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 .
Election/Restrictions
Applicant's election with traverse of the compositions of Claims 1-22 in the reply filed on 11 June 2026 is acknowledged. The traversal is on the ground(s) that Compound 133 of Miracco does not read on the ionizable lipid of “Formula I” of the present claims. This is not found persuasive. Miracco Compound 133 is reproduced below.
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Compound 133 therefore possesses the 2-hydroxyethyl moiety bound to the central nitrogen of Formula I, as well as a C9 alkyl spacer corresponding to each of the (a) and (b) variables required by Formula I. X1 and X2 are hydrolysable ester linkers present in Compound 133 as are required by the present claims. Applicants are reminded that the compound of Formula I recited in Claim 1 requires each of the variable substituents R1 and R2 independently be, among others, the moiety reproduced below.
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This is the exact moiety present in Compound 133 of Miracco, meaning that Compound 133 of Miracco indeed represents an ionizable lipid of the instant claims, meaning the technical feature shared by all of the inventions is not special within the meaning of PCT Rule 13.2, unity of invention required by PCT Rule 13.1 is absent, and restriction proper. Applicants assertion that there would be no undue search burden on the examiner is irrelevant to the question of restriction in a National Stage entry from an International application and is therefore unpersuasive.
The requirement is still deemed proper and is therefore made FINAL.
Status of the Claims
Claims 1-24 and 27 are pending.
Claims 23, 24, and 27 are withdrawn from consideration as directed to a non-elected invention.
Claims 1-22 are presented for examination and rejected as set forth below.
Priority
The instant application is a National Stage entry of International application PCT/US2320/061089 filed 23 January 2023, which claims the benefit of Provisional U.S. application 63/267,084 filed 24 January 2022.
Claim Interpretation
Applicants Claims are directed to lipid nanoparticles containing an ionizable lipid of “Formula I,” reproduced below.
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Variable substituents R1 and R2 are described as any of a number of alternative branched alkanes or linear or branched alkenes. Each of X1 and X2 are generic hydrolysable linkers, separated from the central nitrogen by what the examiner assumes are variable chain length alkanes (a) and (b). Dependent claims narrow the identity of the hydrolysable linker or specify a particular lipid of Formula II as the ionizable lipid of Formula I. Additional dependent claims require the inclusion of cholesterol, a phospholipid, and a PEG-lipid, as well as limit the amounts of each component present in the composition. Additional dependent claims require the inclusion of a nucleic acid, ultimately each of a Cas9 nuclease and a backbone modified guide RNA.
Claim Rejections - 35 USC § 112(b)
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 1-22 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. Specifically, the structure of the ionizable lipid of Formula I recited by Claim 1, shown below, is of such low resolution that neither of the (a) or (b) variables recited by the claim can clearly be identified.
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Applicants are required to submit a revised claim clearly setting forth all variable substituents of the ionizable lipid of Formula I required by Claim 1.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3, reproduced below, incorporates a moiety falling outside of the scope of the Markush-type listing of acceptable substituents R1 and R2 of Claim 1, in that nothing of Claim 1 permits either R1 or R2 to be a dioctyl-methylene moiety as is recited in Claim 3.
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Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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, 4-9, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Miracco (U.S. PGPub. 2020/0071689) in view of Ciaramella (WO2017/070626).
Miracco describes lipid nanoparticles (LNP) containing mRNA encapsulated within a particle comprising a cationic lipid, a PEG-modified lipid, a sterol, and a non-cationic lipid, which in some embodiments contains between 20-60% cationic lipid, 0.5-15% PEG-modified lipid, 25-55% sterol, and 25% non-cationic lipid. [0070-72]. Miracco indicates that the cationic lipids generally fall within the structure described as “Formula (IId),” shown below. [0184].
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More specifically, Miracco describes “Compound 133,” corresponding to the presently claimed ionizable lipid of Formula I, as an exemplary embodiment of the cationic lipid for use in creating such LNP. (Pg.35).
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While describing such cationic lipids as useful in providing mRNA containing LNP where the LNP are formulated from a combination of a cationic lipid, PEG-modified lipid, a sterol, and a non-cationic lipid, the particularly claimed combination of cholesterol, PEG-lipid, and phospholipid of Claims 4-6 are not specifically identified. However, Miracco does incorporate by reference the teachings of Ciaramella concerning the formulation of LNP. [0072](referring to International application PCT/US2016/058327).
Ciaramella also describes LNP formulated from a combination of a cationic lipid, PEG-modified lipid, a sterol, and a non-cationic lipid, where the sterol is cholesterol. (Pg.14, L.21-23). The cationic lipid may, according to Ciaramella, represent between 35-65% of the LNP composition. (Pg.91, L.12-14). Phospholipids are identified by Ciaramella as suitable neutral lipids, incorporated in concentrations of between 0.5-15% of the lipid nanoparticle formulation. (Pg.92, L.29-32). Cholesterol may be included as the sterol in concentrations of about 5-50% of the LNP. (Pg.92, L.32-34). The PEG-lipid may represent between 0.5-20% of the LNP. (Pg.92, L.34 – Pg.93, L.1). A particular disclosed embodiment of the lipid nanoparticle formulations contains 57.1% cationic lipid, 7.1% phospholipid, 34.3% cholesterol, and 1.4% PEG-lipid. (Pg.91, L.4-9).
