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 .
Priority
The present application, filed April 1, 2021, is a national stage application of PCT/US2019/053617, filed September 27, 2019, which claims the benefit of U.S. provisional application 62/739548, filed October 1, 2018.
Status of the Application
Applicant’s communication, received January 8, 2026, wherein claims 2, 9, 23, and 27 are amended and new claim 69 is added, is acknowledged.
Claims 1-33, 39-46, and 62-69 are pending in this application.
Claims 32-33, 39-46, and 62-68, drawn to the non-elected inventions of Groups II and III, were withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim, in the Office action mailed November 26, 2024.
Claims 1-31 and 69 are examined on the merits herein.
Withdrawn Objections
Applicant’s amendment, received January 8, 2026, with respect to the objection to claim 9 for minor informalities, has been fully considered and found to be persuasive to remove the objection because claim 9 is amended to resolve the informalities. Therefore the objection is withdrawn.
Withdrawn Rejections
Applicant’s amendment, received January 8, 2026, with respect to the rejection of claim 2 under 35 U.S.C. 112(d) for failing to include all limitations of the claim from which it depends, has been fully considered and found to be persuasive to remove the rejection because claim 2 is amended to remove the functional groups that fall outside the scope of independent claim 1. Therefore the rejection is withdrawn.
The following rejections are maintained from the previous office action, updated herein to reflect Applicant’s amendment to claim 23 and addition of new claim 69. Applicant’s arguments are addressed following these rejections.
Claim Interpretation
Claim 1 recites the limitation “biodegradable”. This limitation is interpreted based on the definition in the specification, stating: “The biodegradable group(s) include one or more bonds that may undergo bond breaking reactions in a biological environment, e.g., in an organism, organ, tissue, cell, or organelle” (p. 22, middle paragraph, lines 1-3). The specification also provides examples of biodegradable functional groups, such as esters, dithiols, and oximes (p. 22, middle paragraph, lines 3-4). Therefore, any functional group comprising a bond that may be undergo bond breaking in a biological environment is interpreted as satisfying the limitations of “biodegradable”.
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 1-4, 30-31, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Brito (U.S. pre-grant publication no. 20160317458 A1; of record).
Claim 1 claims a compound of formula (A) with variable groups as recited therein, claim 2 requires R'R1R2N-(R)a-Q-(R)b- is one of the groups listed therein, claim 3 requires R1 and R2 are both alkyl, and claim 4 requires group M1 as -OC(O)- or -C(O)O-.
Claim 30 requires the compound of claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt. Claim 31 specifies the compound of claim 1, wherein the compound is in the form of a cationic lipid.
Claim 69 depends from claim 1 and requires M1 is a group shown therein, which includes group -OC(O)-.
Brito teaches cationic lipids that are useful in the delivery of biological agents to cells and tissues (cover page, Abstract, lines 3-6), and cites RNA as one such biological agent to be delivered (p. 1, [0001], lines 1-6). As one example, Brito teaches the compound of example 51 (p. 81, [0911]; structure shown below). This compound satisfies the limitations of claims 1-4 in that R’ is absent, R1 and R2 are methyl, (R)a is (CH2)3, dashed line to Q is absent, b is 0, Z2 is C18 alkenyl, X is C2 alkyl, and M1 is the biodegradable ester group -OC(O)-. However, this compound has Z1 as C18 branched alkyl, which does not satisfy the requirement of claim 1 wherein Z1 is C6-C14 branched alkyl, and it has Q as C(O)O, which is no longer permitted as Q in claim 1.
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In the general formulas describing their compounds (e.g., formula (III) shown on p. 5, [0022]), Brito teaches that alkyl group R2 may comprise the C14 branched structure shown below (p. 7, structure immediately above [0025]). Brito also teaches that variable group R2 may be a group of the formula C1-12 alkyl-OC(O)-C5-20 alkyl (p. 3, left column, lines 5-8).
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In addition, Brito discloses that the headgroup may be the same headgroup of Example 51 above, but with the ester substituted with the OC(O)O group as shown:
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(p. 18, left column, fifth compound shown).
