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 .
Applicant’s cancellation of claim 43, amendment of claims 21 and 42 and the addition of new claim 45 in the paper of 9/2/2025, is acknowledged. Applicants' arguments filed on 9/2/2025, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 21-32, 35-42, 44 and 45 are present and at issue.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21-32, 35-41 and 44 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Newly amended claim 21 (claims 22-32, 35-41 dependent from) continues to be drawn to an enzymatic method comprising a number of components, “wherein steps (i)-(iii) are not carried out in growing cells”. This limitation is indefinite in the recitation “growing cells” as it is unclear and confusing as to what exactly applicants consider a “growing cell”. Applicants specification does not define what a “growing cell” is and thus the recitation is unclear. While applicants amendment and comments clarify that the method steps (i)-(iii) are not carried out in growing cells as opposed to the previous reference to the enzymes not provided by growing cells, the new recitation remains indefinite as to what is a “growing cell”.
As such the newly added limitation “wherein steps (i)-(iii) are not carried out in growing cells” is not given patentable weight.
Claim 42 is indefinite in the recitation “wherein the enzymes used in steps (i)-(iii) are obtained from cell lysates or are purified” in that this recitation is indefinite in the context of the claim and its previous dependent claims. As applicants claim is drawn to an enzymatic method comprising enzymatically oxidizing, regenerating redox cofactor and enzymatically converting it is indefinite how the recitation “wherein the enzymes used in steps (i)-(iii) are obtained from cell lysates or are purified” relates to the claimed method. Does this recitation limit the enzymes recited in the enzymatically oxidizing, regenerating redox cofactor and enzymatically converting or does the recitation limit the claimed “enzymatic method” itself? In support of the indefiniteness of the recitation, previous claim 43 which depended from claim 42 recited “the enzymes are not used in the form of intact cells”. Thus this raises the question as to whether claim 42 includes the use of enzymes in the form of intact cells. In the interest of advancing prosecution the recitation in claim 42 is given its broadest reasonable interpretation in the context of the claim which is the enzymes used are in the obtained from cell lysates or are purified said form including the form of intact cells.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 21-32, 35-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection was stated in the previous office action as it applied to previous claims 21-32, 35-40. In response to the rejection applicants have amended the claims and traverse the rejection as it applies to the newly amended claims.
Applicants traverse the rejection on the basis that applicants submit that the subject matter need not be described literally in order for the disclosure to satisfy the description requirement (MPEP 2163.02) so long as the disclosure reasonably conveys to the skilled person that the invention is supported. Applicants submit that paragraph [0107] provides support for carrying out the method using enzymes in intact cells, permeabilized cells, or cell lysates. Applicants submit that Faber, K. evidences the term whole cells (which is synonymous with “intact cells”) is understood to include “fermenting cells” that have the characteristic of “growing” cells. Applicants submit that thus the application supports carrying out the enzymatic steps in intact, growing cells.
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however is found non-persuasive for the reasons previously made of record and for those reasons repeated herein.
Newly amended claim 21 (claims 22-32, 35-40 dependent from) is rejected under this statute because applicants specification does not support an enzymatic method comprising wherein the steps of the method are not provided by growing cells and thus such a method is considered new matter.
Applicants traverse this rejection on the basis that applicants submit that that paragraph [0107] provides support for carrying out the method using enzymes in intact cells, permeabilized cells or cell lysates. Applicants further submit that “Faber” evidences that the term whole cells is understood to include “fermentating cells” that have the characteristic of being “growing” cells. Applicants submits that thus supports carrying out the enzymatic steps in intact, growing cells.
Applicants amendment of the claims and applicants complete argument is acknowledged, however, is not found persuasive for the reasons stated previously and repeated herein.
As stated previously and referenced by applicants, paragraph [0107] states:
[0107] The enzymes used in the process can be obtained by recombinant expression. In this connection, various systems are known to a person skilled in the art, for example, E. coli, Saccharomyces cerevisiae or Pichia pastoris. Preferably, E. coli is used; for this purpose, a person skilled in the art is familiar with common protocols. The enzymes can be used in intact cells, in permeabilized cells or in the form of cell lysates. In the case of cell lysates, either the enzymes may be used directly, or a further purification may occur, for example, by chromatographic methods for protein purification, which may be found in the literature and/or are known to a person skilled in the art. If cell lysates are used, either no further purification or only a simple purification step (e.g., centrifugation or filtration) is preferably performed.
This does not support an enzymatic method comprising wherein the steps of the method are not provided by growing cells (see also above rejection under 35 U.S.C. 112(b)).
