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 Status
Claims 1-19 were filed on 02/15/2024. No preliminary amendment was filed.
Claims 1-19 are currently pending and under examination.
Priority
The instant application claims domestic benefit to provisional application no. 63/445,854 filed on 02/15/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/24/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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 1-14 and 16-19 is 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.
Claim 1 recites a method to produce a compound with the structure recited as “wherein the R1 and R2 groups are linear, branched and/or cyclic, optionally substituted C3 to C30 alkyl groups, optionally comprising 0-3 carbon-carbon double bonds, optionally comprising heteroatoms selected from N, O, and/or S, optionally comprising homocyclic or heterocyclic ring structures” for describing variables R1 and R2 in the body of the claim below the recited ketone structure. The term “comprising”, recited multiple times in the above limitation, is indefinite because it leads to ambiguity as to what is included in the recited groups of R1 and R2, and one of ordinary skill in the art would not be able to identify what other unrecited chemical moieties are encompassed by the claimed compound. Therefore, the scope of the R1 and R2 groups, as recited in claim 1, are indefinite.
Claims 2-14 and 16-18, which depend upon claim 1, are also found to be indefinite for the same reasons as described above.
Claim 19 also recites the same limitation described above and is found to be indefinite for the same reasons as described above.
Furthermore,
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claim 14 recites “Z is a group selected from structures a-c below:”
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and further recites “Group XYZ, wherein the wavy line represents the bond to W2, is a group chosen from among structures d-i below:” with structures provided (shown above and below). The structures a-i include variables “m” and “n” which are not defined in the claim. Since the variables are undefined, one of ordinary skill in the art would not be able to identify the scope of the undefined variables “m” and “n” and, therefore, the structures of claim 14 are indefinite.
Regarding claim 19, attempts to claim a process without setting forth any steps involved in the process generally raise an issue of indefiniteness under 35 U.S.C 112(b) or pre-AIA 35 U.S.C. 112, second paragraph (see MPEP 2173.05(q)).
Claim 19 recites “use of a double alkylated nucleophilic intermediate to produce an ionizable, cationic amino lipid” but does not recite any active, positive steps delimiting how this use is actually practiced. Therefore, claim 19 is indefinite.
Claim 19 is being interpreted as a method for synthesis of an “ionizable, cationic amino lipid” that uses the double alkylated nucleophilic intermediate of instant claim 19.
Claim Rejections - 35 USC § 112(a)
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.
Claim 1 is 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.
Claim 1 recites “a method for producing an ionizable, cationic amino lipid” and further recites “wherein the ionizable, cationic amino lipid has (i) a pKa of between 6 and 7.5; and (ii) a logP of at least 11.” Therefore, claim 1 lacks written description because the pKa and logP of the ionizable, cationic amino lipid is a function of the lipid and the claim does not provide any structure to be correlated with the function.
MPEP § 2163 states an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.
MPEP § 2163 further states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey to arrive at the claimed ionizable, cationic amino lipid having (i) a pKa of between 6 and 7.5 and (ii) a logP of at least 11.
Scope of the claims
Claim 1 is drawn to a method for producing an ionizable, cationic amino lipid with the active steps of (i) reacting a double alkylated nucleophilic intermediate under conditions effective to convert the intermediate to a ketone and (ii) preparing the ionizable, cationic amino lipid from the ketone using one or more synthetic steps resulting in an addition of an ionizable head moiety, thereby producing the ionizable, cationic amino lipid which has a protonatable amino head group and comprises two lipophilic chains comprising R1 and R2 respectively. R1 and R2 groups are defined as linear, branched and/or cyclic, optionally substituted C3 to C30 alkyl groups, optionally comprising 0-3 carbon-carbon double bonds, optionally comprising heteroatoms selected from N, O, and/or S, optionally comprising homocyclic or heterocyclic ring structures; and wherein R1 and R2 are identical or different. The scope of claim 1 includes a broad scope of ionizable, cationic amino lipids wherein R1 and R2 are as defined above and are identical or different and the head group is any protonatable amine which is further defined by the functions of (i) a pKa of between 6 and 7.5 and (ii) a logP of at least 11.