Finally, Brito teaches that the present compounds and their pharmaceutically acceptable salts are cationic lipids (p. 2, [0012], lines 5-8). This disclosure is interpreted as satisfying the limitations of claims 30-31, which specifies the compound is in the form of a pharmaceutically acceptable salt and is in the form of a cationic lipid.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the C18 branched alkyl group in example 51 of Brito for the C14 branched alkyl group, and to substitute the ester-containing head group of example 51 for the carbamate-containing headgroup. One of ordinary skill in the art would have been motivated to substitute the C18 branched alkyl group for the C14 branched alkyl group, and to substitute the ester-containing head group for the carbamate-containing headgroup because Brito teaches that variable group R2 may be the C14 group shown above, and because Brito also teaches that the ester headgroup may be alternative headgroups, including the carbamate head group. In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Brito teaches cationic lipids for the delivery of biological agents to cells, teaches example 51 as a specific cationic lipid, and further teaches the alternative lipids and headgroups, one ordinary skill in the art would have considered derivatives of example 51 with said substitutions, including the C14 lipid and carbamate-containing headgroup recited above, to arrive at a compound that satisfies the limitations of present claims 1-4, 30-31, and 69.
One of ordinary skill in the art would have had a reasonable expectation of success substituting the C18 branched alkyl group for the C14 branched alkyl group and substituting the ester-containing head group for the carbamate-containing headgroup because Brito expressly teaches these groups as potential substitutes for R2 and for R1, respectively. Therefore, because these substitutions are taught by Brito, one of ordinary skill in the art would have had a reasonable expectation that the resulting cationic lipid products formed by said substitutions would be effective for delivering biological agents to cells and tissues.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: With respect to the previous rejection of claims 1-4, 30-31, and 69 as unpatentable over Brito, Applicant argues that the Office has failed to identify a reason why the compound of Example 51 of Brito would have been selected as a lead compound. Applicant argues that the majority of data in Brito is for compounds other than Example 51 (e.g., Table 3, Table 4, and the tables on p. 160). Applicant further argues that for data for Example 51, numerous compounds were reported to result in higher encapsulation.
In addition, Applicant argues that the Office has not provided any reason to include a C14 branched alkyl group (at the Z1 position of the formula recited in claim 1) or an OC(O)O group (at position Q) in the compound of Example 51.
Applicant’s arguments have been fully considered, but they are not found persuasive. In vitro encapsulation data for the compound of Example 51 shows this compound having an encapsulation efficiency of 89.2% encapsulation of siRNA FVII. Although Brito discloses other compounds that also encapsulate siRNA, with the highest encapsulation efficiency of 92%, the examiner maintains that one of ordinary skill in the art would have recognized Example 51 of Brito as among compounds capable of encapsulating siRNA efficiently, and thus would have reasonably considered Example 51 as a lead compound for modification.
Regarding Applicant’s argument that the majority of data in Brito is drawn to other compounds, the examiner maintains that one of ordinary skill in the art would have considered the whole of Brito’s disclosure, including data demonstrating Example 51 as one such compound that demonstrates robust encapsulation of siRNA.
Regarding the substitutions of a C14 branched alkyl group (at the Z1 position of the formula recited in claim 1) or an OC(O)O group (at position Q) in the compound of Example 51, because Brito suggests the C14 alkyl group for R2 and the same corresponding headgroup of Example 51 with an ester in place of the carbonate group, one of ordinary skill in the art would have considered such modifications to Example 51 as within the scope of Brito’s disclosure, and because one of ordinary skill in the art would have had a reasonable expectation that said modifications would produce cationic lipids capable of being used to deliver nucleic acid therapeutics.
Accordingly, the present rejection of claims 1-4, 30-31, and 69 under 35 U.S.C. § 103 unpatentable over Brito is maintained.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Brito as applied to claims 1-4, 30-31, and 69 above, and further in view of Manoharan ‘373 (Publication no. WO 2013086373 A1; cited in previous office action).
Claim 5 depends from claim 1 and requires Z1 is a C6-C10 branched alkyl group, and claim 6 requires Z1 as one of the groups listed therein, including CH2CH(iPr)(CH2CH2iPr).
Brito teaches as described in the above rejection under 35 U.S.C. 103.
Brito does not teach a specific compound of claim 1 with Z1 as a C6-C10 branched alkyl group, as required by claim 5. In addition, Brito does not teach a compound with Z1 as the -CH2CH(iPr)(CH2CH2iPr) group required by claim 6.
