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 .
This action is written in response to applicant’s correspondence received July 10, 2025. Claims 1-36, 39, 46-47, 49, 51, 53, 55, 57, and 59 are cancelled. Claims 37-38, 40-45, 48, 50, 52, 54, 56 and 58 are currently pending. Claims 40, 44-45, 48, 50, 52, 54, 56 and 58 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 37-38 and 41-43 are examined herein.
Election/Restrictions
The restriction requirements mailed April 11, 2023 and June 6, 2023 are still deemed proper. Applicant elected claim 37 (a) of (i): EC 2.8.3.- and EC 3.1.2.-, and more specifically of enzyme classes: EC 2.8.3.1 and EC 3.1.2.1 (see, for example, claim 38) and for Claim 37 (b) of (iii): EC 6.4.1.4 (see, for example, claim 41), and more specifically of enzyme class: EC 6.4.1.4 (see, for example claim 41) without traverse in the reply filed June 9, 2023 and further elected Group III (B) – “microorganisms” without traverse in the reply filed August 30, 2023.
Claims 40 and 44, 45, 48, 50, 52, 54, 56, 58 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/9/23 and 8/30/23.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Objections – withdrawn
Objection to claim 37 is withdrawn in view of Applicant’s amendment to remove additional periods.
Claim Objections
Claim 42 is objected to because of the following informalities: term (EC 4.2.1.-) is used for two different enzymes. According to the specification on page 68, the term used for 3-hydroxybutyryl-CoA dehydratase should be (EC 4.2.1.55) and the term for enoyl-CoA hydratase should be (EC 4.2.1.17). Appropriate correction is required.
Claim Rejections - 35 USC § 112 – necessitated by amendment
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 41 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 41, depending from amended claim 37, recites “The recombinant organism or microorganism of claim 37, wherein the recombinant organism or microorganism further expresses a polypeptide selected from a methylcrotonyl-CoA carboxylase (EC 6.4.1.4) or a geranoyl-CoA carboxylase (EC 6.4.1.5).”. Claim 37 requires only one of five 3-methylcrotonic acid decarboxylases “selected from:
an FMN-dependent decarboxylase associated with an FMN prenyl transferase (EC 2.5.1.-);
an aconitate decarboxylase (EC 4.1.1.6);
a methylcrotonyl-CoA carboxylase (EC 6.4.1.4);
a geranoyl-CoA carboxylase (EC 6.4.1.5); or
a protocatechuate (PCA) decarboxylase (EC 4.1.1.63)”.
One of the 3-methylcrotonic acid decarboxylases of claim 37 is methylcrotonyl-CoA carboxylase (EC 6.4.1.4). Claim 41 then requires a recombinant organism or microorganism of claim 37, already expressing a methylcrotonyl-CoA carboxylase (EC 6.4.1.4) to “further express” that same methylcrotonyl-CoA carboxylase (EC 6.4.1.4). Therefore, claim 41 fails to further limit the subject matter of the claim from which it depends.
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 § 102 – necessitated by amendment
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 37-38 and 41-43 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Allard et al. (US11124806; published 9/21/2021). This is a new rejection necessitated by the amendment to independent claim 37 removing the recitation requiring both “a CoA transferase (EC 2.8.3.-) and a thioester hydrolase (EC 3.1.2.-)”, thereby changing the scope of the independent claim.
Regarding claim 37, Allard teaches, in claim 1, a method of producing isobutene comprising (a) i) a CoA transferase (EC 2.8.3.-), ii) a thioester hydrolase (EC 3.1.2.-), or iii) a phosphate acetyltransferase (EC 2.3.1.8) and a phosphotransferase with a carboxy group as acceptor (EC 2.7.2.-), and (b) a 3-methylcrotonic acid decarboxylase selected from: i) an FMN-dependent decarboxylase associated with an FMN prenyl transferase (EC 2.5.1.-); or ii) an aconitate decarboxylase (EC 4.1.1.6); or iii) a methylcrotonyl-CoA carboxylase (EC 6.4.1.4); or iv) a geranoyl-CoA carboxylase (EC 6.4.1.5); or v) a protocatechuate (PCA) decarboxylase (EC 4.1.1.63). Allard teaches recombinant organisms and microorganisms for producing isobutene expressing the combinations of enzymes recited in instant claim 37 (columns 51-53 and entire document).
