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 March 20, 2025, wherein claims 1, 9-10, 12, and 28-29 are amended, is acknowledged.
Claims 1-33, 39-46, and 62-68 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Claims 32-33, 39-46, and 62-68, drawn to the non-elected inventions of Groups II and III, were withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim, in the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 are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claim 9 under 35 U.S.C. 102 as anticipated by Maier has been fully considered and found to be persuasive to remove the rejection because claim 9 is amended to no longer recite the structure anticipated by Maier. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claim 9 under 35 U.S.C. 103 as unpatentable over Maier has been fully considered and found to be persuasive to remove the rejection because claim 9 is amended to no longer recite the structures obvious over Maier. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claim 9 under 35 U.S.C. 103 as unpatentable over Akinc has been fully considered and found to be persuasive to remove the rejection because claim 9 is amended to no longer recite the structures obvious over Akinc. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claim 9 under 35 U.S.C. 103 as unpatentable over Maier in view of Akinc has been fully considered and found to be persuasive to remove the rejection because claim 9 is amended to no longer recite the structures obvious over Maier in view of Akinc. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claims 1-4 and 30-31 under 35 U.S.C. 103 as unpatentable over Brito has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to no longer permit ester groups (C(O)O or OC(O)) as options for variable group Q. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claims 5-6, 10-15, and 17-22 under 35 U.S.C. 103 as unpatentable over Brito in view of Akinc has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to no longer permit ester groups (C(O)O or OC(O)) as options for variable group Q. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claims 1-6 and 30-31 under 35 U.S.C. 103 as unpatentable over Manoharan in view of Akinc has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to require variable group X as alkylene, not alkenylene, and to no longer permit ester groups (C(O)O or OC(O)) as options for variable group Q. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claims 1-8, 10-22, and 30-31 under 35 U.S.C. 103 as unpatentable over Colletti ‘579 in view of Akinc has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is to no longer permit ester groups (C(O)O or OC(O)) as options for variable group Q, and because claim 10 is amended to require the head group is from the options listed therein. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the rejection of claims 1-31 under 35 U.S.C. 103 as unpatentable over Colletti ‘126 in view of Akinc has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is to no longer permit ester groups (C(O)O or OC(O)) as options for variable group Q, claim 10 is amended to require the head group is from the options listed therein, and because Applicant’s arguments regarding the specific embodiments cited in Akinc are persuasive. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the non-statutory double patenting rejection of claim 9 as unpatentable over claims 19 and 30 of ‘963 has been fully considered and found to be persuasive to remove the rejection because claim 9 is amended to no longer recite the first and second compounds. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the non-statutory double patenting rejection of claim 9 as unpatentable over claims 19 and 30 of ‘963 in view of Akinc has been fully considered and found to be persuasive to remove the rejection because claim 9 is amended to no longer recite the first and second compounds on p. 5 of the claims. Therefore the rejection is withdrawn.
Applicant’s amendment, received March 20, 2025, with respect to the non-statutory double patenting rejection of claims 1-6, 30 and 31 as unpatentable over claims 25-27 and 36 of ‘498 in view of Akinc has been fully considered and found to be persuasive to remove the rejection because the compound of formula requires an ester group as presently defined group Q, which is no longer permitted by present claim 1. Therefore the rejection is withdrawn.
The following are new and/or modified grounds of rejection in response to Applicant’s amendments, received March 20, 2025, wherein claims 1, 6, 9-10, 12, 23, and 28-29 are amended.
Claim Objections
Claim 9 is objected to because of the following informalities: Claim 9 recites “A compound selected from selected from:”. Please amend claim 9 to recite “A compound selected from:”.
Appropriate correction is required.
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 § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 recites specific options for variable groups R’R1R2N-(R)a-Q-(R)b-, including options (CH3)2N-(CH2)3-C(O)O- and (CH3)2N-(CH2)2-NH-C(O)O-. However, these options require Q as C(O)O, which is no longer permitted in claim 1. Therefore, these options recited in claim 2 fail to include all the limitations of the claim upon which it depends.
For the purposes of expedited prosecution, claim 2 is examined as if it does not recite the options (CH3)2N-(CH2)3-C(O)O- and (CH3)2N-(CH2)2-NH-C(O)O-, consistent with the scope of amended claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35
U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Brito (U.S. pre-grant publication no. 20160317458 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, 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.
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. 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 above and to substitute the ester-containing head group for the carbamate-containing headgroup above because Brito teaches that variable group R2 may be the C14 group 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 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 and 30-31.
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 above 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.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Brito as applied to claims 1-4 and 30-31 above, and further in view of Manoharan ‘373 (Publication no. WO 2013086373 A1; cited in PTO-892).
