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
This application claims benefit of priority to Provisional Application 63/021,554 filed on 05/07/2020. This application is also a Continuation of PCT/US2021/031213 filed on 05/07/2021.
Amendment and Claim Status
In the reply filed on 02/26/2026, Applicant amended claims 1, 3, 11-12 and 17-18 and canceled claim 2. Claims 14-16 remain withdrawn.
Claims 1 and 3-18 are currently pending.
Claims 14-16 are withdrawn.
Claims 1, 3-13 and 17-18 are under examination.
Claim Rejections - 35 USC § 103
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, 3-6 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Katz et al. (US 8420833 B2, 04/16/2013) (IDS Reference of 08/08/2023)1 as applied to claims 1 and 4-6 above, and further in view of Katz et al. (US 8852902 B2, 10/07/2014) (IDS Reference of 08/08/2023)2.
Regarding claim 1, Katz et al.1 disclose a non-naturally occurring, reading on engineered, polyketide synthase (PKS) capable of synthesizing a carboxylic acid or a lactone, and a composition such that a carboxylic acid or lactone is included (Abstract). Further,
A method of producing a lactone of Formula (II),
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wherein R4 is H or —CH3; and R5 and R6 are each independently H, —CH3, or —CH2CH3; and m is 1, 3, 5, 7, or 9; with the proviso that when m is 3, 5, 7, or 9, then R4 is H or —CH3 and R5 and R6 are each H; and
wherein the method comprises culturing a host cell comprising a vector encoding a non-naturally occurring polyketide synthase in a culture medium under conditions where the PKS is expressed and the lactone is produced, wherein the PKS comprises a loading domain, two or more extender modules, and a thioesterase domain positioned 3′ to the terminal extender module, and the PKS is a hybrid PKS comprising a combination of modules which in nature are not found in this combination (Claim 8).
Katz et al.1 go on to disclose multiple delta lactones in Figure 6 which utilize a spiramycin and chalcomycin module and the delta lactones of Figure 7 utilize spinosyn and tylosin modules. Each lactone presented in Figures 6 and 7 contains multiple modules, each of which contains an actyltransferase (AT). As each module is from a different source, the module containing an AT reads on a first acyltransferase swap. Additionally, the extender modules, the modules after the loading module, contain reductive loops from difference sources, and therefore read on a reductive loop swap. For example, TylosinLD-Mod1-nysmod5-eryTE from Figure 7, contains four modules, the first three contain AT and the middle two contain a reductive loop, from different sources, reading on a AT swap and an RL swap. Katz et al.1 further disclose the modules can be cloned in vectors that can be introduced into a variety of Streptomyces hosts (Column 15, Lines 19-20).
Regarding the new limitations of claim 1 that were previously limitations of now canceled claim 2, Katz et al.1 do not disclose the PKS comprises a lipomycin (Lip) PKS 1 (LipPKS1) module comprising a first AT swap or a second LipPKS2 module comprising the RL swap.
However, Katz et al.2 disclose a polyketide synthase (PKS) capable of synthesizing trimethylpentanoic acid (Abstract). It is noted trimethylpentanoic acid is a carboxylic acid and Katz et al.1 disclose a PKS for producing a carboxylic acid or a lactone. Therefore, it appears the method of making a carboxylic acid could also produce a lactone. Katz et al.2 further disclose the PKS comprises a loading module capable of using isobutyryl-CoA as a starter unit, wherein that loading module can be KS1 of Lipomycin (Column 6, Lines 57-59). Additionally, Figures 2C and 2D of Katz et al.2 further show the use of Lipomycin Load Module for AT, ACP and KS1.
Exemplary rationales that may support a conclusion of obviousness include simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the spiramycin or chalcomycin module for a lipomycin load module for the AT and RL swap in the polyketide synthase of Katz et al.1 as it was a known and effective load module for building polyketide synthases, and all three are antibiotics, as disclosed by Katz et al.2 as it amounts to simply substitution of one known element for another to obtain predictable results.
Regarding claim 3, Katz et al.1 disclose a second module comprising a second AT swap
(Figure 6).
Regarding claims 4-5, Katz et al.1 disclose a dimethylated delta-lactone and a single-methylated delta-lactone (Figure 6).
Regarding claim 6, Katz et al.1 disclose a nonmethylated delta-lactone (Figure 7).