Regarding claim 38, Allard teaches the CoA transferase (EC 2.8.3.-) is selected from a propionate:acetate-CoA transferase (EC 2.8.3.1), an acetate CoA-transferase (EC 2.8.3.8) or a succinyl-CoA:acetate CoA-transferase (EC 2.8.3.18) (see claim 2).
Regarding claim 41, Allard teaches the method using a methylcrotonyl-CoA carboxylase (EC 6.4.1.4) or a geranoyl-CoA carboxylase (EC 6.4.1.5) (see claim 5).
Regarding claim 42, Allard teaches the method using a 3-methylglutaconyl-coenzyme A hydratase (EC 4.2.1.18), a 3-hydroxyacyl-CoA dehydratase (EC 4.2.1.-) or an enoyl-CoA hydratase (EC 4.2.1.-) (claim 6).
Regarding claim 43, Allard teaches using a HMG- CoA synthase (EC 2.3.3.10) (see column 16, lines 22-28; column 38, lines 21-33; and column 62, lines 4-21).
Allard teaches each and every limitation of claims 37-38 and 41-43, and therefore, Ruddock anticipates claims 37-38 and 41-43.
Claim Rejections - 35 USC § 103 - maintained
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.
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 37-38 and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over Guentner (WO2016034691A1; filed September 3, 2015; cited in the IDS filed June 29, 2021). This rejection has been modified in view of Applicant’s amendment to cancel claim 39 and to amend claim 37 to remove “a thioesterase (EC 3.1.2.-)”.
The claimed invention embraces a recombinant microorganism or organism capable of producing isobutene, the term ‘capable’ does not require that the organism or microorganism actually produce isobutene. The microorganism or organism expresses EC 2.8.3.- or EC 2.3.1.8 and EC 2.7.2.- and a 3-methylcrononic acid decarboxylase selected from items i)-v) in instant claim 37.
Guentner’s disclosure is directed to recombinant microorganisms comprising endogenous enzymes that convert acetyl-CoA to alkenes (see abstract).
Regarding claim 37, Guentner teaches a recombinant microorganism comprising heterologous nucleic acid sequences encoding enzymes capable of producing isobutene (paras 0157, 0233, 0293, and 0302). Furthermore, Guentner teaches pathways, including key enzymes, specifically to produce isobutene from carbon monoxide and/or from carbon dioxide and identifies relevant intermediates such as acetyl-CoA, HMG-CoA, 3-methylcrotonyl-CoA, and 3-methylcrotonate through enzymatic reactions (see para 0157 describing FIG. 1E). Guentner teaches recombinant microorganisms expressing the enzyme CoA transferase (EC 2.8.3.-) and a thioesterase (EC 3.1.2.-) to produce alkenes (see at least paras 0057-0061, 0082-0083, 0090-0091, 0094, 0139-140, 0146, 0148-0149, 0302, 0308, 0310, 0318, 0322, and claim 8). Guentner further teaches recombinant microorganisms expressing 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (see at least paras 0022, 0062-0065, 0112, 0134, and 0340). Guentner further teaches recombinant microorganisms expressing enzyme butyrate kinase (EC 2.7.2.7) (see at least paras 0025, 0034-0038, 0045-0048, 0050, 0054, 0085-0089, 0097-0098, 0100, 0116, 0121-0123, 0127-0130, 0137-0147 and 0149). Guentner teaches Plasmid SG582 comprising an acyl-CoA thioesterase enzyme (EC 3.1.2.-) WP 000637982.1 and a 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) WP_003113506.1 and WP_003100387.1, Plasmid SG601 comprising an acyl-CoA thioesterase enzyme (EC 3.1.2.-) WP_005652441.1 and a 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) WP_003113506.1, Plasmid SG882 comprising an acyl-CoA thioesterase enzyme (EC 3.1.2.-) WP 000637982.1 and a 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) WP_003113506.1 and WP_003100387.1 and Plasmid SG901 comprising an acyl-CoA thioesterase enzyme (EC 3.1.2.-) WP_005652441.1 and a 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) WP_003113506.1 (see Figure 66).