Manoharan ‘373 teaches novel cationic lipids that can be used in combination with other lipid components to form lipid nanoparticles with oligonucleotides (cover page, Abstract, lines 1-2). Specifically, Manoharan ‘373 teaches the compound below (p. 131, right column of table, sixth structure from the top). Relating this compound to the structure of claim 1, this compound has variable group Z1 as a C10 branched alkyl group, specifically the -CH2CH(iPr)(CH2CH2iPr) group, which satisfies the limitations of Z1 recited in claims 5 and 6.
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Manoharan ‘373 further teaches additional suitable hydrophobic groups, including the structures below (one of which is present on the compound above), and one of which has the CH2CH(iPr)(CH2CH2iPr) alkyl group attached with a thioester group in place of an ester (p. 98, first two structures).
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In addition, Manoharan ‘373 teaches additional representative asymmetrical cationic lipids, such as the lipids of the general structure shown below (p. 16, left column, structure XVII). This is interpreted as teaching that the invention disclosed by Manoharan ‘373 encompasses structures comprising both symmetrical and asymmetrical cationic lipids, with group m of lengths from 4-25 (p. 17, lines 4-7).
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the C18 branched alkyl group in the cationic lipid example 51 taught by Brito with the -CH2CH(iPr)(CH2CH2iPr) alkyl group taught by Manoharan ‘373. One of ordinary skill in the art would have been motivated to substitute the C18 branched alkyl group in the cationic lipid taught by Brito with the -CH2CH(iPr)(CH2CH2iPr) alkyl group taught by Manoharan ‘373 because Brito teaches in their general formula that the C18 alkyl group may be C5-C20 alkyl, and because Manoharan ‘373 teaching lipids for the same purpose as Brito, delivery of nucleic acid therapeutic agents, that include the CH2CH(iPr)(CH2CH2iPr) alkyl group.
In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Brito teaches in their general formula that the alkyl chain attached to the lipid via ester may be C5-20 alkyl (as part of the formula C1-12 alkyl-OC(O)-C5-20 alkyl), one of ordinary skill in the art would have considered alkyl groups of these lengths for this position in example 51 of Brito. In addition, because Manoharan ‘373 teaches cationic lipids for delivery of nucleic acids with the CH2CH(iPr)(CH2CH2iPr) alkyl group, one of ordinary skill in the art would have considered substituting this group in place of the C18 alkyl group in example 51 of Brito, because these elements are each known in the prior for generating cationic lipids to facilitate delivery of nucleic acids to cells.
One of ordinary skill in the art would have had a reasonable expectation of success modifying the lipids of Brito with the CH2CH(iPr)(CH2CH2iPr) group taught by Manoharan ‘373 because the lipids of both Brito and Manoharan ‘373 may be used for the purpose of delivering therapeutic nucleic acids, and thus one or ordinary skill in the art would have had a reasonable expectation that modifying the individual components of a cationic lipid of Brito with a component of another cationic lipid, such as the CH2CH(iPr)(CH2CH2iPr) group of Manoharan ‘373, used for the same purpose would produce a cationic lipid that effective for delivering nucleic acid therapeutics.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: With respect to the present rejection of claims 5-6 as unpatentable over Brito in view of Manoharan ‘373, Applicant argues that one skilled in the art would not have selected Example 51 as a lead compound for further modification. Furthermore, Applicant argues the Office has not provided a reason that one skilled in the art would have been motivated to replace the C18 group in Example 51 with the C10 branched group at page 131 of Manoharan '373, and only with the improper use of hindsight that one would perform such a substitution.
Applicant’s arguments have been fully considered but they are not found persuasive. The examiner maintains the selection of Example 51 for modification would have been obvious in view of Brito disclosing Example 51 as effective for siRNA encapsulation, as described above. Regarding modification of the C18 group with the C10 group disclosed by Manoharan ‘373, because Brito teaches their alkyl group may be a C5-C20 alkyl group, one of ordinary skill in the art would have contemplated the full scope of alkyl groups of this size disclosed in the prior art and recognized for the delivery of nucleic acids, including, as one example, the group disclosed by Manoharan ‘373, because these compounds would be expected to be effective for delivery of nucleic acids, absent evidence of non-obviousness with respect to such a substitution.
Accordingly, the present rejection of claims 5-6 under 35 U.S.C. § 103 as unpatentable over Brito in view of Manoharan ‘373 is maintained.