Description of Representative Species in the Specification
Claim 15 recites the specific examples of ionizable, cationic amino lipids to include KC2 and MC3 (shown in Scheme 1 of the instant specification). Neither the claims nor the specification discuss the pKa or the logP of KC2 or MC3. However, the art teaches the pKa of KC2 is approximately 6.7 (see Jayaramen et al. discussed below in Table 1, ID 1) and the pKa of MC3 is approximately 6.4 (see Jayaramen et al. discussed below in Table 1, ID 16) which would fall into the recited range of 6 to 7.5. Regarding the logP of KC2, the art teaches calculated logP values which are dependent on the calculation method used. An example of a calculated logP calculated using XLogP3 3.0 by PubChem et al. is 15.7 (NPL, published 06/18/2019, PTO-892). The logP of MC3 is also only known computational and varies depending on the computational method used. For example Chem Scene et al. (NPL, published 2026, PTO-892) teaches a calculated logP of 13.6 while Pan et al. (NPL, published 05/05/2026, PTO-892) teaches a logP of 10.79 (see section 3.4). No examples are disclosed of ionizable, cationic amino lipids being tested for a pKa of between 6 and 7.5 and a logP of at least 11. There is no guidance disclosed on how to achieve the recited pKa and logP.
State of the Relevant Art
Jayaraman et al. (NPL, published 07/10/2012, IDS dated 05/24/2024) teaches 56 different amino lipid structures and their corresponding pKas ranging from 4.17 to 8.12 (see Table 1 shown below). Amino lipid pKa values were determined for each LNP by measuring the fluorescence of 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) during titration from pH 3 to 10 in increments of 0.5 pH units (Supporting Information, page 40). To further investigate the pKa–activity relationship, a selected group of lipids were studied in more detail. These novel lipids were designed around the structure of dilinoleylmethyl-4-dimethylaminobutyrate (16, ED50=0.03 mg kg−1, pKa=6.44) also referred to as DLin-MC3-DMA, one of the most active cationic lipids from the group of 56 lipids. In the first group of lipids (31, 30, 38, and 37), the distance between ester and amine is maintained at three methylene units and the substitution on the N-atom altered to create a pKa range between 5.44 and 7.62. In the second group (14, 15, 17, and 18), the dimethylamino moiety is maintained but the distance between the ester and the amine is varied from one to five methylene units to generate lipids with pKa values ranging from
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4.17 to 7.16 (see page 8530-8531).
Sun et al. (NPL, published 01/04/2023, PTO-892) teaches cationic lipids, which have permanent positive charges, can facilitate better electrostatic interactions with negatively charged cell membrane, but are cytotoxic due to their permanent positive charges and amphiphilicity, which causes cytotoxicity by dissolving lipid bilayer cell membrane. Neutral amino lipids such as DODMA and DODAP were then developed to reduce the cytotoxicity of the cationic lipids with permanent changes. The concept of pH-sensitive protonatable or ionizable amino lipids for pH-sensitive amphiphilic endosomal escape was first introduced in the design of the multifunctional pH-sensitive protonatable or ionizable lipids and systemically demonstrated with these lipids (see bottom of page 41). The pH-sensitive protonatable or ionizable lipids are neutral at physiological pH and are protonated or ionized at acidic endosomal pH to become amphiphilic to destabilize the endosomal membrane for endosome escape. It is shown that the structures of both amino head group and lipid tails are essential to control the pH sensitivity and pH dependent cell membrane destabilization. The amino lipids EHCO and ECO with a small amino head group, ethylenediamine, and unsaturated oleoyl tails exhibited the best pH sensitivity in the pH range of 5.4–7.4. ECO shows effective pH-sensitive cell membrane destabilization and mediates efficient endosomal escape for cytosolic delivery of nucleic acids. The concept has now been broadly adopted in the design and development of ionizable lipids to promote membrane destabilization and facilitate endosomal escape of LNP. Since the pH-sensitivity of ionizable lipid plays a crucial role in gene delivery using LNPs, the pKa of the head group has significant impact on the pH-sensitivity. It has been shown that the most effective amino lipids have a pKa around 6.5 and the lipids with pKa values less than or equal to 5.4 demonstrates significantly lower efficiency. For systemic delivery for the liver targeting, it was reported that the pKa between 6.2 and 6.5 of amino lipids are optimal for systemic siRNA delivery to the liver. If the criterion for a proper pKa value is not met, LNP may have with low efficiency. Proper pKa values can facilitate a non-bilayer phase structure when mixed with anionic lipids, which serves as a measure of their bilayer-destabilizing capacity and relative endosomolytic potential (see top of page 42).