However, Guentner does not specifically teach a recombinant microorganism expressing the combinations of enzymes cited in claim 37.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Guentner by trying different combinations of enzymes to produce isobutene. One of ordinary skill in the art would have been motivated to try different combinations of enzymes to maximize the yield of isobutene produced. Guentner teaches intermediates and enzymes necessary to specifically produce isobutene (see para 0157 and FIG. 1). One of ordinary skill in the art would have had a reasonable expectation of success of arriving at the claimed invention comprising a CoA transferase (EC 2.8.3.-) and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) because the reference teaches various combinations of enzyme classes and specific enzymes to produce alkenes, including isobutene, and it would have amounted to a simple substitution of known elements. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 38, Guentner teaches the CoA transferase EC 2.8.3.1 (see paras 0058 and 0302).
Regarding claim 41, Guentner teaches recombinant microorganisms expressing 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (see at least paras 0062-0065, 0112, 0134, and 0340).
Regarding claim 42, Guentner teaches 3-methylglutaconyl-CoA hydratase (EC 4.2.1.18), (see paras 0022, 0062-0065, 0070-0073, 0077, 0100, 0112, 0134, 0138, and 0339). Guentner further teaches the enzyme enoyl-CoA hydratase 2 (EC 4.2.1.119) (see at least paras 0021, 0068-0069, 0049-0050, 0089-0092, 0095, 0110, and 0331).
Regarding claim 43, Guentner teaches 3-hydroxy-3-methylglutaryl-CoA synthase (see at least paras 0022, 0065, 0070-0073, 0076-0077, 0112, 0134, 0138, and 0338).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Guentner by trying different combinations of enzymes to produce isobutene. One of ordinary skill in the art would have been motivated to try different combinations of enzymes to maximize the yield of isobutene produced. One of ordinary skill in the art would have had a reasonable expectation of success because the references teaches various combinations of enzyme classes and specific enzymes to produce alkenes, including isobutene, and it would have amounted to a simple substitution of known elements because Guentner teaches intermediates and enzymes necessary to specifically produce isobutene. Thus, the claimed invention as a whole is prima facie obvious.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the time of the effective filing date.
Response to Declaration
The declaration under 37 CFR 1.132 filed 7/10/2025 is insufficient to overcome the rejection of claims 37-38 and 41-43 based upon obviousness over Guentner (WO2016034691A1; filed September 3, 2015; cited in the IDS filed June 29, 2021) under 35 U.S.C. 103 as set forth in the last Office action because: the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
In the declaration entitled “Declaration Under 37 C.F.R § 1.132 By Frédéric Pâques”, Dr. Pâques gives his opinion as to whether the teachings Guentner teaches a person reading and understanding the following claim (referred to as “claim 37”): A recombinant organism or microorganism capable of producing isobutene and comprising a polynucleotide encoding:
i) a CoA transferase (EC 2.8.3.-); or
ii) a phosphate acetyltransferase (EC 2.3.1.8) and a phosphotransferase with a carboxy group as acceptor (EC 2.7.2.-); and
a 3-methylcrotonic acid decarboxylase selected from:
an FMN-dependent decarboxylase associated with an FMN prenyl transferase (EC 2.5.1.-);
an aconitate decarboxylase (EC 4.1.1.6);
a methylcrotonyl-CoA carboxylase (EC 6.4.1.4);
a geranoyl-CoA carboxylase (EC 6.4.1.5); or
a protocatechuate (PCA) decarboxylase (EC 4.1.1.63)”.
First, Dr. Pâques establishes that the level of expertise of the POSITA is high. Dr. Pâques states that they agree with examiner’s statement in the 2/10/2004 Office Action, page 6, lines 7-8, that Guentner does not specifically teach recombinant microorganisms expressing the exact combinations of enzymes” as in claim 37.
The Office concurs with the above statement, as directed towards newly amended claim 37, though the statement was made regarding claim 37 filed on 10/02/2024. However, as discussed in the 102 rejection above over US 11124806 (“the ‘806 patent”), Allard teaches, in claim 1, a method of producing isobutene using a CoA transferase (EC 2.8.3.-) and an aconitate decarboxylase (EC 4.1.1.6). Allard further teaches recombinant organisms and microorganisms for producing isobutene expressing combinations of enzymes recited in instant claim 37 (columns 51-53 and entire document).