Claims 23-29 are rejected under 35 U.S.C. 103 as being unpatentable over Colletti ‘126 (Publication no. WO 2013116126 Al; cited in IDS received April 1, 2021).
Claim 23 recites a compound of Formula (A-II), which structure shown therein. Claim 24 requires b as 1, claim 25 specifies s is 2, 3, or 4, claim 26 requires s is 3, claim 27 requires R100 is a C9-C12 alkyl, claim 28 requires R200 is C12-C14 alkyl, C12-C14 alkenyl, or C12-C14 alkynyl, and claim 29 requires R200 is C18-C20 alkyl, C18-C20 alkenyl, or C18-C20 alkynyl.
Colletti ‘126 teaches cationic lipids that may be used to form lipid nanoparticles with oligonucleotides (cover page, Abstract, lines 1-2). Colletti ‘126 specifically teaches compound 172 (p. 51, structure shown below).
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With respect to present claims 23-29, this compound satisfies the limitations of Formula (A-II) wherein b is 1, R200 is C19 alkenyl, and s is 1. However, this compound has R100 as C2 alkyl, which does not meet the limitations of variable group R100.
Colletti ‘126 additionally teaches in general Formula A (p. 2, line 23) that variable group R6, which corresponds to the ethyl group above, may be optionally substituted with one to three substituents selected from R′, including substituents of R″, which includes C1-C6 alkyl groups. This is interpreted as a teaching that the C1-2 alkyl group of R6 may be substituted with 1-3 additional alkyl groups. Consideration of two or three C4-6 alkyl groups, for example, would produce a compound that satisfies the R100 group recited in claim 23.
Colletti ‘126 further teaches in general Formula A (p. 2, line 23) that group R5, which corresponds to the C6 alkyl group linking the tertiary carbon to the ester group, may be C4-C8 alkyl (p. 3, lines 7-8). Furthermore, Colletti ‘126 teaches that variable groups R3 and R4, which make up the C19 alkenyl group, may be C4-C20 alkyl or alkenyl and C1-C16 alkyl or alkenyl (p. 3, lines 3-6).
Colletti ‘126 does not teach a specific embodiment or compound that satisfies all limitations of claim 23 and its dependent claims with respect to variable group R100. Colletti ‘126 also does not teach a specific embodiment wherein s is 2, 3, or 4, or is 3 as recited in claim 26, or wherein R200 is C12-C14 alkyl, alkenyl, or alkynyl, as recited in claim 28.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the ethyl group of compound 172 disclosed by Colletti ‘126 with a C9-C12 alkyl group. One of ordinary skill in the art would have been motivated to substitute the ethyl group of compound 172 disclosed by Colletti ‘126 with a C9-C12 alkyl group because Colletti ‘126 teaches that the C1-C2 alkyl group may be substituted by additional alkyl substituents, including 2-3 C1-C6 alkyl groups, and thus one of ordinary skill in the art would have contemplated alkyl groups of this size in place of the alkyl group of compound 172, arriving at a compound with, for example, a C9-12 alkyl group that satisfies the limitations of claims 23-24, 27, and 29.
One of ordinary skill in the art would have had a reasonable expectation of success substituting the ethyl group of compound 172 disclosed by Colletti ‘126 with a C9-C12 alkyl group because Colletti ‘126 teaches that the C1-C2 alkyl group may be substituted by 1-3 C1-C6 alkyl substituents, and thus one of ordinary skill in the art would have had a reasonable expectation that the substitutions suggested by Colletti ‘126 would have produced a lipid that may be used to form lipid nanoparticles with oligonucleotides.
With respect to the size of the alkyl group linking the tertiary carbon to the ester group, in view of Colletti ‘126 teaching that variable group R5 may be C4-C8, one of ordinary skill in the art would have considered derivatives with both longer and shorter alkyl groups in this position. For example, substitution of the C6 alkyl group in compound ‘172 above with the C8 alkyl group suggested by Colletti ‘126 would have generated a compound with s as 3. Similarly, in view of Colletti ‘126 teaching that variable groups R3 and R4 may be alkyl or alkenyl groups of various lengths, one of ordinary skill in the art would have considered substituting the C19 alkenyl group of compound 172 above with alkyl or alkenyl of varying lengths, including the C12-C14 alkyl or alkenyl groups required by claim 28.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: Regarding the present rejection of claims 23-29 under 35 U.S.C. as unpatentable over Colletti ‘126, Applicant argues that the Office has not cited a rationale for why one skilled in the art would have selected compound 172 as a lead compound. Second, Applicant argues the Office has not provided any rationale for replacing the ethyl group in compound 172 with a longer alkyl group, such as a C6 alkyl group.
