DETAILED ACTION
Claims 1-8, 52, 54-65 and 68-70 are currently pending. Claims 9-51, 53, 66 and 67 are cancelled.
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 without traverse of Invention Group I in the reply filed on 10/29/2025 is acknowledged.
Claim 65 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 10/29/2025.
Priority
Acknowledgement is made of the instant application which claims the benefit of provisional application No. 63/264,263, filed November 18, 2021 and provisional application No. 53/374,756, filed September 7, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 28, 2023 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
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.
Claim(s) 1-5, 55-58 and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over Kanasty (NATURE MATERIALS, Vol. 12, NOVEMBER 2013, pages 967-977; see PTO-892) (“Kanasty”), in view of Benenato et al., (WO 2017/049245; see PTO-892) (“Benenato”), Sharma et al., (International Journal of Biological Macromolecules 183 (2021) 2055-2073; see PTO-892) (“Sharma”) and further in view of Benenato et al., (WO/2021/055849, published March 25, 2021; see PTO-892) (“Benenato 2021”).
Regarding claims 1-5, 55-58, and 61-64, it is initially noted that Kanasty teaches that many liposomes (lipid nanoparticles) used for delivering RNA include cationic/ionizable lipids since positively charged lipids improve the entrapment of negatively charged nucleic acids and increase cellular uptake. Kanasty notes work has continued for developing new ionizable lipids and these lipids generally comprise a three-part structure having an (1) an amine head group, (2) a linker group (esters), and (3) hydrophobic tails (Figure 4a). Kanasty acknowledges these lipids are formulated by synthesizing in a combinatorial manner that alters the three specific sections systematically in an attempt to develop structure-function correlations (page 971, left col, Cationic and ionizable lipids). Figure 4a is copied below for Applicant’s convenience:
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Kanasty does not further teach the compound of Formula (I). However, Benenato teaches the use of pharmaceutical compositions (claim 64) comprising lipid nanoparticles (LNPs, claims 55 and 64) for targeted delivery of biologically active nucleic acids (e.g., an mRNA, as recited in claims 61-62) and the lipid nanoparticles generally include one or more cationic and/or ionizable lipids, phospholipids, structural lipids and/or lipids containing polyethylene glycol (PEG lipids) (Abstract; [0002]-[0004] and [0019]).
Benenato further teaches the nanoparticle compositions comprise a lipid component including at least one compound according to various Formulas ([00133]-[00135]), including Compounds 1-232 and the nanoparticle composition includes one or more other lipids in addition to the various Formulas ([00188]-[00189]). The additional lipids include PEG lipids, e.g., PEG-DMG ([00190]) and structural lipids, e.g., cholesterol [00191]).
As to the claimed compounds (claims 1-2, 4-8, 52, 54-55 and 68), it is noted that Benenato (page 28) teaches the Formula (I) Compound 29 (page 29), which comprises ionizable lipid compounds of the general structure set forth by Kanasty.
The structure of Benenato’s Compound 29 is copied below, wherein (a) and (b) = 7 (claims 1, 4-5 and 8), (h) = 0 (claim 1), R3 and R4 = (CH2)7CH3, i=7 (claim 1):
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Although Benenato’s amine headgroup employs a tertiary amine, as compared to the claimed secondary amine headgroup, it is noted that Sharma is directed to a review of non-viral delivery of therapeutic nucleic acids (Abstract) and discusses chemical methods using cationic lipids (page 2063, 3.1.2 Chemical methods and 3.1.2.1 Cationic lipids). Sharma further acknowledges that cationic lipids used for gene delivery purposes consist of three essential components: polar headgroup, linker, and a hydrophobic tail, wherein the amine headgroup can be selected from any of primary, secondary, tertiary, or quaternary amines. Sharma acknowledges that cationic lipids can be easily modulated to impart cell specificity and environment-specific DNA release properties. Thus, Sharma has established it was well-known that primary, secondary, tertiary, or quaternary types of amines are suitable cationic lipid headgroups.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute secondary amines for tertiary amines since both types are known for use in the amine polar headgroup. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of amine group for another useful for the same purpose (providing a positively charged polar headgroup) ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