Weidinger et al. (NPL, published 06/17/2026, PTO-892) teaches to further analyze the lipophilicity, the logarithmic octanol–water partition coefficient (logP) was evaluated. LogP has long been applied as a simple descriptor of lipophilicity and resulting biodistribution. Experimental application to ILs (ionizable lipids), is however, hindered by their inherent ionizable, highly lipophilic, and amphiphilic nature, and no suitable experimental method is available. Instead, computational calculations of clogP or clogD have been applied for structure–activity relationships in LNPs. Most monovalent ILs have clogP values between 15 and 20 (see section 2.2.2.).
Kah et al. (NPL, published 08/2008, PTO-892) teaches the octanol/water partition coefficient (Kow) for organic compounds has been widely used in predictive environmental studies. Lipophilicity is a very important molecular descriptor that often correlates well with the bioactivity of chemicals. This parameter has been used in equations for estimating bioaccumulation in animals and plants and to predict the toxic effects of a substance in QSAR studies. Lipophilicity of organic chemicals has also been identified as an important parameter to predict adsorption in soils and sediments. Literature reviews can yield Kow values that differ by more than one order of magnitude for some compounds. Reliable determination of the lipophilicity of ionizable compounds is still a problem. Several recent articles compare techniques to measure or estimate lipophilicity. In all articles, the greatest variability between techniques was observed for ionizable compounds (see Introduction section).
Regarding pKa, the art teaches variability of the pKa by changing the ionizable head (amine group), the substituents, and chain length near the ionizable head of the ionizable lipids.
Regarding logP, the art teaches there is no suitable method for determining logP (or Kow also known as the inverse log of logP) of an ionizable compound because the experimental determination of logP is hindered by their inherent ionizable, highly lipophilic, and amphiphilic nature.
Analysis/Conclusion
Regarding scope of the claim, claim 1 recites a broad genus of ionizable, cationic amino lipids produced by the instant method defined by Markush groups for the lipophilic tails and a protonatable amino head. The claim further recites the produced ionizable, cationic amino lipids having a pKa of between 6 and 7.5 and a logP of at least 11. Accordingly, the broad scope of amino lipids produced by the method of claim 1 is defined by the intrinsic properties of pKa and logP, both being functions of the specific amino lipid produced.
The specification discloses no examples of the ionizable, cationic amino lipids having a pKa of between 6 and 7.5 and a logP of at least 11. Furthermore, the specification does not provide guidance on how to achieve these functions.
The prior art highlights that, while pKa of ionizable, cationic amino lipids can be predicted using general chemistry rules governing acidity, there is no clear correlation between changes in structure and a specific pKa range of between 6 and 7.5. Furthermore, the prior art highlights that the specific protonatable amino head group plays a large role in determination of the pKa of the compound which is broadly defined in instant claim 1. Regarding logP, the prior art highlights that logP cannot be measuring reliably with ionizable compounds due to their inherently ionizable behavior. Accordingly, the skilled artisan would be unable to envisage the ionizable, cationic amino lipid produced from the method based on pKa and logP.
Based on the analysis described above, claim 1 lacks written description due to a broad scope of ionizable, cationic amino lipids recited with minimal structure regarding the ionizable head in the claims while being described by a recited function, there is an absence of representative species in the specification, and neither the specification nor the prior art disclose a functional relationship between a ionizable, cationic amino lipid produced by the claimed method and its pKa or logP.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 19 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The claim does not fall within at least one of the four categories of patent eligible subject matter because “Use” claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101 (see MPEP 2173.05(q)).
