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 .
Claim Objections
Claim 12, 17, 20 and 21 is objected to because of the following informalities:
Claims 12, 17, 20 and 21 recite “mutant thereof” of several recited enzymes. For example, triose phosphate isomerase or a mutant thereof, fructose-bisphosphate aldolase or a mutant thereof, 1,2-alpha-D-glucan branching enzyme or mutant thereof, etc. Every enzyme with the same generic function is a mutant relative to every other enzyme in that class. That is, in view of a first enzyme being a triose phosphate isomerase and a second enzyme being a triose phosphate isomerase, assignment of the first enzyme and the second enzyme as being a mutant is arbitrary. As such, there is no scope difference between “a triose phosphate isomerase” and “a mutant of a triose phosphate isomerase” since both read on any generic triose phosphate isomerase. The same analysis applies to all of the “mutant thereof” recitations in the claims. As such, recitation of “mutant thereof” does not change the scope of the claims and should be removed from the claims.
Claim 12 in the preamble and step (3) recites a method for synthesis of “starch” (see also end of claim 12) while sub-step (3-2) being the last active method step of the claim produces “amylose.” Starch is understood in the art as being a complex product that includes several different kinds of glucose polymers including amylose and amylopectin. Amylose is understood to be a glucose polymer with only alpha-1,4 linkages. As such, starch can be considered to be a genus that includes amylose as a species thereof. Regardless, claim 12 should be consistent in reciting whether amylose or starch is the produce produced by the method. In the rejections below, production of amylose only as recited in step (3) of claim 12 is considered to meet the limitations of claim 12 for production or synthesis of starch as within the broadest reasonable interpretation of the claim.
Appropriate correction is required.
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.
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.
Claim(s) 12 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (Synthesis of sugars by aldolase-catalyzed condensation reaction, J. Org. Chem 48, 1983, 3199-3205) (previously cited) further in view of Ohdan et al. (Enzymatic synthesis of amylose, Biocatalysis and Biotransformation 24, 2006, 77-81), Fujita et al. (Purification and Properties of Fructose-1,6-bisphosphatase of Bacillus subtilis, J. Biol. Chem. 254, 1979, 5340-49), and Leaver et al. (WO 98/023757 A1) as evidenced by Stiers et al. (Biology, Mechanism, and Structure of Enzymes in the α-D-Phosphohexomutase Superfamily, Adv. Protein Chem. Structural Biol. 109, 2017: 265-304).
Wong, abstract, teaches enzymatic production of glucose-6-phosphate from dihydroxyacetone by several enzymes including glycerol kinase, triose phosphate isomerase, aldolase and additional enzymes as show in Scheme III. Wong, abstract and Scheme III, describe preparation of dihydroxyacetone phosphate (DHAP) from dihydroxyacetone by action of a glycerol kinase and conversion of DHAP to D-glycerol-3-phosphate by action of triose phosphate isomerase (TPI), condensation of DHAP to produce fructose-1,6-bisphosphate (FDP), conversion of FDP to fructose-6-phosphate by non-enzymatic means, and conversion of fructose-6-phosphate to glucose-6-phosphate (G6P). Relevant portion of Scheme III is as follows:
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Agan, Wong, abstract, emphasizes that DHAP can be prepared by “glycerol kinase catalyzed phosphorylation using ATP.”
The above is a description of the following by Wong:
step (1-1): converting dihydroxy acetone into DHAP by a reaction catalyzed by glycerol kinase;
step (1-2): converting DHAP obtained in step (1-1) into D-glyceraldehyde 3-phosphate (D-Gd-3-P) catalyzed by triose phosphate isomerase (TPI);
step (2-1): converting D-glyceraldehyde 3-phosphate into fructose bisphosphate (FDP) an aldolase (classified as EC 4.1.2.13 in Wong, page 3199, right), which is necessarily a fructose-bisphosphate aldolase, and further conversion of FDP to fructose6-phosphate (F-6-P); and
step (2-2): converting D-fructose-6-phosphate from step (2-1) into glucose-6-phosphate (G-6-P) catalyzed by glucose phosphate isomerase (PGI).