As to Benenato’s amine headgroup substituent comprising a hydroxyl group, as compared to the cyclic ether groups of the claimed substituent “A” (claims 1-3), it is noted that Benenato 2021 is directed to lipid nanoparticles comprising cationic/ionizable lipids for the delivery of therapeutic nucleic acids to mammalian cells (Abstract and [0002]). Benenato 2021 discloses lipid compounds 1-119, comprising a variety of amine group substituents that are all suitable for use in lipid nanoparticles for delivery of therapeutic nucleic acids to mammalian cells ([0082]). Benenato 2021 further discloses amine headgroup substituents comprising cyclic ether groups, e.g., tetrahydrofuran, tetrahydropyran, as set forth in cationic lipid compounds 107, 110, 112 and 114 (page 21). Compounds 107 and 110 disclose the claimed oxetane substituent (e.g., (c) and (d) = 1, (e) =0 or 1), Compound 112 discloses the claimed tetrahydrofuran (oxolane) substituent (e.g., (c) = 1 and (d) =2, (e) = 0 or 1), and Compound 114 discloses the claimed tetrahydropyran (oxane) substituent (e.g., (c) =2 and (d) =2, (e) = 0 or 1). Thus, Benenato 2021 has established that, prior to the filing of the instant application, it was known to employ oxetane, tetrahydrofuran or tetrahydropyran as amine polar headgroup substituents.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute oxetane, tetrahydrofuran or tetrahydropyran as amine polar headgroup substituents since they are known for use in the amine polar headgroup. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of amine headgroup substituent for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Regarding claim 56-58, Benenato teaches the lipid nanoparticles generally include one or more cationic and/or ionizable lipids, phospholipids (e.g., neutral lipids), structural lipids and/or lipids containing polyethylene glycol (PEG lipids) (Abstract; [0002]-[0004] and [0019]). Benenato teaches the neutral phospholipids include DSPC, DOPE and DMPC ([00193]), the structural lipids include cholesterol ([00191]) and the polymer-conjugated lipids include PEG-DMPE or PEG-C-DOMG ([00190]), thus meeting the limitations of claims 56-58.
Regarding claim 63, Benenato teaches the RNA includes modified RNA ([00173]), thus meeting the limitation of claim 63.
Claims 6-8 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Kanasty, in view of Benenato, Sharma and Benenato 2021, as applied to claims 1-5, 55-58 and 61-64 above, and further in view of Tam et al., (WO 2016/176330, published 3 November 2016; see PTO-892) (“Tam”).
The teaching of Kanasty, in view of Benenato, Sharma and Benenato 2021 is set forth above.
Regarding claim 52, it is initially noted that Benenato does not specifically exemplify the compounds recited in claim 52. However, one of the compounds recited in claim 52 is the compound bis(3-pentyloctyl) 9-(((tetrahydrofuran-3-yl)methyl)amino)heptadecanedioate (compound 3, page 30) having the following structure:
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As set forth above at the rejection of claim 1, the combination of Kanasty, Benenato and Sharma render obvious cationic lipids comprising secondary amines in the amine head group.
As to the claimed tetrahydrofuran in the amine head group, it is noted this limitation is rendered obvious above at the rejection of claim 1 by the cited reference to by Benenato 2021.
Benenato’s Compound 29 teaches (a) and (b) = 7, thus meeting the limitation of claim 52.
Further regarding claims 6, 8 and 52, although Benenato’s disclosed Compound 29 teaches h=0, and does not further teach the range of length of the alkyl linker component comprises 2 additional carbon molecules, it is noted as set forth above, Sharma teaches the linkers often influence the stability, transfection efficiency and biocompatibility of the lipid and Sharma acknowledges that cationic lipids can be easily modulated to impart cell specificity and environment-specific DNA release properties (3.1.2.1 Cationic lipids). Kanasty has further acknowledged these lipids are formulated by synthesizing in a combinatorial manner (i.e., routine optimization) that alters the three specific sections systematically in an attempt to develop structure-function correlations (page 971, left col, Cationic and ionizable lipids).
Additionally, Tam teaches lipid nanoparticles (LNP) for delivery of RNA (page 2, lines 16-18) wherein the lipid nanoparticles comprise cationic lipids that are amino lipids (page 58, lines 29-30; page 60, lines 7-8; page 61 line 5).
Tam’s cationic lipid structure identified as No. I-10 (page 70) discloses a 2-carbon alkyl group attached to the hydrophobic portion (i.e., hexane) of the lipid, which reads on h=2.
Thus, taking into hand the teachings of Sharma, Kanasty and Tam, one of ordinary skill would recognize that the range of length of the alkyl linker component can be optimized as a matter of routine experimentation, as taught by Kanasty. One of ordinary skill in the art would have found it obvious to substitute the 2-carbon alkyl group linking to the hydrophobic portion of the cationic lipid for Benenato’s linkage (h-=0) because Tam identifies a structurally similar linkage as effective in the preparation of lipid nanoparticles comprising cationic lipids for the delivery of RNA. The skilled artisan could have substituted one alkyl linkage for another because Tam teaches the linkages were both known to be suitable for preparing lipid nanoparticles for the delivery of RNA.