Applicant’s arguments have been fully considered but they are not persuasive.
Regarding selection of compound 172 for modification, although Colletti ‘126 does not provide functional data for their compounds, Colletti ‘126 teaches and claims compound 172 for preparation of lipid nanoparticles for delivery of siRNA oligonucleotide (e.g., pp. 79, line 6 (recited as part of claim 4) and claims 5-9), and accordingly, one of ordinary skill in the art would have had a reasonable expectation that compound 172 would be effective for the claimed purposes.
Moreover, Colletti ‘126 discloses additional compounds that could have been similarly modified to arrive at a compound of claim 23, including compounds 167, 168, and 171. In this instance, the examiner maintains that one of ordinary skill in the art would have recognized this group of similar variants as effective for delivering nucleic acid therapeutics, and would have contemplated variations of this group of compounds based on guidance provided in the disclosure of Colletti ‘126.
Regarding replacement of the ethyl group for in compound 172 with a longer alkyl group, because Colletti ‘126 expressly suggests groups substitution of R6 with one to three R', one of ordinary skill in the art would have reasonably considered the full scope of compounds with said substituents, including, for example, multiple R" groups. These R" groups include the C1-C6 alkyl substituents disclosed in the above rejection. Therefore, one of ordinary skill in the art would have considered such a modification because Colletti ‘126 recognizes such substitutions as part of their invention.
In addition, because these modifications to the compounds of Colletti ‘126 are recognized by Colletti ‘126, one of ordinary skill in the art would have had a reasonable expectation that said modifications would produce cationic lipids capable of being used to deliver nucleic acid therapeutics.
Accordingly, the present rejection of claims 23-29 under 35 U.S.C. § 103 as unpatentable over Colletti ‘126 is maintained.
Claims 1-22, 30-31, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Colletti ‘126 (Publication no. WO 2013116126 Al; cited in IDS received April 1, 2021) in view of Manoharan ‘373 (Publication no. WO 2013086373 A1; cited in previous office action).
Claim 1 claims a compound of formula (A) with variable groups as recited therein, claim 2 requires R'R1R2N-(R)a-Q-(R)b- is one of the groups listed therein, claim 3 requires R1 and R2 are both alkyl, claim 4 requires group M1 as -OC(O)- or -C(O)O-, claim 5 requires Z1 is a C6-C10 branched alkyl group and claim 6 requires Z1 as one of the groups listed therein, including CH2CH(iPr)(CH2CH2iPr). Claim 7 requires Z2 is a C19 alkenyl containing one or two double bonds, claim 8 requires Z2 is (CH2)9CH=CHCH2CH=CH(CH2)4CH3, and claim 69 requires M1 is selected one of the groups recited therein.
Claim 10 claims a compound of formula (A-I), with variable groups as defined therein. Claims 11 and 12 further limit the properties and identify of head group W, claims 13 and 14 require variable s is 3-5 and 4, claims 15 and 16 require variable t is 4-6 and 5, claims 17 and 18 require variable q is 2-4 and 3, claims 19 and 20 require variable u is 0-2 and 1, and claims 21-22 require variable v is 0-2 and 1.
Claim 30 requires the compound of claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt. Claim 31 specifies the compound of claim 1, wherein the compound is in the form of a cationic lipid.
Colletti ‘126 teaches as described in the above rejection under 35 U.S.C. 103. Specifically, Colletti ‘126 specifically teaches compound 172 (p. 51, structure shown below).
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With respect to the present claims 1-8 and 69, this compound has R’ as absent, R1 and R2 as methyl, (R)a as (CH2)2, Q as absent, dashed line to Q as absent, b as 0, Z2 as C19 alkenyl, X as alkylene, M1 as the biodegradable ester group as recited in claim 69, and Z1 as C2 alkyl. This compound has R'R1R2N-(R)a-Q-(R)b- as (CH3)2N-(CH2)2- as recited in claim 2, R1 and R2 as alkyl as recited in claim 3, M1 as C(O)O- as recited in claim 4, Z2 as a C19 alkenyl group containing two bonds as recited in claim 7, Z2 as (CH2)9CH=CHCH2CH=CH(CH2)4CH3 as recited in claim 8. This compound satisfies all limitations of claims 1-8 and 30-31, except for the requirements regarding the Z1 branched alkyl group.