Wong, page 3205, left col. (bottom) makes clear that glucose-6-phosphate and fructose-6-phosphate as discussed by Wong are D-glucose-6-phosphate and D-fructose-6-phosphate.
All of the reactions described by wrong are performed by in vitro methods outside of any living cell. For example, Wong, page 320, describes the reactions from Scheme III discussed above performed in solutions utilizing commercially purchased enzymes and reagents (i.e. “Enzymes were from Sigma,” “Dihydroxyacetone was obtained from Sigma”) performed in a buffer in vitro with no use of any living cell.
However, Wong does not teach in step (2-1) that conversion of FDP to D-fructose-6-phosphate is an enzymatic conversion catalyzed by fructose-bisphosphatase (FBP) nor the requirements of step 3 as recited in claim 12.
Regarding use of a FBP in step (2-1), as discussed, Wong Scheme III, shows enzymatic conversion of glyceraldehyde-3-phosphate (G3P) to D-fructose-1,6-bisphosphate catalyzed by an aldolase, a singe enzyme having function of catalyzing conversion of DHAP and glyceraldehyde 3-phosphate to D-fructose-1,6-bisphosphate. However, further conversion of D-fructose-1,6-bisphosphate is shown in Scheme III of Wong to be a non-enzymatic acid hydrolysis to D-fructose-6-phosphate.
However, conversion of D-fructose-1,6-bisphosphate to D-fructose-6-phosphate is further known to be catalyzed enzymatically by fructose-1,6-bisphosphatase as explained by abstract of Fujita. Considering that all of the other steps illustrated in Scheme III of Wong are catalyzed by enzymes, an ordinarily skilled artisan at time of filing would have been motivated to substitute an enzyme, D-fructose-1,6-bisphosphate, in replacement for a non-enzymatic dephosphorylation of fructose-1,6-bisphosphatase with an expectation of success in producing the same product being D-fructose-6-phosphate. Just as Wong teaches all enzymatic conversions to be performed by in vitro methods, Fujita also teaches fructose-1,6-bisphosphatase utilized in vitro wherein “A Fru-P2ase assay measuring the liberation of Pi from Fru-P2 was used for the study of catalytic properties of the partially purified enzyme.” Fujita, page 5341, left col.
As discussed, Wong teaches that any produced fructose-6-phosphate is converted into D-glucose-6-phosphate by a single phosphoglucoisomerase (PGI) enzyme.
Regarding step (3) as recited in claim 12, Wong, pages 3202-03 teaches: “Aldolase-catalyzed condensation provides a practical route to a wide variety of simple sugars and sugar derivatives, and especially to those (glucose, fructose, and derivatives) centrally important in intermediary metabolism. The procedure has the advantage that it is applicable to unprotected sugars in aqueous solution at pH 7. Epimeric mixtures can, in favorable cases, be separated without chromatography by taking advantage of substrate-selective enzymatic phosphorylation. The sugar phosphates prepared here are of 80-90% purity.” “Overall, these reactions seem to have genuine value as a method of synthesis for polyhydroxy compounds.”
That is, the teachings of Wong are directed towards the preparation of sugar phosphates (e.g. glucose-6-phosphate) that are otherwise difficult or costly to obtain for further use in applications wherein the same are required.
Ohdan teaches a further application of phosphorylated glucose. “Amylose is a linear polymer of a-1,4-linked glucose and is expected to be used in various industries as a functional biomaterial. However, pure amylose is currently not available for industrial purposes, since the separation of natural amylose from amylopectin is difficult. It is known that amylose has been synthesized using various enzymes. Glucan phosphorylase, together with its substrate, glucose-1-phosphate, is the most suitable system for the production of amylose since the molecular size of amylose can be controlled precisely. However, the problem with this system is that glucose-1-phosphate is too expensive for industrial purposes. This review summarizes our work on the enzymatic synthesis of essentially linear amylose, together with recent progress in the production of synthetic amylose using sucrose or cellobiose through the combined actions of phosphorylases.” Ohdan, abstract.