It would have been prima facie obvious for a skilled artisan at the time the instant application was filed to have used “Compound 133” as a cationic lipid to formulate LNP encapsulating mRNA, where the LNP is formed from a combination of a cationic lipid such as “Compound 133,” a phospholipid, cholesterol, and a PEGylated lipid in concentrations overlapping and falling within the values recited by the present claims. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). This is because Miracco indicates that mRNA may be encapsulated within LNP formed from a combination of a cationic lipid such as “Compound 133,” a sterol, a non-cationic helper lipid, and a PEGylated lipid, while also incorporating by reference the teachings of Ciaramella concerning the formation of LNP, which specifies the non-cationic lipid may be the phospholipids of the instant claims, and cholesterol the sterol of both Miracco and the instant claims, each of which may be used in concentrations overlapping and therefore rendering obvious the concentration ranges of instant Claim 6.
Claims 1, 2, and 4-22 are rejected under 35 U.S.C. 103 as being unpatentable over Miracco and Ciaramella as applied to claims 1, 2, 4-9, and 22 above, and further in view of Kim (Dongyoon Kim, et al, Nanovesicle-Mediated Delivery Systems for CRISPR/Cas Genome Editing, 12 Pharmaceutics 1233 (2020)) and Yin (Hao Yin, et al, Structure-Guided Chemical Modification of Guide RNA Enables Potent Non-Viral in vivo Genome Editing, 35 Nat. Biotech. 1179 (2017)).
Miracco and Ciaramella, discussed in greater detail above, suggest formulating LNP combining a cationic lipid, cholesterol, PEGylated lipid, and phospholipid according to the instant claims to encapsulate mRNA for use in treatment of disease.
Neither Miracco nor Ciaramella identify the mRNA to be encapsulated within LNP as any of the endonucleases of the instant claims, nor is the incorporation of a guide RNA, let alone a modified guide RNA required by the instant claims, identified as a suitable mRNA for inclusion in these LNP.
Kim discusses the use of liposomal nanoparticles for the delivery of CRISPR/Cas9 compositions for genome editing in disease treatment and diagnosis. Pg.2. The CRISPR/Cas9 system combines the guide RNA of the instant claims with Cas proteins to permit the insertion of modifications of genomes into host chromosomes. Id. In some forms, the guide RNA is combined with mRNA encoding the Cas proteins, rather than the proteins themselves. (Pg.3). Kim indicates that preferred liposomal delivery constructs incorporate cationic lipids in order to reduce the susceptibility of the encapsulated nucleic acids from degradation by endogenous nucleases. (Pg.4). A particular cationic liposome delivering a combination of mRNA and guide RNA combines a cationic lipid with a phospholipid, cholesterol, and PEG-lipid. (Pg. 4, “Table 1”; Pg.5).
Yin also describes the use of LNP for the encapsulation of CRISPR Cas9 RNA, guide RNA, and template RNA used for gene editing. (Pg.1179). Yin also recognizes the sensitivity of RNA to endogenous nucleases, but indicates that chemical modification of the RNA phosphate backbone, particularly by the incorporation of the presently claimed 2’OMe and 2’F sugar modifications as well as thioester groups, substantially increases nuclease resistance of these RNAs and improves in vivo function as a result. Id. Yin indicates that modification of various quantities and regions of the nucleotides of the gRNA strands of the Cas9-sgRNA complex were used to assess the degree of alteration of the crRNA. (Pg.1180-82). Yin indicates that particular modifications with phosphate thioesters demonstrates significantly improved genome editing potency. (Pg.1182). This suggests to the skilled artisan that the degree to which the sugars and backbone of the RNA molecules have been modified directly impacts the nuclease resistance and potency of genome editing the CRISPR/Cas9 systems provide, making the degree of nucleotide modification a result effective variable, and the requirements of Claim 17 obvious thereby. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that 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.).
It would have been prima facie obvious for a skilled artisan to have utilized the LNP suggested by the combined teachings of Miracco and Ciaramella to serve as the LNP encapsulating sugar and/or backbone modified CRISPR/Cas9 mRNA, gRNA, and template nucleotide sequences suggested by Kim and Yin. The skilled artisan would have been motivated to do so because the LNP suggested by Miracco and Ciaramella are described as useful for the encapsulation of mRNA, and each of Kim and Yin indicate that the use of such cationic LNP to encapsulate CRISPR/Cas9 guide and messenger as well as template RNA conveys benefits in terms of nuclease resistance. The modification of the RNA strands by the incorporation of either 2’OMe or 2’F sugar modifications or thioester backbone modifications improves not only nuclease resistance but also the potency of genome editing. While the art is silent as to the ratio of nitrogen in the lipid to phosphate groups of the RNA, this appears to represent a ratio of the quantity of lipid to quantity of RNA in the LNP, and obvious thereby. See Aller, supra. While not describing the use of LNP to separately encapsulate each of the gRNA and mRNA to be used in the CRISPR/Cas9 compositions, the art does indicate that encapsulation of these RNA sequences conveys benefits to the protection and activity of the nucleotides so encapsulated. Applicants are reminded that the duplication of parts has no patentable significance unless a new and unexpected result is obtained. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960).
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: While no claims are presently in condition for allowance, the Examiner notes that the ionizable lipid recited by Claim 3, that of “Formula II,” is free of the art and would, if incorporated into Claim 1 as a required component of the LNP claimed, distinguish the LNP claimed from that of the prior art. Applicants are advised to contact the Examiner to discuss appropriate amendments to the claims to overcome the rejections of record and place the application in condition for allowance.
Conclusion
No Claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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