With respect to present claim 9, this compound has the same structure as the fifth structure shown on p. 5, except for the branched alkyl substituent of the ester and the 8 carbon chain connecting the head group to the ester.
With respect to present claim 10, this compound has W as (CH3)2N-(CH2)2-, q as 3, t as 5, and s as 1, which satisfies the limitations of claim 10, except for the identity of the branched alkyl substituent of the ester group. With respect to the limitation of claim 11 wherein the head group is a protonatable amine group having a pKa of between about 4 and about 11, Jayaraman (Jayaraman, M.; et al. Angewandte Chemie International Edition 2012, vol. 51, pp. 8529-8533; of record) discloses the pKa of head group number 52, which is structurally similar to the head group of compound 172 taught by Colletti ‘126, as 5.73 (p. 8531, Table 1).
Colletti ‘126 further teaches in general Formula A (p. 2, line 23) that R5, which corresponds to the C6 group linking the tertiary carbon to the ester group, may be C4-C8 alkyl (p. 3, lines 7-8).
Finally, Colletti ‘126 teaches that their invention includes the free form of cationic lipids of Formula A, as well as the pharmaceutically acceptable salts and stereoisomers thereof (p. 15, lines 1-4).
Colletti ‘126 does not teach a compound of claim 1 wherein Z1 is a C6-C14 branched alkyl group required by claims 1-4 and 7-8, wherein Z1 is a C6-C10 branched alkyl group recited in claim 5, wherein Z1 is the -CH2CH(iPr)(CH2CH2iPr) group recited in claim 6, a compound of claim 9, or a compound that satisfies all limitations of claim 10 and its dependent claims with respect to the identity of the branched alkyl group.
Manoharan ‘373 teaches as described in the above rejection under 35 U.S.C. 103. Specifically, Manoharan ‘373 teaches the branched alkyl group discussed in the above rejection, which has each of groups u and v as defined in claim 10 as 1.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the ethyl group of compound 172 disclosed by Colletti ‘126 with a C8-C12 alkyl group, such as the CH2CH(iPr)(CH2CH2iPr) branched alkyl group disclosed by Manoharan ‘373. One of ordinary skill in the art would have been motivated to substitute the ethyl group of compound 172 disclosed by Colletti ‘126 with a C8-C12 alkyl group, such as the CH2CH(iPr)(CH2CH2iPr) branched alkyl group as disclosed by Manoharan ‘373, because Colletti ‘126 teaches that the C1-C2 alkyl group may be substituted by additional alkyl substituents, and thus one of ordinary skill in the art would have considered additional larger alkyl substituents in this position. Because Manoharan ‘373 teaches cationic lipids that may also be used for delivery of siRNA, including the examples comprising the CH2CH(iPr)(CH2CH2iPr) branched alkyl group of claim 10, one would have considered this alkyl group in place of the substituted ethyl group taught by Colletti ‘126.
In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because both Colletti ‘126 and Manoharan ‘373 teach cationic lipids for the delivery of therapeutic oligonucleotides, Colletti ‘126 teaches compound 172 and further teaches said ethyl group may be substituted by larger alkyl groups, and Manoharan ‘373 teaches embodiments with the branched alkyl group of the compounds of claim 10, one of ordinary skill in the art would have recognized each of these prior art elements that are recognized by the prior art for the same purpose, and considered a cationic lipid that includes both such elements.
One of ordinary skill in the art would have had a reasonable expectation of success substituting the ethyl group of compound 172 disclosed by Colletti ‘126 with a C8-C12 alkyl group, such as the CH2CH(iPr)(CH2CH2iPr) branched alkyl group taught by Manoharan ‘373, because Colletti ‘126 teaches that the C1-C2 alkyl group may be substituted by additional alkyl substituents, and because Manoharan ‘373 discloses compounds with the CH2CH(iPr)(CH2CH2iPr) branched alkyl group for delivery of active pharmaceutical ingredients such as siRNA. Thus one of ordinary skill in the art would have had a reasonable expectation that substitution of the substituted ethyl group in compound 172 of Colletti ‘126 with the CH2CH(iPr)(CH2CH2iPr) branched alkyl group would have provided a cationic lipid that may be successfully used for the purpose of delivering therapeutic oligonucleotides.
