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 without traverse of Group I in the reply filed on 22 June 2026 is acknowledged.
Claims 14-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Election was made without traverse in the reply filed on 22 June 2026.
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 1-13 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter regarded as the invention.
Claim 1 recites in step (a) a second diol having the formula HO-L¹-CH₂-OH and a corresponding second ester alcohol having the formula R²-C(O)-O-L¹-CH₂-OH. Step (b), however, recites oxidation of that second ester alcohol to a second ester aldehyde having the formula R²-C(O)-O-L²-CHO, and Formula I depicts the corresponding second arm using L². Because L¹ and L² are defined as independently selected linkers, it is unclear whether the second diol and second ester alcohol must contain L¹ or L², whether L¹ and L² must be identical, or whether the claimed method requires an unexplained conversion of an L¹-containing intermediate into an L²-containing intermediate.
The inconsistency is confirmed by paragraph 0321 of the specification, which describes the second diol and second ester alcohol using L². Accordingly, the claim language does not correspond to the disclosed reaction sequence and permits more than one reasonable interpretation.
Claim 1 also uses L¹ and L² inconsistently between the ester-aldehyde intermediates and Formula I. The claimed ester aldehydes have the formulas R¹-C(O)-O-L¹-CHO and R²-C(O)-O-L²-CHO. Reductive amination of the aldehyde groups produces terminal -CH₂-N- linkages. Formula I, however, depicts the arms as R¹-C(O)-O-L¹-N and R²-C(O)-O-L²-N without separately depicting the methylene carbons derived from the aldehydes. Paragraph 0339 of the specification states that the aldehyde carbons “are part of or become part of L¹ and L².” It is therefore unclear whether L¹ and L² in the ester-aldehyde formulas exclude the aldehyde carbon but include that carbon in Formula I, or whether Formula I should separately depict -L¹-CH₂-N and -L²-CH₂-N. The same variables consequently identify different structural moieties at different stages of the claimed process.
Claim 1 further recites that the method “does not involve isolation and/or purification by chromatography” of the listed intermediates “and/or” does not involve using intermediates “isolated and/or purified by chromatography.” The repeated use of “and/or” leaves unclear whether the claim requires: (1) no isolation of any kind and no chromatographic purification; (2) no isolation by chromatography and no purification by chromatography; (3) satisfaction of either negative clause; or (4) satisfaction of both negative clauses. Although a negative limitation is not inherently indefinite, the boundaries of this particular limitation are unclear because the alternatives materially differ in scope.
Claims 2-13 incorporate the indefinite limitations of claim 1 and are rejected for the same reasons. Claim 13 additionally repeats the ambiguous “isolation and/or purification by chromatography” and “and/or” language with respect to the first and second acyl chlorides.
CLAIM INTERPRETATION FOR PRIOR-ART EXAMINATION
For purposes of the following prior-art rejections, claim 1 is interpreted as requiring L² in the second diol and second ester-alcohol formulas. L¹ and L² in Formula I are interpreted as including the methylene carbons derived from the respective aldehyde groups.
The negative limitations in claims 1 and 13 are interpreted as excluding chromatographic isolation or purification of the identified intermediates. They are not interpreted as excluding filtration, phase separation, concentration, solvent removal, washing, recovery, or other nonchromatographic workup operations. If a different scope is intended, clarification by amendment is required.
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.
Claims 1, 6, and 12 are rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115.
Ansell discloses compounds having two ester-containing hydrocarbon arms joined through a tertiary amine and methods for preparing such compounds. The saturated or unsaturated C₁-C₂₄ alkyl and cycloalkyl groups and linker lengths disclosed by Ansell fall within the broader R¹, R², L¹, L², and L³ definitions of claim 1. Claim 1 permits R¹ and R², and L¹ and L², to be identical; therefore, the symmetric compounds disclosed by Ansell fall within the claimed alternatives.
Ansell’s General Reaction Scheme 2 and paragraph 0173 disclose treating diol B-1 with acid chloride B-2 and a base, such as triethylamine, to produce an ester alcohol. The crude product is treated with an oxidizing agent, such as pyridinium chlorochromate, to obtain ester aldehyde B-3. Crude B-3 is then reacted with N,N-dimethylaminoamine B-4, an acid, and sodium triacetoxyborohydride to obtain final tertiary-amine lipid B-5. Thus, Ansell teaches the claimed sequence of acid-chloride esterification, oxidation of ester alcohol to ester aldehyde, and reductive amination to form the final cationic lipid.
Under the interpretation stated above, paragraph 0173 also teaches carrying the crude ester-alcohol and ester-aldehyde intermediates into the succeeding reactions without chromatographic purification. Ansell states that the “crude product” is oxidized and that a solution of “crude B-3” is used in the reductive-amination reaction. Ansell does not establish the absence of every possible isolation operation, but claim 1 is not interpreted as excluding all nonchromatographic workup.
As to claim 6, paragraph 0173 identifies triethylamine as the base used during the acid-chloride esterification. Example 1 likewise adds triethylamine to octan-1,8-diol and 2-ethylhexanoyl chloride; see paragraphs 0178-0179.