“Glucan phosphorylase (GP; EC 2.4.1.1) [i.e. starch phosphorylase, [Symbol font/0x61]GP] catalyzes the reverse reaction of the phosphorylation of α-1,4 glucan, as shown in the following equation:
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Amylose can be synthesized when glucose 1-phosphate (G-1-P) is in excess, and where a glucan synthetic reaction predominates. It has been reported that essentially linear amylose can be synthesized using potato GP, and the Mw of amylose can be controlled by the G-1-P/primer molar ratio.” Ohdan, pages 78-79. Table II of Ohdan reports production of amylose using combination of specific primers catalyzed by GP with 50 mM glucose-1-phosphate. As indicated in the preceding equation, all glucose and derivates thereof are of D-glucose.
Ohdan teaches production of amylase utilizing glucan phosphorylase in an in vitro system. “These enzymes are involved in the formation of starch and glycogen in vivo, and are potential candidates for the production of amylose in vitro.” Ohdan, page 78, left col. Table II of Ohdan teaches a reaction mixture without a living cell (i.e. an in vitro method) containing 50 mM G-1-P, GP enzyme and other reagents in a 50 mM sodium acetate, pH 5.5, buffer.
While Ohdan reports that glucose 1-phosphate is an expensive chemical precluding its industrial use, Ohdan in Table II nevertheless reports synthesis of amylose/starch using glucose-1-phosphate as a substrate for GP (i.e., Glucan phosphorylase (GP; EC 2.4.1.1)). As discussed above, Wong reports production of glucose phosphate (i.e. D-glucose-6-phosphate) in a “practical” manner. As far as repeating the amylose production reported in Table II of Ohdan requires obtaining D-glucose-1-phosphate (G1P) from some source, an ordinarily skilled artisan at the time of filing would have been motivated to obtain such G1P from any suitable source including the “practical” sources reported by Wong. Ohdan requires G1P while Wong reports production of D-glucose-6-phosphate. Leaver relates to genetically modified potato plants for increased starch content. As discussed, Ohdan teaches potato GP for starch/amylose production. As shown in Fig. 1A of Leaver, it is well understood that amylose in potato and other plants is produced from glucose-6-phoshate by the activity of phosphoglucomutase (i.e phosphohexose phosphate mutase) converting glucose-6-phosphate to glucose-1-phosphate (D isomers), which then serves as a substrate for starch synthesis either directly as taught by Ohdan or by further conversion to ADP-glucose as taught by Leavers, Fig. 1A. As such, at the time of filing, an ordinarily skilled artisan at the time of filing would have been motivated to convert D-glucose-6-phosphate as produced by the methods of Wong to D-glucose-1-phosphate by applying activity of a suitable phosphoglucomutase (phosphohexose phosphate mutase) as a further valuable glucose phosphate that can be produced from DHA/DHAP as taught by Ohdan. An ordinarily skilled artisan at the time of filing would have been motivated to do this since it is understood that glucose-6-phosphate is a precursor to starch/amylose biosynthesis as taught by Leaver but requiring further conversion/isomerization to glucose-1-phosphate that is readily performed by the activity of phosphoglucomutase. Once when glucose-1-phosphate is produced by the “practical” methods of Ohdan plus an additional step with phosphoglucomutase, an ordinarily skilled artisan at the time of filing would have been motivated to apply such produced glucose-1-phosphate to any suitable application including the methods taught in Table II of Ohdan for an amylose/starch synthesis with GP as an enzyme, which further meets the features of claim 17.
Again, Wong, Fujita and Ohdan, as discussed above, all discuss enzymatic conversion occurring in in vitro systems wherein Ohdan in particular teaches production of amylose in an in vitro method. As such, in modifying and extending the embodiments of Wong as discussed above such that D-glucose-6-phosphate produced by the in vitro methods of Wong is further enzymatically converted to amylose by in vitro methods, all enzymatic conversion discussed above relate to a method for synthesis of starch/amylose carried out in vitro by in vitro methods.