Further regarding claims 7-8 and 52 and the claimed length of the hydrophobic alkyl tails, i.e., R3 and R4 = (CH2)4CH3, as set forth above Benenato’s Compound 29 discloses R3 and R4 = (CH2)7CH3, i=7. However, Tam discloses hydrophobic alkyl tails ranging in length from 2-4 in structure No. I-4, from 6-8 in structure I-5, from 4-6 in structure No. I-20, for example. Thus, Tam has established it was well known that the hydrophobic alkyl tails could range from 2 to 8 carbons in length.
Therefore, one of ordinary skill would recognize that the range of length of the hydrophobic alkyl tails can be optimized as a matter of routine experimentation. One of ordinary skill in the art would have found it obvious to substitute the R3 and R4 = (CH2)4CH3 for Benenato’s hydrophobic tails having R3 and R4 = (CH2)7CH3 because Tam identifies structurally similar hydrophobic tails as effective in the preparation of lipid nanoparticles comprising cationic lipids for the delivery of RNA. The skilled artisan could have substituted one alkyl hydrophobic tail for another because Tam teaches the various lengths of hydrophobic tails were known to be suitable for preparing lipid nanoparticles for the delivery of RNA.
Claims 54 and 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Kanasty, in view of Benenato, Sharma, Benenato 2021 and Tam, as applied to claims 6-8 and 52 above, and further in view of Bull et al., (Chem. Rev. 2016, 116, 12150-12233; see PTO-892) (“Bull”).
The teachings of Kanasty, in view of Benenato, Sharma, Benenato 2021 and Tam is set forth above.
Regarding claim 54, it is noted the only difference between the compound of claim 52 and claim 54 (compound 1, page 28) is the type of cyclic ether in the amine head group, i.e., the 4-carbon cyclic ether(tetrahydrofuran) versus the 6-carbon cyclic oxetane ether of claim 54.
Although Benenato 2021 renders obvious cyclic ethers (e.g., tetrahydrofuran) in the amine head group, Benenato 2021 does not specifically teach the cyclic oxetane ether of claim 54. However, Bull teaches the oxetane ring is known as a stable motif in medicinal chemistry and has spawned the synthesis of numerous new oxetane derivatives (Abstract; Introduction, page 12150).
Therefore, one of ordinary skill in the art would have found it obvious to substitute the cyclic oxetane group for Benenato’s tetrahydrofuran because Bull identifies the cyclic oxetane group as effective in providing a stable motif in the preparation of medicinal compounds.
The person of ordinary skill in the art would have been motivated to use a cyclic oxetane group, as taught by Bull, for the predictable result of providing a stable cyclic ether motif in the amine head group, thus meeting the limitation of claim 54.
The skilled artisan would have had a reasonable expectation of success in substituting the cyclic oxetane group because Bull has shown that cyclic oxetanes are stable motifs employed in medicinal chemistry preparations.
Regarding claim 68, as set forth above at the rejection of claim 1, Benenato renders obvious lipid nanoparticles comprising cationic lipids (Abstract; [0002]-[0004] and [0019]).
Regarding claim 69-70, as set forth above at the rejection of claim 1, Benenato renders obvious pharmaceutical compositions comprising a plurality of lipid nanoparticles comprising nucleic acids (Abstract; [0002]-[0004], [0018]-[0019] and [00169]), thus meeting the limitations of claims 69-70.
Claims 59-60 are rejected under 35 U.S.C. 103 as being unpatentable over Kanasty, in view of Benenato, Sharma and Benenato 2021, as applied to claims 1-5, 55-58 and 61-64 above, and further in view of Arteta et al., (PNAS, vol. 115, no. 15, E3351-E3360; see PTO-892) (“Arteta”).
The teaching of Kanasty, in view of Benenato, Sharma and Benenato 2021 is set forth above.
Regarding claims 59-60, although Benenato teaches the polymer-conjugated lipids include PEG-DMPE ([00190]), Benenato does not further comment on the PEG-DMPE comprising PEG2000, i.e., PEG2000-DMPE, as recited in claims 59 and 60. However, Arteta is directed to methods of preparing lipid nanoparticles (LNPs) formed by an ionizable cationic lipid, helper lipids and a PEG lipid for delivery of mRNA (Abstract). Arteta specifically teaches the PEG lipid is DMPE-PEG2000 (page E3352, right col, Results, In Vitro Transfection Efficacy of LNPs of Different Size.)
One of ordinary skill in the art would have found it obvious to substitute the DMPE-PEG2000 for Benenato’s PEG-DMPE because Arteta identifies DMPE-PEG2000 as an effective conjugated PEG lipid in the preparation of lipid nanoparticles comprising cationic lipids for the delivery of RNA. The skilled artisan could have substituted one conjugated PEG lipid for another because Arteta teaches the conjugated PEG lipids were both known to be suitable for preparing lipid nanoparticles for the delivery of RNA.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633