DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-5 and 13-17) and species of:
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in the reply filed on 06/01/2026 is acknowledged. The traversal is on the ground(s) that 1) Written Opinion of the ISA did not indicate lack of unity and that the requirements of 37 CFR 1.475(b) are satisfied. This is not found persuasive because “The examiner may make a lack of unity requirement in a national stage application even if no such requirement was made by the ISA or IPEA.” MPEP 1893.03(d). Unity of Invention requires satisfaction of the provision of both 37 CFR 1.475(a) and 1.475(b). The requirements of 37 CFR 1.475(a) are not met since the claims do not recite a special technical feature that makes a contribution over the prior art for the reasons set forth in the prior Office Action and rejections over prior art set forth below.
The requirement is still deemed proper and is therefore made FINAL.
Claims 6-12 and 18-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/01/2026.
Claims 5 and 17 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/01/2026. Claim 4 reads on the elected species of fourth enzyme and not claim 5. Claim 16 reads on the recited species of third enzyme and not claim 17.
Claim Interpretation
The various second, third and fourth enzymes are not required to operate on a specific substrate, although any embodiment of the alims must produce tulipalin A. The first enzyme is understood to have an activity to operate on itaconic acid as a substrate. In particular, the fourth enzyme is not recited to catalyze any particular reaction and an embodiment of claim 4 is a thioesterase or a lactonase being contacted and carrying out no reaction.
In claim 4, “selected from the group consisting of at least one thioesterase and at least one lactonase” is understood to mean a lactonase or a thioesterase, particularly in view of recitation of “a” (i.e. singular) fourth enzyme. A lactonase is understood to be distinct from a carboxyesterase. If both a lactonase and a thioesterase are intended, claim 4 could be amended to recite “the method further comprises contacting the reaction mixture with a lactonase and a thioesterase.”
In claims 3 and 4, recitation of a third or a fourth enzyme is not interpreted as requiring that three or four enzymes, respectively are present. For example, an embodiment of claim 4 is contacting the reaction mixture with the first enzyme and a fourth enzyme without a second or third enzyme.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 13 and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Selifonov et al. (WO 01/68803 A2, Maxygen, Inc.) (see IDS 03/13/2024) as evidenced by Uniprot, Accession No. P38947, 2020, www.uniprot.org.
Selifonov, abstract, states:
Methods for producing enzymes, biochemical pathways, and whole cell bioprocesses that convert simple carbon sources into polymerizable substrates, and into polyhydroxyalkanoates (PHAs) are provided. Artificial pathways for converting itaconate to the polymerizable substrate methylene-y-butyrolactone via regioselective reduction of the C(1) or C(4) carbons are described. Novel enzymes for converting such polymerizable substrates to PHA are provided.
“Embodiments provide independent conversion steps which can be practiced in vitro or by transforming one or more suitable hosts, either singly or in combination.” “Recombinant, isolated, or artificially evolved enzymes, or a combination thereof, can be supplied as assay components (e.g., bioreactors) of the kits or systems of the present invention, to catalyze the conversion of selected reactants to one or more products, e.g., the conversion of inexpensive carbon sources to useful products. In certain embodiments, reactants can be added to a reaction mixture in solution, e.g., as a in batch method approach, or into the liquid stream of a continuous feed process.”
The above is understood as describing that the various biochemical pathways described by Selifonov can be performed in vitro by providing a reaction mixture containing appropriate starting materials and enzymes as described by Selifonov, as further indicated in claims 1 and 18 of Selifonov.
Figure 1 is a schematic illustration of an artificial regioselective reduction pathway for the enzymatic conversion of itaconate to 2-methylene-4(y)-hydroxybutyrate.” Selifonov, page 2, 15-16.
Fig. 1 of Selifonov shows a process of producing 2-methylene-γ-buyrolactone (MBL) from a pathway starting from itaconate (itaconic acid) converting itaconate to itaconyl-CoA with a first enzyme being succinate-citramalate-itaconitate CoA-transferase (i.e. an itaconate CoA-transferase), which anticipates claims 1 and 13.