Regarding specific recitation of phosphohexose phosphate mutase (PGM, EC 5.4.2.2), Stiers, Table 1, evidences that the enzyme classified as EC 5.4.2.2 is also known in the art as phosphogluomutase (PGM) such that the phosphogluomutase taught by Leaver as discussed above is understood to be a phosphohexose phosphate mutase (PGM, EC 5.4.2.2) as recited.
Wong, page 3201, left col., states that the TPI used therein is classified as EC 5.3.1.1. Wong, page 3199, right col., states that the aldolase used is “rabbit muscle, E.C. 4.1.2.13.” Any enzyme classified as EC 4.1.2.13 that catalyzes the condensation of DHAP and glyceraldehyde-3-phosphate to fructose bisphosphate (FDP) is understood to be a fructose-bisphosphate aldolase EC 4.1.2.13 as recited. Wong, page 3205, left col., states that the PGI employed is classified as 5.3.1.9 as recited.
The glucan phosphorylase EC 2.4.1.1 taught by Ohdan as discussed above is understood to be a starch phosphorylase E.C. 2.4.1.1 as recited. Fujita, abstract, states fructose-1,6-bisphsophatase is classified in EC 3.1.3.11.
Regarding claim 28, at least Wong teaches the conversion of DHA to glucose-6-phosphate as a “step by step” process. More specifically, Wong, page 3203-04, describe conversion of DHA to DHAP, aldolase catalyzed condensation of DHAP and glyceraldehyde , etc., as occurring step by step such that all of the steps discussed above are proposed or suggested by the prior art to occur step by step as opposed to a simultaneously.
Claim(s) 12, 17 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (Synthesis of sugars by aldolase-catalyzed condensation reaction, J. Org. Chem 48, 1983, 3199-3205), Ohdan et al. (Enzymatic synthesis of amylose, Biocatalysis and Biotransformation 24, 2006, 77-81), Fujita et al. (Purification and Properties of Fructose-1,6-bisphosphatase of Bacillus subtilis, J. Biol. Chem. 254, 1979, 5340-49) and Leaver et al. (WO 98/023757 A1) as evidenced by Stiers et al. (Biology, Mechanism, and Structure of Enzymes in the α-D-Phosphohexomutase Superfamily, Adv. Protein Chem. Structural Biol. 109, 2017: 265-304) as applied to claims 12 and 28 above, and further in view of Jo et al. (Vibrio vulnificus glycogen branching enzyme preferentially transfers very short chains, FEBS Lett. 589, 2015, 1089-94) and Jung et al. (Structural and functional characteristics of clustered amylopectin produced by glycogen branching enzymes having different branching properties, Food Chem. 311, 2020: 125972).
Regarding claim 17, “The glycogen branching enzyme from Vibrio vulnificus (VvGBE) transfers short side chains (DP 3–5) significantly greater than any other bacterial glycogen branching enzyme (GBE).” Jo, abstract. “Glycogen is a major polysaccharide of energy reservoir in animals and microorganisms. It is a highly branched polysaccharide, in which glucose residues are linked by a-1,4 glycosidic bonds to from linear chains and at every 10 residues, other linear chains are linked by a-1,6-glycosidic bonds to form sides chains. Formation of side chains in glycogen is catalyzed by glycogen branching enzyme (GBE) or branching enzyme (BE) (EC 2.4.1.18). GBE catalyzes formation of a-1,6-glycosidic linkage by cleaving a 1, 4 linkages of substrate and transferring the non-reducing end of the chain to an acceptor.” Jo, page 1089, left col. “The activity of VvGBE was measured by the iodine assay. The mixture of 0.04% (w/v) potato amylose (or 0.05% maize amylopectin) in 50 mM MOPS buffer (pH 7.5) and VvGBE was incubated at 30 C.” Jo, page 1090, right col.
“Three bacterial glycogen branching enzymes (GBEs) having different branching characteristics were used to produce clustered amylopectin (CAP), and structure and functional properties of CAPs were intensively analyzed.” Jung, abstract. “Bacterial branching enzymes: The plasmids containing EcGBE, DgGBE or VvGBE genes were individually expressed in E. coli MC1061 and purified as described previously (Jo et al., 2015).” Jung, sec. 2.1.
