without the step of preforming the lipid nanoparticles (e.g., combining the lipids directly with the mRNA). The higher potency and/or efficacy of such a formulation can provide for lower and/or less frequent dosing of the drug product”, quoted from paragraph [0127], anticipating instant claim 22. Also see paragraph [0293]. Paragraph [0113] anticipates administration to mammals, anticipating instant claim 23.
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.
Claims 11, 12, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Karve et al. as applied to claims 1-5, 7-10, 13-16, and 19-23 above, and further in view of Ball et al. (International Journal of Nanomedicine. 2017 Dec 30:305-15).
See the teachings of Karve et al. above. Karve et al. do not mention the LNP composition being lyophilized, recited in instant claim 11, lyophilized and reconstituted, recited in claim 12, or a freeze-thaw cycle of at least twice, recited in claim 18.
Ball et al. teach lyophilization and plural freeze-thaw cycles of nucleic-acid-loaded LNPs, see “Freeze–thaw studies” and “Lyophilization of LNPs”.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have lyophilized the loaded- and -empty LNP composition of Karve et al., as taught by Ball et al., to increase shelf-life and stability of LNP during storage. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have maintained the shelf-life and stability of the loaded- and empty- LNP composition of Karve et al. comprising about 30% (w/v) of sucrose (cryoprotectant) in paragraph [0231] in multiple freeze-thaw cycles, as taught by Ball et al., because Ball et al. specifically teach that the incorporation 20% (w/v) of sucrose as a cryoprotectant maintained cargo efficacy and activity within LNPs, see “Trehalose and sucrose stabilized LNPs through three freeze–thaw cycles” and Figure 2.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Alameh et al. (Immunity. Dec 2021; 54: 2877–2892.e2877) teach empty LNPs have adjuvanting activity. See the graphical abstract and Figures 1-4.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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