Regarding claim 2 and 15, Figure 1 of Selifonov shows a second enzyme converting itaconyl-CoA to itaconic 4-semialdehyde that is a coenzyme A- and NADP-dependent succinate semialdehyde dehydrogenase (SucD) that is understood to be an oxidoreductase. Regarding claim 15, a succinate semialdehyde dehydrogenase (oxidizing a semialdehyde to a carboxylic acid CoA ester) and a succinyl-CoA reductase (reducing a carboxylic acid CoA ester to a semialdehyde) are the same enzyme. That is, an enzyme catalyzing the reversible conversion of an acyl-CoA thioester to an aldehyde can be named as oxidizing an aldehyde (i.e. aldehyde or semialdehyde dehydrogenase) or as reducing an acyl-CoA thioester (i.e. acyl-CoA reductase), but nevertheless are synonyms for the same enzymatic activity. For example, Table 1 (page 10) of Selifonov references protein P38947 as an exemplary succinate-semialdehyde dehydrogenase enzyme wherein Uniprot P38947 evidences is an enzyme classified as EC 1.2.1.76 (succinate-semialdehyde dehydrogenase (acetylating). The specification, page 25, defines succinyl-CoA reductase as an enzyme classified as EC 1.2.1.76.
Regarding claim 3, Figure 1 of Selifonov shows a third enzyme converting itaconic 4-semialdehyde to 2-methylene-4-hydroxybutyrate (2-methylene-4-ol-butyric acid) being an NAD-dependent 4-hydroxybutyrate dehydrogenase, that is an alcohol dehydrogenase converting an aldehyde group to a hydroxy group.
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.
Claim(s) 1-3 and 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Selifonov et al. (WO 01/68803 A2, Maxygen, Inc.) (see IDS 03/13/2024) as evidenced by Uniprot, Accession No. P38947, 2020, www.uniprot.org as applied to claim 1-3, 13 and 15 above, and further in view of Uniprot, Accession No. P0A836, 2020, www.uniprot.org, and Uniprot, Accession No. P0AGE9, 2020, www.uniprot.org.
Regarding claim 14, “In some embodiments, an enzyme with itaconate-itaconyl-CoA converting activity is artificially evolved from a sucC and/or sucD gene derived from E.coli.” Selifonov, page 3, lines 32-33. In view of such a direct teaching to employ an evolved sucD and/or sucD gene, an ordinarily skill artisan at time of filing would have been motivated to utilize the enzymes encoded by such genes in an in vitro method for conversion of itaconic acid to tulipalin A as taught by Selifonov. More specifically, while a itaconate-CoA transferase is discussed above, Selifonov teach that at least an evolved form of the enzymes encoded by sucC and sucD from E. coli can catalyze the same conversion of itaconate to itaconyl-CoA and directly suggests utilizing the same enzyme.
Uniprot P0A836 teaches that the sucC gene from E. coli strain K12 encodes an enzyme having over 99% identity to recited SEQ ID NO: 2. Uniprot P0AGE9 teaches that the sucD gene from E. coli strain K12 encodes an enzyme having over 99% identity to recited SEQ ID NO: 4.
As such, the cited prior art suggests that any “evolved” from of enzymes encoded by sucC and sucD genes that are suggested by Selifonov would have at least 70% identity to recited SEQ ID NOS: 2 and 4, respectively. As such, an ordinarily skilled artisan at time of filing would have been motivated to employ an enzyme having itaconate-itaconyl-CoA converting activity (first enzyme) having a high degree of identity to SEQ ID NOS: 2 and 4 (including over 70% identity) within the methods of Selifonov as discussed above.
Claim(s) 1-4, 13 and 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Selifonov et al. (WO 01/68803 A2, Maxygen, Inc.) (see IDS 03/13/2024) as evidenced by Uniprot, Accession No. P38947, 2020, www.uniprot.org as applied to claims 1-3, 13 and 15 above, and further in view of Lau et al. (WO 2016/196962 A1) (see IDS, 03/13/2024) and GenBank, Accession No. BAE77068, 2018, www.ncbi.nlm.nih.gov.