“Slowly digestible starch (SDS) has a smaller effect on blood glucose than RDS due to slow hydrolysis and absorption in the small intestine.” Jo, page 1, left col. “Enzymatic synthesis of SDS from normal starch often use two strategies: shortening of branch length by hydrolysis or introducing more α-1,6-bonds. One kind of enzymes that were used for generating α-1,6-glycosidic branches is bacterial glycogen branching enzymes (GBEs).” Jung, page 1, right col.
That is, it is known in the prior art to contact amylose/starch with an enzyme classified in 2.4.1.18 as to be a 1,4-alpha-D-glucan branching enzyme that introduces alpha-1,6-glycosidic bonds into amylose (i.e. branching) to produce a slowly digestible starch. Any starch modified to have a significant amount of alpha-1,6-glycosidic bonds (branching) is within the broadest reasonable meaning of amylopectin. As far as Jo and Jung teach that it is advantageous to contact amylose/starch with an enzyme classified in 2.4.1.18 as to be a 1,4-alpha-D-glucan branching enzyme, an ordinarily skilled artisan at time of filing would have been motivated to convert amylose obtained from any source, including amylose obtained via methods consistent with the teachings of Ohdan discussed above, as to meet the limitations of step (3-3) of claim 17 of converting amylose as obtained as discussed above into amylopectin as catalyzed by an enzyme classified as EC 2.4.1.18.
Both Jo and Jung teach the use of GBEs in in vitro methods. Specifically, sec. 2.1 and 2.2. of Jung discuss producing purified GBEs and employing the same in in vitro reaction mixtures based upon MOPS (pH 7.5) buffer without a living cell for modification of amylopectin solutions. Jo in sections 2.4 and 2.5 further teaches the use of purified VvGBE in in vitro reaction mixtures based upon MOPS (pH 7.5) buffer without a living cell for modification of amylose.
Again, Wong, Fujita and Ohdan, as discussed above, all discuss enzymatic conversion occurring in in vitro systems wherein Ohdan in particular teaches production of amylose in an in vitro method. As such, in modifying and extending the embodiments of Wong as discussed above such that D-glucose-6-phosphate produced by the in vitro methods of Wong is further enzymatically converted to amylose and amylopectin by in vitro methods, all enzymatic conversions discussed above relate to a method for synthesis of starch/amylose and further amylopectin carried out in vitro by in vitro methods.
Claim(s) 12, 20 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (Synthesis of sugars by aldolase-catalyzed condensation reaction, J. Org. Chem 48, 1983, 3199-3205), Ohdan et al. (Enzymatic synthesis of amylose, Biocatalysis and Biotransformation 24, 2006, 77-81), Fujita et al. (Purification and Properties of Fructose-1,6-bisphosphatase of Bacillus subtilis, J. Biol. Chem. 254, 1979, 5340-49) and Leaver et al. (WO 98/023757 A1) as evidenced by Stiers et al. (Biology, Mechanism, and Structure of Enzymes in the α-D-Phosphohexomutase Superfamily, Adv. Protein Chem. Structural Biol. 109, 2017: 265-304) as applied to claims 12 and 28 above, and further in view of Desmons et al. (Formaldehyde as a Promising C1 Source, ACS Catalysis 9, 2019, 9575-88).
Regarding claim 20, as discussed, dihydroxyacetone (DHA) is the starting material shown in Scheme II and III of Wong through which DHAP and glucose-6-phosphate is produced. Desmons teaches that DHAP can be advantageously produced from formaldehyde. “In the context of the depletion of fossil resources, formaldehyde is an emerging C1 source exhibiting high and versatile reactivity.” Desmons, abstract. Figure 1 of Desmons shows the following reaction wherein the compound of the right is DHA:
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As such, since Desmons teaches that reaction of formaldehyde with a single enzyme being formolase to produce DHA is a desirable means of producing DHA, an ordinarily skilled artisan would have been motivated to provide DHA by any suitable means in order to practice the methods of Wong including a step of converting formaldehyde into DHA with a formolase enzyme having activity for the same.