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 tails, 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 general structure shown below (p. 16, left column, structure XVII). This is taken as an express 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: Regarding the previous rejections under 35 U.S.C. over Brito and over Brito in view of Akinc, Applicant argues that claim 1 is now amended to remove ester groups as potential groups for Q. In addition, Applicant argues that the compound at p. 78 of Akinc is removed by proviso, and thus one of ordinary skill in the art would not have looked to this compound in this first place.
As described in the above rejections, the present rejection relies on Brito teaching carbamate groups as head groups, and relies on Manoharan ‘373 in place of Akinc teaching an alkyl group with the required branched structure. Accordingly, these rejections are deemed proper.
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 C8-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 an express teaching that the C1-2 alkyl group of R6 may be substituted with additional alkyl groups, and thus this group would overlap with the size of the alkyl groups of R100 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 C8-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 C8-C12 alkyl group because Colletti ‘126 teaches that the C1-C2 alkyl group may be substituted by additional alkyl substituents, including C1-C6 alkyl groups, and thus one of ordinary skill in the art would have considered alkyl groups of this size in this position of compound 172, arriving at a compound with a C8 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 C8-C12 alkyl group because Colletti ‘126 teaches that the C1-C2 alkyl group may be substituted by C1-C6 alkyl substituents, and thus one of ordinary skill in the art would have had a reasonable expectation that said substitution 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 would have generated a compound with s as 3, as required by claims 25-26, and is taught as one such substition by Colletti ‘126. 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 previous rejection under 35 U.S.C. over Colletti ‘126 in view of Akinc, Applicant argues that each of the exemplified compounds of Colletti ‘126 that contains a terminal CO2(alkyl) group contains only either a -CO2Me or a -CO2Et group, and that Colletti ‘126 specifies in the very broad genus of compounds of Formula A at page 2 that in the chain -R5-Q2-R6, variable R6 is a C1-C2 alkyl group, which may be optionally substituted with one to three R' groups. Applicant argues that variable R' may be selected from multiple options (halogen, R", -OR", -SR", -CN, -CO2R" and - CON(R")2) in which R" may itself be selected from multiple options (H and C1-6 alkyl, which may be substituted with halogen and -OH). Applicant argues that there is nothing in Colletti ‘126 that would motivate a person of ordinary skill in the art to (i) specifically select R" as variable R', and then (ii) specifically select unsubstituted C1-6 alkyl variable R".
Applicant’s arguments have been fully considered but they are not persuasive. Because Colletti ‘126 expressly suggests groups for 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 are taught by Colletti ‘126 as potential modifications to the compounds of 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.
Claims 1-22 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Colletti ‘126 in view of Manoharan ‘373.
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 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, and claim 8 requires Z2 is (CH2)9CH=CHCH2CH=CH(CH2)4CH3.
Claim 9 claims a compound selected from those listed in claim 9.
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 group s is 3-5 and 4, claims 15 and 16 require variable group t is 4-6 and 5, claims 17 and 18 require variable group q is 2-4 and 3, claims 19 and 20 require variable group u is 0-2 and 1, and claims 21-22 require variable group 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, 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, 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, and 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; cited in previous office action) discloses the pKa of head group number 52, which is 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 cationic lipids, 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 example 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 groups prior art elements 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 previous rejection under 35 U.S.C. 103 over Colletti ‘126 in view of Akinc, Applicant argues that each of the exemplified compounds of Colletti ‘126 that contains a terminal CO2(alkyl) group contains only either a -CO2Me or a -CO2Et group, and that Colletti ‘126 specifies in the very broad genus of compounds of Formula A at page 2 that in the chain -R5-Q2-R6 variable R6 is a C1-C2 alkyl group, which may be optionally substituted with one to three R' groups. Applicant argues that variable R' may be selected from multiple options (halogen, R", -OR", -SR", -CN, -CO2R" and - CON(R")2) in which R" may itself be selected from multiple options (H and C1-6 alkyl, which may be substituted with halogen and -OH).
Applicant argues that there is nothing in Colletti ‘126 that would motivate a person of ordinary skill in the art to (i) specifically select R" as variable R', and then (ii) specifically select unsubstituted C1-6 alkyl variable R", and that there is no motivation in Colletti ‘126 to specifically a C6-C14 branched alkyl group, as recited in claim 1, or the specific group -(CH2)u-CH(iPr)-(CH2)v-CH2-CH(Me)2, as recited in claim 10.
Applicant’s arguments have been fully considered but they are not persuasive. Because Colletti ‘126 expressly suggests groups for 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 are taught by Colletti ‘126 as potential modifications to the compounds of 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.
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 considered additional alkyl groups known in the art 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, and contemplated a derivative of compound 172 that substitutes such an alkyl group, 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 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.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/SCARLETT Y GOON/ Supervisory Patent Examiner, Art Unit 1693
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