As to claim 12, Ansell purifies the final cationic lipid by silica-gel chromatography. In Example 1, the product of reductive amination is passed through silica-gel columns using a methanol/methylene-chloride gradient; see paragraph 0179. Disclosure of the silica-gel alternative is sufficient because claim 12 recites extraction, precipitation, silica-gel chromatography, polymer-resin chromatography, or a combination thereof in the alternative.
It would have been obvious to use the reactants and conditions disclosed in Ansell to prepare a species within the broadly claimed Formula I genus because Ansell expressly teaches the same sequence for preparing structurally corresponding cationic lipids. The reactants perform the same functions in the claimed method as in Ansell, and the expected product results from the same esterification, oxidation, and reductive-amination chemistry.
Claims 2-5 and 13 are rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115, in view of Bapat et al., US 2018/0214472, and further in view of Misra et al., US 5,100,889.
Ansell discloses the method of claim 1 as set forth above and employs fatty-acid chlorides as esterification reagents but does not describe in detail how those acid chlorides are prepared.
Bapat teaches preparing palmitoyl chloride by adding one drop of DMF and oxalyl chloride to palmitic acid in DCM, stirring the reaction at room temperature for three hours, removing the solvent in vacuo, and using the resulting product in the next step without further purification; see paragraph 0416. Bapat provides the same teaching for preparing an acid chloride from lauric acid; see paragraph 0428.
As to claim 2, Bapat therefore teaches forming a fatty-acid chloride from a fatty acid using oxalyl chloride, one of the oxychlorides expressly identified in claim 2.
As to claim 4, Bapat performs the fatty-acid/oxalyl-chloride reaction at room temperature, which falls within the claimed range of 15 °C to 30 °C.
As to claim 5, Bapat performs the reaction in the presence of DMF.
As to claim 13, Bapat removes the solvent and uses the resulting acid-chloride product in the next step without further purification. Under the interpretation stated above, Bapat teaches using the acid chloride without chromatographic isolation or purification. Bapat reports an isolated yield and therefore does not establish an absence of all isolation or recovery operations; the rejection does not rely on such an interpretation.
As to claim 3, Misra discloses dissolving a carboxylic acid in dry DCM, adding one drop of DMF, and adding dropwise a 2 M solution of oxalyl chloride in DCM. After gas evolution ceases, the mixture is concentrated to provide crude acid chloride; see Example 44, Part E, column 84, lines 47-56. Misra thus expressly teaches contacting a fatty-acid solution with an oxychloride solution.
It would have been obvious to prepare the fatty-acid chlorides used in Ansell by the oxalyl-chloride/DMF procedures of Bapat and Misra. Ansell requires an acid-chloride starting material, while Bapat and Misra teach conventional procedures for producing such acid chlorides from the corresponding carboxylic acids. Employing those known procedures would predictably supply the acid-chloride reagents needed for Ansell’s esterification without changing their function in the subsequent reaction. Applying the same known procedure separately to the first and second fatty acids would likewise have produced the respective first and second acid chlorides with a reasonable expectation of success.
Claims 8 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115, in view of Fritz-Langhals et al., US 2003/0073871.
Ansell discloses oxidizing ester alcohol B-2 to ester aldehyde B-3 using pyridinium chlorochromate; see paragraph 0173. Ansell does not require that the oxidation be catalyzed.
Fritz-Langhals teaches catalytic oxidation of primary alcohols to aldehydes using nitroxyl catalysts, including TEMPO and 4-hydroxy-TEMPO, in aqueous-organic reaction systems; see paragraphs 0004-0005. More particularly, Fritz-Langhals oxidizes the ester alcohol 2-n-butyryloxyethanol using TEMPO or 4-hydroxy-TEMPO and sodium hypochlorite, optionally with sodium bromide; see paragraphs 0051-0052 and 0055-0057. The oxidation products are washed with aqueous hydrochloric acid, sodium-thiosulfate solution, and water, producing the corresponding ester aldehyde in 70% or 80% yield; see paragraphs 0053 and 0058.
As to claim 8, Fritz-Langhals teaches catalyzing oxidation of an ester alcohol to an ester aldehyde with a TEMPO oxidation catalyst. Applying that teaching to both ester-alcohol arms of Ansell would satisfy the first and second oxidation-catalyst limitations.
As to claim 9, Fritz-Langhals teaches washing the oxidation-product mixture containing the ester aldehyde with hydrochloric acid, sodium thiosulfate, and water before recovering and further using the aldehyde.
It would have been obvious to substitute the TEMPO/sodium-hypochlorite oxidation of Fritz-Langhals for the PCC oxidation of Ansell because Fritz-Langhals teaches that the catalytic procedure converts the same class of ester alcohol functionality to the corresponding ester aldehyde while retaining the ester group. The substitution represents use of a known oxidation technique for its established purpose and would have provided predictable aldehyde formation. It also would have been obvious to use the disclosed acid and thiosulfate washes to remove residual oxidant and catalyst before the reductive-amination step.