Regarding claim 12, Katz et al.1 disclose the acyltransferase domain of each module determines the extender unit incorporated, e.g., malonyl CoA, methylmalonyl CoA (Paragraph [0056]). The ketoreductase (KR) domain reduces the ketone to the OH function, the dehydratase (DH) domain removes water from the α and β carbons and the enoylreductase domain (ER) reduces the double bond to a β-methylene center (Column 11, Lines 35-38). Katz et al.1 further disclose a delta lactone wherein a malonyl-CoA selecting analog, AT is a malonyl-CoA selecting analog, is employed in the first and second module (Figure 6). Further, multiple lactones from Figure 7 comprise a first and second module containing an AT, a KR only in the first module and a full reductive loop in the second module. For example, TylosinLD-Mod1-nysmod5-eryTE from Figure 7 shows a loader module, a first extender module containing KS, AT, KR and ACP and a second extender module containing KS, AT, DH, ER, KR and ACP. The combination of KR, DH and ER constitute a full reductive loop. Thus, this disclosure meets the limitations of instant claim 12.
Claims 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Katz et al. (US 8420833 B2, 04/16/2013) (IDS Reference of 08/08/2023)1 as applied to claims 1 and 4-6 above, and further in view of Hagen et al. (US 20180273930 A1, 09/27/2018) (IDS Reference of 08/08/2023).
The teachings of Katz et al.1 are disclosed above.
Regarding claims 7 and 9, Katz et al.1 do not disclose the first AT swap being a borrelidin (Bor) AT swap or the second AT being a borrelidin (Bor) AT swap.
However, Hagen et al. disclose a polyketide synthase capable of synthesizing a carboxylic acid wherein the PKS comprises a synthetic or hybrid module (Abstract). Hagen et al. further disclose a polyketide synthase capable of synthesizing a carboxylic acid comprising a BorA2 KS domain, a BorA2 AT domain, a heterologous KR domain, a heterologous ER domain and a BorA2 ACP domain (Paragraph [0010]).
Exemplary rationales that may support a conclusion of obviousness include simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the AT domain in the spiramycin or chalcomycin module for a borrelidin (Bor) AT domain in the composition of Katz et al.1 as it was a known and effective module containing an AT domain for building polyketide synthases as disclosed by Hagen et al. as it amounts to simply substitution of one known element for another to obtain predictable results.
Regarding claim 8, Katz et al.1 do not disclose the RL swap is a nanchangamycin (NanA2) RL swap.
However, Hagen et al. disclose the heterologous KR domain and ER domain can be NanA2 (Paragraph [0040]). KR and ER domains are both reductive loop (RL) domains.
Exemplary rationales that may support a conclusion of obviousness include simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the RL with the NanA2 RL in the composition of Katz et al.1 as it was a known and effective RL for building polyketide synthases as disclosed by Hagen et al. as it amounts to simply substitution of one known element for another to obtain predictable results.
Regarding claim 10, Katz et al.1 do not disclose the first AT swap being a Bor AT swap or the RL swap being a NanA2 RL swap to produce a single-methylated delta lactone.
However, Katz et al.1 do disclose a PKS for producing a single-methylated delta lactone, as discussed regarding claims 1 and 5. Additionally, Hagen et al. disclose the use of Bor AT and NaNA2 RL as discussed regarding claims 7 and 8.
Thus, the combination of Katz et al.1 and Hagen et al. makes obvious a PKS for producing a single-methylated delta lactone with the first AT swap being a Bor AT swap and the RL swap being a NanA2 RL swap.
Regarding claim 11, Katz et al.1 do not disclose the first AT swap being a Bor AT swap, the RL swap being a NanA2 RL swap or a LipPKS2 module comprising a second AT swap to produce a non-methylated delta lactone.
However, Katz et al.1 do disclose a PKS for producing a non-methylated delta lactone, as discussed regarding claims 1 and 6. Additionally, Hagen et al. disclose the use of Bor AT and NaNA2 RL as discussed regarding claims 7-9.
Thus, the combination of Katz et al.1 and Hagen et al. makes obvious a PKS for producing a non-methylated delta lactone with the first AT swap being a Bor AT swap, the RL swap being a NanA2 RL swap and a second LipPKS2 module comprising a second AT swap.
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Katz et al. (US 8420833 B2, 04/16/2013) (IDS Reference of 08/08/2023)1 in view of Katz et al. (US 8852902 B2, 10/07/2014)2 as applied to claims 1 and 3-6 and 12 above, and further in view of Hagen et al. (US 20180273930 A1, 09/27/2018) (IDS Reference of 08/08/2023).