Allowable Subject Matter
Instant claims 1-19 would be allowable if amended to overcome the 112(a), 112(b), and 101 rejections above.
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The closest prior art is Rajappan et al. (WO2022235935A2, published 05/05/2022, PTO-892). Rajappan et al. teaches the synthesis of ATX-209 ( general scheme shown below). Rajappan et al. further teaches the calculated logD and calculated and experimentally determined pKa’s of ATX-209 (shown
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below and see 0315).
Regarding the interpretation of instant claim 1, instant claim 1 recites “wherein R1 and R2 are identical or different” which is intended to mean symmetrical or unsymmetrical groups wherein R1 and R2 may be symmetrical or unsymmetrical when compared to each other but stay the same in the method step of (i) to turn the nucleophilic intermediate into the ketone. In other words, the R1 of the nucleophilic intermediate of instant claim 1 is the same group as the R1 of the ketone. This interpretation is based on claims 5 and 7 reciting “wherein R1 and R2 are identical, such that the ionizable, cationic amino lipid so produced is symmetrical” and “wherein R1 and R2 are different, such that the ionizable, cationic amino lipid so produced is unsymmetrical”. Furthermore, the examples given in the specification show the R1 and R2 groups, while they may be identical or different when comparing between R1 and R2, do not change and are identical when comparing the R1 groups of the nucleophilic intermediate compounds and the ketone compounds.
Regarding instant claim 1, Rajappan et al. teaches ATX-209-1, corresponding to the instant double alkylated nucleophilic intermediate wherein Z is isocyano, Z’ is tosyl, R1 and R2 are linear, heteroatom substituted C10 alkyl groups which are identical. ATX-209-1 is reacted with HCl to produce ketone, ATX-209-2, corresponding to the instant ketone wherein R1 and R2 are linear, heteroatom substituted C6 groups which are identical to one another and different from the R1 and R2 groups of the intermediate compound. ATX-209, a cationic ionizable amino lipid, is further prepared from the ketone by alkylation of the carboxylic acids, reduction of the ketone to an alcohol, and finally, esterification of the alcohol to produce ATX-209, an ionizable, cationic amino lipid, corresponding to the instant step of preparing the ionizable, cationic amino lipid from the ketone resulting in an addition of an ionizable head group moiety to (b) an alcohol produced from reduction of the ketone to produce an alcohol (see Example 5, 0248-0260). Regarding pKa of 209, Rajappan et al. teaches the calculated pKa of ATX-209 is 9.37.
Rajappan et al. does not teach wherein the variables of R1 and R2 do not change throughout the steps to produce the ionizable, cationic amino lipid (see claim interpretation section above) and wherein the ionizable, cationic amino lipid has (i) a pKa of between 6 and 7.5 and (ii) a logP of at least 11.
While it would have been obvious to one of ordinary skill in the art that the alkyl chains containing heteroatoms in ATX-209-1 are protected carboxylic acids and the unprotected carboxylic acids produced in the step to make ATX-209-2 are functional equivalents of one another, it would not have been obvious that the compound produced by the method has a pKa of between 6 and 7.5 because the calculated pKa of ATX-209, as taught by Rajappan et al., to be 9.37 which does not fall within the recited range of the instant ionizable, cationic amino lipid. Furthermore, while logP can be calculated from pKa and logD, the pH used in the calculation of logD is required and this was not disclosed by Rajappan et al. Therefore, the calculated pKa is not within recited range of instant claim 1 and logP cannot be determined based on the teachings of Rajappan et al. Furthermore, as discussed above, pKa and logP are functions of the specific ionizable, cationic amino lipid produced from the method and therefore, one of ordinary skill in the art would not be able to envisage a specific amino lipid to achieve these recited ranges. Therefore, instant claims 1-19 are free of prior art.
Conclusion
No claim is found allowable.
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/KRISTEN W BRADY/ Examiner, Art Unit 1692
/SCARLETT Y GOON/ Supervisory Patent Examiner, Art Unit 1693
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