Desmons, sec. 3.4.2., further describes “The engineered formolase (FLS) catalyzes the di- and trimerization of formaldehyde into GA and DHA, respectively (Figure 18, steps a + a′). The production of DHA and GA was monitored over time as a function of the concentration of introduced formaldehyde. The product profile is shown to be concentration-dependent. At a high concentration of formaldehyde (10 mM), DHA is obtained as the major product.” The preceding is understood as describing use of formolase in an in vitro method wherein, for example, a specific concentration of formaldehyde (10 mM) is used and no living cell appears to be involved. As such, when the methods discussed above in regards to claim 12 are modified to further include formolase converting formaldehyde into dihydroxyacetone, the overall method remains an in vitro method.
Claim(s) 12, 20, 21 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (Synthesis of sugars by aldolase-catalyzed condensation reaction, J. Org. Chem 48, 1983, 3199-3205), Ohdan et al. (Enzymatic synthesis of amylose, Biocatalysis and Biotransformation 24, 2006, 77-81), Fujita et al. (Purification and Properties of Fructose-1,6-bisphosphatase of Bacillus subtilis, J. Biol. Chem. 254, 1979, 5340-49), Leaver et al. (WO 98/023757 A1) and Desmons et al. (Formaldehyde as a Promising C1 Source, ACS Catalysis 9, 2019, 9575-88) as evidenced by Stiers et al. (Biology, Mechanism, and Structure of Enzymes in the α-D-Phosphohexomutase Superfamily, Adv. Protein Chem. Structural Biol. 109, 2017: 265-304) as applied to claims 12, 20 and 28 above, and further in view of Chistoserdova, Applications of methylotrophs, Curr. Opinion Biotechnol. 50, 2018, 189-94).
Regarding claim 21, Desmons, page 9575, left col., teaches: “For the chemical industry, formaldehyde is an important building block, and more than 20 million tons of it are produced each year, mostly from partial oxidation of methanol.” As such, it is understood that that formaldehyde is produced from methanol. Chistoserdova, page 192, teaches the following:
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And from Chistoserdova, page 191, right col.:
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As discussed within Chistoserdova, methylotrophy is the conversion of methanol to formaldehyde that can then be utilized to produce multicarbon products. As such, an ordinarily skilled artisan at time of filing would have readily recognized methanol oxidase as an oxidase that oxidizes methanol for formaldehyde.
As discussed, it is known in the prior art to employ formolase to convert formaldehyde to DHA. The claims are directed include in vitro reactions not taking place in a host cell. Regardless, Chistoserdova teaches that it is known to provide for the formaldehyde substrate to be utilized by formolase by oxidation of methanol with a Mdh (methanol dehydrogenase) enzyme that converts methanol to formaldehyde and further that the same formaldehyde can be provided by the activity of a methanol oxidase, which is an alcohol oxidase known to convert methanol to formaldehyde. As such, in any system employing a formolase enzyme, whether in vitro or within a host cell, it is predictable and suggested by the prior art for the needed formaldehyde substrate to be provided by an enzymatically catalyzed conversion of methanol to formaldehyde through the activity of a methanol dehydrogenase or a methanol/alcohol oxidase that severs to oxidize methanol to formaldehyde. Again, at least Wong and Ohdan teach in vitro methods for producing glucose-6-phosphate and amylose/starch. As such, in employing an alcohol/methanol oxidase to generate formaldehyde, an ordinarily skilled artisan at filing would have been motivated to maintain all steps leading to production of starch/amylose as in vitro method steps as otherwise taught by Wong and Ohdan.
Response to arguments
Applicant argues:
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In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a multi-enzyme cascade) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The claims have been read carefully. The term “multi-enzyme cascade” as argued cannot be located in the claims. The claim term “the method is performed in an in vitro” system does not mean a “multi-enzyme cascade.” Rather, claim 28 recites (as part of a Markush group) “where the steps of the method. . . are performed step by step.” Step by step means, for example, a first step is performed is a first reaction mixture and first product is isolated therefrom. Then, the first product is added to a structurally separate second reaction mixture and a second product is isolated therefrom. Any further steps are performed in the same manner. There is no requirement in the claims that two different enzyme by present in the same composition, solution, mixture or container.