The teachings of Katz et al.1 and Katz et al.2 are disclosed above.
Regarding claim 17, neither Katz et al.1 or Katz et al.2 disclose the lipomycin PKS1 altered with an AT-swap from borrelidin and a LipPKS2 altered with a RL from NanA2 to produce a single-methylated lactone.
However, Hagen et al. disclose a polyketide synthase capable of synthesizing a carboxylic acid wherein the PKS comprises a synthetic or hybrid module (Abstract). Hagen et al. further disclose a polyketide synthase capable of synthesizing a carboxylic acid comprising a BorA2 KS domain, a BorA2 AT domain, a heterologous KR domain, a heterologous ER domain and a BorA2 ACP domain (Paragraph [0010]).
Exemplary rationales that may support a conclusion of obviousness include simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the AT in LipPKS1 for a borrelidin (Bor) AT in the method of Katz et al.1/Katz et al.2 as it was a known and effective AT in polyketide synthases as disclosed by Hagen et al. as it amounts to simply substitution of one known element for another to obtain predictable results.
Additionally, it is noted there is no definition of ‘configured to’ in the instant Specification. Therefore, ‘configured to’ is interpreted to simply mean ‘capable of.’
As such, the combination of Katz et al.1/Katz et al.2 and Hagen et al. would be expected to be capable of producing a single-methylated lactone.
Regarding claim 18, neither Katz et al.1 nor Katz et al.2 disclose an AT swap on LipPKS2 from borrelidin to produce a non-methylated delta lactone.
However, as disclosed above regarding claim 17, the AT in borreledin is a known and effective AT. Further, Katz et al.1 disclose the acyltransferase domain of each module determines the extender unit incorporated, e.g., malonyl CoA, methylmalonyl CoA (Column 11, Lines 35-38). Therefore, as the AT domain is responsible for the extender unit incorporated onto the polyketide chain, it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add an AT swap to LipPKS2 to produce a polyketide synthase with the number of extender units desired. For example, to create a non-methylated delta lactone, adding an AT could further extend the chain and go from a methylated delta lactone to an ethylated delta lactone. An ethylated delta lactone with no methyl constituents reads on a non-methylated delta lactone.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Katz et al. (US 8420833 B2, 04/16/2013) (IDS Reference of 08/08/2023)1 as applied to claims 1 and 4-6 above, and further in view of Salas et al. (US 20090286291 A1, 11/12/2009) (IDS Reference of 08/08/2023).
The teachings of Katz et al.1 are discussed above.
Regarding claim 13, Katz et al.1 does not disclose wherein the microbe is Streptomyces albus.
However, Salas et al. disclose the biosynthesis of polyketides, including polyketide synthase (Abstract). Salas et al. further disclose a host cell capable of expressing a polyketide synthase (Claim 74), wherein the microbe is selected from a group including Streptomyces albus (Claim 80).
As such, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized Streptomyces albus as the microbe in the polyketide synthase of Katz et al.1 as it was a known and effective microbe for expressing a polyketide synthase in the prior art as disclosed by Salas et al.
USC § 103 – Response to Arguments
Applicant's arguments filed 02/26/2026 have been fully considered but they are not persuasive.
In the reply filed 02/26/2026, Applicant argued neither Katz 1 nor Katz 2 teach, suggest or motivate a LipPKS1 module comprising an acyltransferase swap and a LipPKS2 module comprising a reductive loop swap on Page 10.
It is the Examiner’s position that Katz 1 in view of Katz 2 does teach, suggest or motivate such swaps for the reasons stated above. Additionally, it is noted the Applicant stated Katz 2 only recites ‘lipomycin’ twice. It is the Examiner’s position that the recitations of lipomycin recited by Katz 2 are not the only teachings of Katz 2 utilized for the rejection set forth above. As stated in the Non-Final mailed 08/26/2025 and restated above, Katz 2 specifically discloses the use of a Lipomycin Load Module in Figures 2C and 2D. Therefore, it is simple substitution to swap known components of polyketide synthases.
The remainder of Applicant’s arguments state the additional references utilized by the Examiner do not teach, suggest or motivate a LipPKS1 module comprising an acyltransferase swap and a LipPKS2 module comprising a reductive loop swap.
The additional references were not utilized to teach, suggest or motivate such. Additionally, this argument was addressed immediately above.
Conclusion
Claims 1, 3-13 and 17-18 are rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653