Claim 10 is rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115, in view of Imai, US 4,207,260.
Ansell discloses reductive amination of ester aldehyde B-3 with an amine using sodium triacetoxyborohydride; see paragraph 0173.
Imai teaches preparing tertiary amines by reacting an aldehyde, hydrogen, and a nitrogen-containing compound, including a primary amine, in the presence of a rhodium- or ruthenium-containing catalyst; see column 2, lines 38-51, and column 3, lines 37-50. Imai further teaches an aldehyde-to-nitrogen-compound molar ratio of approximately 1:1 to 3:1, depending on the number of available N-H hydrogens; see column 3, lines 16-23.
It would have been obvious to use the catalytic hydrogen reductive-amination procedure of Imai in place of Ansell’s hydride reductive amination. Both procedures react an aldehyde with an amine to form a tertiary amine, and Imai expressly identifies hydrogen as the reducing agent. Substitution of one known reductive-amination system for another would have been expected to produce the corresponding tertiary-amine lipid without changing the functions of the aldehyde and amine reactants.
Claim 11 is rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115 A1, in view of Imai, US 4,207,260, and further in view of Bader et al., US 5,430,188.
For purposes of this rejection, “the reduction . . . is quenched with a base” is interpreted as encompassing the addition of base after hydrogenation to neutralize acidic components and terminate or work up the hydrogenation mixture. The limitation is not interpreted as requiring the base itself to consume or displace hydrogen gas.
Ansell and Imai disclose the method of claim 10 as set forth above. Bader teaches catalytic reductive alkylation of an amine and carbonyl compound using hydrogen, platinum on carbon, and an acid cocatalyst. After hydrogenation, a base is added, the catalyst is removed by filtration, and the product is recovered; see column 2, lines 15-23. Bader identifies KOH and NaOH as suitable bases and states that sufficient base is added to neutralize the acid cocatalyst; see column 3, lines 1-4. Bader separately teaches displacing unreacted hydrogen with an inert gas before filtration; see column 3, lines 5-8.
It would have been obvious to apply Bader’s post-hydrogenation base treatment to the hydrogen reductive-amination process resulting from the combination of Ansell and Imai. Bader teaches that the base neutralizes the acidic reaction component and facilitates catalyst separation and product recovery. The base would perform the same neutralization and workup function in the modified Ansell process, with predictable results.
Claim 21 is rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115 A1, in view of Suzuki et al., US 2019/0218180 A1.
Ansell discloses cationic lipids within the broad scope of Formula I and purification of the final reductive-amination products by silica-gel chromatography; see General Reaction Scheme 2 and paragraphs 0173 and 0179. Ansell does not use the claimed n-heptane/ethyl-acetate eluent mixture for purification of the final cationic lipid.
Suzuki teaches purification of a final cationic lipid by silica-gel column chromatography using n-heptane/ethyl acetate as the eluent; see paragraph 0270.
It would have been obvious to use Suzuki’s n-heptane/ethyl-acetate silica-gel system to purify Ansell’s cationic lipid. Both references concern chromatographic purification of hydrophobic cationic lipids containing long hydrocarbon chains and polar amine-containing regions. Suzuki teaches the claimed solvent pair for that purpose. Selecting that known silica-gel eluent system for Ansell’s cationic lipid would have amounted to applying a known purification technique to a closely related product, with a reasonable expectation that solvent proportions could be adjusted to obtain separation. Because claim 21 recites silica-gel chromatography, polymer-resin chromatography, or a combination thereof in the alternative, the disclosure of silica-gel chromatography satisfies the claim.
Claim 22 is rejected under 35 U.S.C. § 103 as being unpatentable over Ansell et al., US 2015/0376115 A1, in view of Suzuki et al., US 2019/0218180 A1, and further in view of Wishart et al., US 2003/0009034 A1.
Ansell and Suzuki disclose the method of claim 21 as set forth above. Suzuki does not expressly state that the n-heptane/ethyl-acetate mixture is supplied as a gradient having an increasing concentration of ethyl acetate.
Wishart teaches silica-gel chromatography using 25% ethyl acetate in n-heptane, followed by further silica-gel chromatography using a 0% to 25% ethyl-acetate-in-n-heptane gradient; see paragraph 0084.
It would have been obvious to provide Suzuki’s n-heptane/ethyl-acetate eluent as a gradient having an increasing ethyl-acetate concentration. Wishart demonstrates that increasing ethyl acetate in n-heptane was a known silica-gel gradient technique. Ethyl acetate is the more polar component of the solvent pair, and increasing its concentration predictably increases eluent strength and elutes compounds having progressively stronger interaction with the silica. Applying that conventional gradient technique to the purification of Ansell’s cationic lipid would have involved routine adjustment of the mobile-phase composition to achieve separation, with a reasonable expectation of success.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEBORAH D CARR whose telephone number is (571)272-0637. The examiner can normally be reached Monday-Friday (10:30 am -6:30 pm).
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/DEBORAH D CARR/Primary Examiner, Art Unit 1691
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