Regrading recitation in the claims of “wherein the method for synthesis of starch is carried out in vitro,” the chart presented on page 8 of applicant’s remarks appears to describe that Wong and Ohdan teach in vitro methods. It is noted that all of the enzymatic transformations taught by Wong are in vitro wherein there is no suggestions in Wong of performances of any step of Scheme III leading to the production of D-glucose-6-phosphate in a living cell such that all enzymatic conversions are in vitro. As stated in the chart presented on page 8 of applicant’s remarks, the critical starch/amylose synthesis of Ohdan is done in vitro. A claim element is only required to be taught by a single reference; being taught by multiple references or by all references cited is not required. As far as Wong and Ohdan teach in vitro methods for producing sugar phosphates and starch in vitro, an ordinarily skilled artisan would have been motivated for any combination of these references including additional enzymatic reactions to the same purpose of forming starch and derivatives therefrom (i.e. amylopectin) to be in vitro.
Applicant argues:
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In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., multi-enzyme cascade, integrated reactions in a continuous, enzyme-catalyzed) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The lack of recitation of a multi-enzyme cascade in the claims is discussed above. It is not clear precisely what applicant intends the meaning of a “continuous, enzyme-catalyzed in vitro system,” although the same is not recited in the claims and therefore is not relevant to the grounds of rejection. Regardless, step by step as recited in claim 28 would appear to be a NOT continuous method.
Applicant argues:
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In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., multi-enzyme cascade) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
No multienzyme cascade is recited in the claims as far as such term appears to be a reference to a method that is not performed step by step as recited in claim 28, but rather with multiple enzymes in the same solution.
“Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)”; MPEP 2123(II).
Ohdan, for example in Table II, teaches the production of amylose by working example from 50 mM glucose-1-phosphate as starting material. The fact that Ohdan states that glucose-1-phoshpate is not a teaching away that the same can be used for amylose synthesis as Ohdan actually successfully demonstrates. This is particularly true in view of the teachings of Wong regarding how one may obtain sugar phosphates central for intermediary metabolism.
Applicant argues:
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In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of 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).
The lack of recitation in the claims of a “cascade” is addressed above. The motivation for use of a fructose-1,6-bisphosphatase is that Fujita teaches an enzymatic means to achieve the same conversion of fructose-1,6-bisphophate to fructose-6-phosphate taught by Wong. That is, the motivation for the substitution originates in Fujita.
Substitution of known elements is obvious upon a finding of:
(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
(2) a finding that the substituted components and their functions were known in the art;
(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. (MPEP 2143(I)(B)).
The declaration under 37 CFR 1.132 filed 06/24/2026 is insufficient to overcome the rejection of the pending claims based upon 35 U.S.C. 103 as set forth in the last Office action because:
It refer(s) only to the system described in the above referenced application and not to the individual claims of the application. Thus, there is no showing that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
From the declaration:
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97
719
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61
732
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39
732
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65
755
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That is, the declarant states that Wong teaches conversion as a step-by-step process. The claims recite a conversion as recited in claim 28: “wherein the steps of the method . . . are performed step by step.”
The burden is on applicant to establish that results are unexpected and significant. MPEP 716.02(b). "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992); MPEP 716.02(b). The declarant does not make clear what separates:
The step-by-step in vitro method taught by Wong; and
The step-by-step in vitro method recited in the claims, as in claim 28 wherein claim 12 includes the scope of claim 28, which is understood as including each enzyme separately in its own reaction composition without another enzyme present.
Rather, the declaration makes several confusing references to features that are not recited in the claims, including the a “multi-enzyme cascade” and requirements that plural enzyme be present and operating at the same time, which would not appear to read on a step-by-step method as recited in claim 28 and encompassed by claim 12. That is, the invention is the presented claims and only the presented claims are subject to examination. The declaration appears to be directed towards claims that are not presented.
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.
Conclusion
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.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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