The above substitution of the ethyl group of compound 172 of Colletti ‘126 with the CH2CH(iPr)(CH2CH2iPr) branched alkyl group would have produced a compound that satisfies the limitations recited in present claims 1-8, 10-12, 15-22, and 30-31.
With respect to the size of the alkyl group linking the tertiary carbon to the ester group, in view of Colletti ‘126 teaching that this group may be C4-C8 alkyl, one of ordinary skill in the art would have contemplated derivatives with both longer and shorter alkyl groups in this position, including the C8 alkyl disclosed by Colletti ‘126. Substitution of the C6 alkyl group in compound ‘172 above with the C8 alkyl group would have generated a compound that is the fifth compound of claim 9 and would have had s as 3 as required by claim 13.
In addition, in view of Colletti ‘126 teaching the alkyl group linking the tertiary carbon to the ester group may be C4-C8 and Manoharan ‘373 teaching in their general formula for cationic lipids that this group may be up to 25 carbons, one of ordinary skill in the art would have considered derivatives with even longer alkyl groups in this position, including a C9 alkyl linker, which would give s as 4 and satisfy the limitations of claim 14. In this instance, in view of the ranges disclosed by both Colletti ‘126 and Manoharan ‘373, one of ordinary skill in the art would have recognized that the length of this specific chain may vary, and thus would have contemplated compounds with different length alkyl groups to optimize the physical and chemical properties of the lipids for delivery of therapeutic agents.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: Regarding the present rejection under 35 U.S.C. 103 over Colletti ‘126 in view of Manoharan ‘373, Applicant argues that one skilled in the art would not have selected compound 172 as a lead compound for further modification. Furthermore, Applicant argues the Office has not provided a reason that one skilled in the art would have been motivated to replace the ethyl group in compound 172 of Colletti '126 with the branched group at page 131 of Manoharan '373. It is only with the improper use of hindsight that one would perform such a substitution. Applicant argues that Manoharan '373 discloses numerous groups, and despite this, the Office has not provided any rationale for selecting the branched group at page 131 of Manoharan '373 for combination with compound 172 of Colletti '126 in order to arrive at the compounds recited in claims 1, 9, and 10.
Applicant’s arguments have been fully considered but they are not persuasive. Regarding the modification of compound 172 of Colletti ‘126, the examiner maintains modification of compound 172 is reasonable for the same reasons described above.
Regarding substitution of ethyl group for alternative alkyl groups, because Colletti ‘126 suggests the ethyl group may be substituted with one to three R', one of ordinary skill in the art would have naturally considered the full scope of compounds with said substituents, which includes R' as R". Moreover, one of ordinary skill in the art would have considered the scope of C1-C6 alkyl group substituents as R". In addition, because these substitutions are taught in the general formula of Colletti ‘126, one of ordinary skill in the art would have had a reasonable expectation that said modifications to compound 172 would produce cationic lipids capable of being used to deliver nucleic acid therapeutics.
Regarding the combination of Colletti ‘126 with Manoharan ‘373, because Colletti ‘126 and Manoharan ‘373 each teach cationic lipids for the delivery of nucleic acids to cells, and because Manoharan ‘373 discloses the specific branched alkyl group recited in claim 6 and required by claim 10 and its dependent claims, one of ordinary skill in the art would have recognized this branched chain alkyl group may be used for delivery of nucleic acids. Absent a showing of nonobviousness, one of ordinary skill in the art would have recognized additional alkyl groups in the prior art, including the specific branched alkyl group disclosed by Manoharan ‘373 and cited above, that may be used for delivery of nucleic acids, and would have contemplated a derivative of compound 172 with the full scope of alkyl groups in the art, because such a lipid may improve the delivery of nucleic acid therapeutics to cells. Moreover, because the lipids taught by Colletti ‘126 and by Manoharan ‘373 are used for the same purpose, delivery of nucleic acid therapeutics, one of ordinary skill in the art would have had a reasonable expectation that said modifications would produce cationic lipids capable of being used to deliver nucleic acid therapeutics.
Accordingly, the present rejection of claims 1-22, 30-31, and 69 under 35 U.S.C. § 103 as unpatentable over Colletti ‘126 in view of Manoharan ‘373 is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693
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