Dr. Pâques states that enzymes phosphate acetyltransferase (EC 2.3.1.8), FMN-dependent decarboxylase associated with an FMN prenyl transferase (EC 2.5.1.-), aconitate decarboxylase (EC 4.1.1.6), geranoyl-CoA carboxylase (EC 6.4.1.5), and protocatechuate (PCA) decarboxylase (EC 4.1.1.63) are not taught anywhere in Guentner.
This argument is not persuasive because Guentner teaches recombinant microorganisms expressing the enzyme CoA transferase (EC 2.8.3.-) to produce alkenes (see at least paras 0057-0061, 0082-0083, 0090-0091, 0094, 0139-140, 0146, 0148-0149, 0302, 0308, 0310, 0318, 0322, and claim 8) and further teaches recombinant microorganisms expressing 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (see at least paras 0022, 0062-0065, 0112, 0134, and 0340). Thus, Guentner suggests the use of these enzymes to produce alkenes.
Dr. Pâques summarizes Guentner’s teachings on pages 4-6 and states that “the Examiner has argued that because enzyme family EC 2.8.3.- is taught elsewhere in Guentner for the production of other alkenes, the skilled reader would have immediately substituted or added the use of EC 2.8.3.- to the isobutene pathway shown in Figure 1E to generate Claim 37”.
The Office disagrees with the characterization of the Office’s position that the POSITA would have “immediately” substituted or added the use of EC 2.8.3.- to the isobutene pathway shown in Figure 1E to generate claim 37. Rather, the Office believes it would have been obvious to the POSITA to have arrived at the claimed invention by trying different combinations of enzymes to maximize the yield of isobutene produced. The Office draws a distinction between a “simple” substitution of one known enzyme used for the biosynthesis of alkenes for another and an “immediate” substitution. The legal concept of prima facie obviousness does not include a POSITA “immediately” substituting one known element for another. See MPEP 2142 and 2143.MPEP 2141 II.C. Rationales to support rejections under 35 U.S.C. 103 recites, “Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art.” See also MPEP 2141. FACTORS TO CONSIDER IN DETERMINING LEVEL OF ORDINARY SKILL
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (1) "type of problems encountered in the art;" (2) "prior art solutions to those problems;" (3) "rapidity with which innovations are made;" (4) "sophistication of the technology; and" (5) "educational level of active workers in the field." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995). "In a given case, every factor may not be present, and one or more factors may predominate." Id. See also Custom Accessories, Inc. v. Jeffrey-Allan Indust., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983).
Claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Dr. Pâques summarizes more of Guentner’s teachings in paragraphs 13-16 and argues that Guentner teaches that additional enzymes would also be needed to complete the reaction to form the resulting products and that this teaches away from addition of enzyme 2.8.3.- to Figure 1E.
The Office disagrees that this teaches away from addition of enzyme 2.8.3.- to those of Figure 1E. Guentner teaches various combinations of enzyme classes and specific enzymes to produce alkenes, including isobutene. Guentner further teaches intermediates and enzymes which would render a recombinant organism or microorganism capable of producing isobutene. Claim 37 recites the limitation “wherein said microorganism expresses polypeptides comprising:…”, which is broad such that the claimed microorganism can comprise additional enzymes not recited in the claim language. Therefore, Guentner teaching additional enzymes may be required for isobutene production does not teach away from adding EC 2.8.3.-.
Additionally, claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Dr. Pâques further argues that Guentner teaches four plasmids having specific combinations of enzymes showed in Fig. 1E for producing isobutene and the POSITA would not have looked to other parts of Guentner’s teachings regarding enzyme 2.8.3.- to combine with the disclosed enzymes for producing isobutene.