Lau, abstract, states:
The description relates to, inter alia, recombinant microorganisms, engineered metabolic pathways, chemical catalysts, and products produced through the use of the described methods and materials. The products produced include functionalized alpha substituted C4 dicarboxylic acids, as well as functionalized malonyl-CoA, malonic semialdehyde, and acrylic acids, and their salts, esters and lactones.
Figure 17 shows a fully biological route to alpha hydroxyethyl acrylic acid using the itaconic acid intermediate. The alpha hydroxyethyl acrylic acid can be converted to the lactone form, tulipalin A, by an enzyme having the activity described in the table of Figure 18, row C. Figure 18 shows a table which includes specific enzymes that can be used to make recombinant microorganisms to produce the alpha hydroxyethyl acrylic acid and/or tulipalin A from itaconic acid, for instance, through the route illustrated in Figure 17.
Fig. 17 is as follows:
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Fig. 18 is as follows:
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Lau appears to only teach recombinant microorganisms engineered with pathways as described above. However, as discussed above, Selifonov teaches that conversion of itaconic acid to tulipalin A (2-methylene-4(γ)-hydroxybutyrate) can be implemented by engineered a pathway in a microorganism or by providing the appropriate enzymes and starting material (e.g. itaconic acid) in vitro in a reaction mixture. As such, at the time of filing an ordinarily skilled artisan would have been motivated to implement the reactions shown in Fig. 17 of Lau converting itaconic acid to tulipalin A in vitro in a reaction mixture, since Selifonov teaches that it is advantageous to produce tulipalin A in an in vitro reaction mixture as an advantageous method of producing tulipalin A from itaconic acid.
Figs. 17 and 18 of Lau disclose a pathway/method for producing tulipalin A ([Symbol font/0x61]-methylene-y-butyrolactone) from itaconic acid by reacting/contacting itaconic acid with a first enzyme being succinate-semialdehyde dehydrogenase or an aldehyde reductase. Fig. 17 shows the catalyzed reaction being reduction of a carboxylic acid group in itaconic acid to an aldehyde group in 2-methylene-succinyl semialdehyde (same compound as itaconate semialdehyde shown in Fig. 2 of specification). Such a catalyzed reduction is necessarily a carboxylic acid reductase reaction. That is, aldehyde dehydrogenase is a synonym for carboxylic acid reductase.
Figs. 17 and 18 of Lau further report conversion of 2-methylene-succinyl semialdehyde (itaconate semialdehyde) to alpha-hydroxyethyl acrylate (2-methylene-4-ol-butyric acid as shown in Fig. 2 of the specification) by activity of an aldehyde reductase, wherein aldehyde reductase (reducing an aldehyde to an alcohol) is a synonym for an alcohol dehydrogenase (third enzyme) as recited in claim 3. Figs. 17 and 18 further report conversion of alpha-hydroxyethyl acrylate (2-methylene-4-ol-butyric acid) to tulipalin A with a 1,4-lactonase (fourth enzyme). Upon implementing this same pathway as shown in Figs. 17 and 18 of Lau in an in vitro reaction mixture having itaconic acid as a starting material and three enzymes described above, the features of claims 1, 3-4 and 13 are reached.
Regarding claim 16, Fig. 17 of Selifonov states that the aldehyde reductase (alcohol dehydrogenases) can be GenBank BAE77068. GenBank BAE77068 evidences that such an alcohol dehydrogenase is identical to recited SEQ ID NO: 42. As such, the teachings of Selifonov and Lau directly suggest that an enzyme (alcohol dehydrogenase) identical to SEQ ID NO: 42 be used to convert itaconic acid to tulipalin A such that an ordinarily skilled artisan at time of filing would have been motivated to do the same.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TODD M EPSTEIN whose telephone number is (571)272-5141. The examiner can normally be reached Mon-Fri 9:00a-5:30p.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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