In response to applicant's arguments against the different sections of the Guentner reference individually, one cannot show nonobviousness by attacking parts of the reference individually where the rejections are based on combinations of different parts of reference and the totality of the references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As detailed in the 35 U.S.C 103 rejection above, Guentner teaches intermediates and enzymes necessary to specifically produce isobutene and other alkenes (see para 0157 and FIG. 1). Guentner teaches that CoA-transferase (EC 2.8.3.-) catalyzes the conversion of acetyl-CoA to crotonyl-CoA (abstract and para 0021), that acyl-CoA thioesterase (EC 3.1.2.-) and phenyl acrylic acid decarboxylase 30 (EC 4.1.1.-) catalyze the conversion of crotonyl-CoA to an alkene (abstract and para 0025), and 3-methylcrotonylCoA carboxylase (EC 6.4.1 .4) catalyzes the conversion of acetyl-CoA to 3-methylcrotonyl-CoA (abstract and para 0022). The POSITA would not have been limited to Fig. 1E for guidance, but could refer to different parts of Guentner teaching combinations of enzymes and intermediates to produce the desired alkene. Taken together, Guentner’s teachings enzyme classes and intermediates for the POSITA to have arrived at the claimed invention capable of producing isobutene comprising a CoA transferase (EC 2.8.3.-) and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4). Furthermore, claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Dr. Pâques further argues that they did not find any suggestion in Guentner that multiple alkene pathways should be included in the same manufacturing host system and that it would result in a mixture of alkenes, requiring further processing steps and thus would not be a reasonable interpretation of Guentner. Dr. Pâques further argues that there is no motivation or suggestion to add additional enzyme family EC 2.8.3.- into the isobutene pathway described in Figure 1E. Dr. Pâques further argues that the POSITA would need to ignore the clear teaching that EC 2.8.3.- is to be used on different substrates to produce different products, none of which are included in the isobutene pathways of Figure 1E.
In response to applicant’s argument that there is no teaching, suggestion or motivation to combine different parts of the reference, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in different parts of the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Guentner teaches in the abstract that the recombinant microorganism contains a heterologous nucleic acid sequence encoding one or more enzymes that allow the conversion of acetyl-CoA to an alkene with a main chain of I to 5 carbon atom, and further teaches that the one or more enzymes catalyze the conversion of acetyl-CoA to crotonyl-CoA, of crotonyl-CoA to an alkene, or of acetyl-CoA to 3-methylcrotonyl-CoA and that further catalyze the conversion of 3-methylcrotonyl-CoA to an alkene. The Office disagrees with Dr. Pâques’s premise that the POSITA would disregard other teachings regarding EC 2.8.3.- used on different substrates to produce different products because they are not specified in the isobutene pathways of Figure 1E. Claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Furthermore, this argument is not persuasive because the claim does not require that the claimed product produce only isobutene and no other alkenes. The claim only requires that the recombinant microorganism be capable of producing isobutene, but does not recite limitations on the quantity or whether other alkenes are also capable of being produced by the same recombinant microorganism. The claimed invention is directed to a product expressing polypeptides and not a method of producing isobutene.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Response to Arguments
Applicant's arguments filed 07/10/2025 have been fully considered but they are not persuasive. Applicant, on pages 6-8, argues that Dr. Pâques explains why a POSITA reading Guentner would not find the specific combination of the recited enzymes as obvious and summarizes Dr. Pâques’s reasons, especially those in paragraphs 16-20.
Applicant argues that enzyme families 56, 64, and 100 are expected to be used when glutamate, 4-aminobutanoate, and lactate are substrates in pathways and because none of these substrates are shown in Fig. 1E (production of isobutene), there would be no motivation or suggestion to select these three enzyme families from the over 40 families of enzymes to add to a reaction where no substrates are expected. These enzymes would not be expected to function in the isobutene pathway. See, Declaration, paragraph 17.
The Office disagrees. Guentner teaches recombinant microorganisms expressing the enzyme CoA transferase (EC 2.8.3.-) and expressing 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (see 103 rejection discussion above). Thus, Guentner suggests the use of these enzymes to produce alkenes. Additionally, claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner. Accordingly, the POSITA would expect these enzymes to be capable of producing isobutene.
Applicant argues that enzyme families 56 and 64 are included in each pathway that involves the intentional production of crotonyl-CoA as part of the pathway, referring to Figs. 1C (propene), 1F (1,3 butadiene), and 1H (1-pentene). Applicant further argues that enzyme family 100 is used when either acryloyl-CoA or lactoyl-CoA is intentionally produced (See, Fig. 1B (ethene) and 1D (1-butene)). Applicant argues that none of these products are shown in Fig. 1E as intermediates in the production of isobutene. See, Declaration, paragraph 18.
This argument is not persuasive because Guentner teaches in the abstract that the recombinant microorganism contains a heterologous nucleic acid sequence encoding one or more enzymes that allow the conversion of acetyl-CoA to an alkene with a main chain of 1 to 5 carbon atom, and further teaches that the one or more enzymes catalyze the conversion of acetyl-CoA to crotonyl-CoA, of crotonyl-CoA to an alkene, or of acetyl-CoA to 3-methylcrotonyl-CoA and that further catalyze the conversion of 3-methylcrotonyl-CoA to an alkene. The Office disagrees with Dr. Pâques’s premise that the POSITA would disregard other teachings regarding EC 2.8.3.- enzyme families used on different substrates to produce different products because they are not specified in the isobutene pathways of Figure 1E. Furthermore, claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Applicant argues that if one were to use enzymes 56, 64, and 100, Guentner teaches that additional enzymes would also be needed to complete the reaction to form the resulting products. In other words, depending on the desired product, enzymes 56, 64, and 100 require other enzymes to complete the reaction, and don't function alone. See, Declaration, paragraph 16.
This argument is not persuasive because claim 37 recites the limitation “wherein said microorganism expresses polypeptides comprising:…”, which is broad such that the claimed microorganism can comprise additional enzymes not recited in the claim language. Therefore, Guentner teaching additional enzymes may be required for isobutene production does not teach away from adding EC 2.8.3.-. Additionally, claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Applicant argues that Guentner teaches that the resulting product (whether it is isobutene or any of the other products shown in Figs. 1B-1H) is dependent upon the specific combination of enzymes which are added to the starting substrate, acetyl-CoA. See, Declaration, paragraph 19. Applicant further argues that in the Declaration (paragraph 20) that that the person skilled in the art reading Guentner would have to ignore the teaching of Guentner that based on Fig. 1E, glutamate, 4-aminobutanoate and lactate are not substrates and alutaconvl-CoA, 3-butenovl-CoA, and lactovl-CoA are not products in the isobutene production pathway, such that the POSITA would not immediately envision the addition of enzyme 2.8.3.-.
This argument is not persuasive because Applicant and the Declaration rely on the argument that the POSITA would only look to Figures 1B-1H and limit the starting substrate to acetyl-CoA. Indeed, Guentner teaches producing isobutene and other alkenes more broadly with enzymes that catalyze the conversion of acetyl-CoA to crotonyl-CoA, of crotonyl-CoA to an alkene, or of acetyl-CoA to 3-methylcrotonyl-CoA and that further catalyze the conversion of 3-methylcrotonyl-CoA to an alkene.
Applicant argues that in paragraph 23 of the Declaration, to argue that a completely unrelated enzyme family, such as enzyme EC 2.8.3.-, would readily have been added to the production of isobutene by the skilled artisan when there are no shared substrates, intermediates, or products, is not reasonably suggested in Guentner. And that they did not find any suggestion in Guentner that multiple alkene pathways should be included in the same manufacturing host system. To do so would result in a mixture of alkenes, requiring further processing steps. It would not be a reasonable interpretation of Guentner.
This argument is not persuasive because claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
Applicant argues that Dr. Pâques concludes that there is no motivation or suggestion to add additional enzyme family EC 2.8.3.- into the isobutene pathway described in Figure 1 E. To do so, the POSITA would need to ignore the clear teaching that EC 2.8.3.- is to be used on different substrates to produce different products, none of which are included in the isobutene pathways described in Figure 1 E.
This argument is not persuasive because claim 1 of the ‘806 patent teaches using (EC 2.8.3.-) and (EC 6.4.1.4) in the same method as suggested by Guentner.
The arguments have been addressed in the Response to Declaration section above.
Accordingly, the obviousness rejection over Guentner is maintained.
Conclusion
No claim is 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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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636