Newly added claim 45 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Newly added claim 45 is drawn to an enzymatic method for obtaining oxidation products from a mixture of n sugars selected from the group consisting of C5 and C6 sugars, wherein n is at least 2 and the mixture of sugars contains xylose and arabinose, the process comprising: (i) enzymatically oxidizing the sugars xylose and arabinose to xylonic acid and arabonic acid, respectively, by means of one or more dehydrogenase(s) using an oxidized redox cofactor selected from NAD* and/or NADP*;
(ii) regenerating the redox cofactor selected from NAD* and/or NADP+ by an enzymatic cofactor regeneration system, wherein the enzymatic cofactor regeneration system uses enzymes selected from the group consisting of NAD(P)H oxidases and lactate dehydrogenases and does not use xylose reductase; and (iii) enzymatically converting arabonic acid which has formed and xylonic acid which has formed further into 2-keto-3-deoxysugar acids by means of a dehydratase, wherein steps (i)-(iii) are not carried out in intact cells. This newly added method “wherein steps (i)-(iii) are not carried out in intact cells” is not supported by applicants specification at the time of filing and is thus considered new matter. Applicants disclosed methods do not support that the claimed methods “wherein steps (i)-(iii) are not carried out in intact cells”. While applicants specification at paragraph [0107] describes how the enzymes used can be obtained and that the enzymes can be used in intact cells, in pearmeabilized cells or in the form of cell lysates. This does not support that the steps (i) enzymatically oxidizing, (ii) regenerating the redox cofactor and (iii) enzymatically converting are not carried out in intact cells.
Claim Rejections - 35 USC § 102
The rejection of claim(s) 21-25, 31, 33, 35, and 42 under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Frost (US 2006/0234363) as evidenced by Wirtz et al. (WO 2014/076012, for an English translation see US 2015/0291988, all citations herein refer to the US document) and Auriol et al. (PNAS Vol 108, No 4, pp 1278-1283, January 2011) is withdrawn based upon applicants amendment of the claims in the paper of 2/12/2024.
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.
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.
The rejection of claims 21-25, 31, 33-41 and 42 under 35 U.S.C. 103 as being unpatentable over Wirtz et al. (WO 2014/076012, for an English translation see US 2015/0291988, all citations herein refer to the US document), Nidetzky et al., Stephens et al. (J. of Bacteriology, Vol 189, Issue 5, pp 2181-2185, March 2007) and Vincent et al. (US 2015/0044723) is withdrawn based upon applicants arguments presented in the paper of 10/10/2023.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Frost (US 2006/0234363) as evidenced by Auriol et al. (PNAS Vol 108, No 4, pp 1278-1283, January 2011), Wirtz et al. (WO 2014/076012, for an English translation see US 2015/0291988, all citations herein refer to the US document) and Ertl et al. (WO 2013/117584).
This rejection was stated in the previous office action as it applied to previous claims 21-25, 31, 35, 42, and 44. In response applicants have amended the claims and traverse the rejection as it applies to the newly amended claims. For applicants convenience the original rejection is repeated below.
Frost teach a bioengineered synthesis scheme for the production of L-1,2,4-butanetriol. Frost D-1,2,4-butanetriol methods for producing D,L-1,2,4-butanetriol comprising the conversion of D-xylose, L-arabinose, or both inside of a transformed host cell (see summary and supporting text). Frost further teach methods for producing D,L-1,2,4-butanetriol comprising the conversion of D-xylonic acid, L-arabonic acid, or both inside of a transformed host cell and racemic mixtures thereof from a carbon source. Frost teaches a process of converting D-xylose and/or L-arabinose to D-xylonic acid or L-arabonic acid by means of one or more dehydrogenases (see claims 1-2 and supporting text). Frost teaches the above method wherein the D-xylonic acid and L-arabonic acid formed, are further converted into 2-keto-3-deoxysugar acids by means of a dehydratase (see claim 1, Figure 2 and supporting text).
Frost does not specifically disclose regenerating the redox cofactor NAD+ and/or NADP+ by an enzymatic cofactor regeneration system using an NAD(P)H oxidase, although the methods taught by Frost which take place in a transformed E. coli cell, inherently comprise such a regeneration step using such a NAD(P)H oxidase as the transformed E. coli cells used by Frost inherently comprise a NAD(P)H oxidase regeneration system. The presence of such a NAD(P)H oxidase regeneration system is evidenced by Auriol et al. (PNAS Vol 108, No 4, pp 1278-1283, January 2011) who teach that E. coli comprise at a minimum the NuoF enzyme in the respiratory complex I that can oxidize both NADH and NADPH. Wirtz et al. evidence that both D-xylose and L-arabinose are oxidized by means of an arabinose dehydrogenase in that Wirtz teach that arabinose dehydrogenase oxidizes both D-xylose and L-arabinose (see Example 6 of Wirtz et al.).
Frost teach the above methods for making D-3-deoxy-glycero-pentulosonic acid, comprising culturing a microbe expressing D-xylonate dehyrdratase and/or L-arabinonate dehydratase in the presence of D-xylonic acid and/or L-arabonic acid.
Frost teach the isolation and cloning of the L-arabinonate dehydratase genes from Pseudomonas fragi for use in the above methods of transforming E. coli. Frost further teaches that E. coli naturally expresses D-xylonate dehydratase (paragraph [0156]).
Frost teach that the methods of enzymatically oxidizing the sugars xylose and arabinose to xylonic acid and arabonic acid, respectively, by means of one or more dehydrogenase(s) using an oxidized redox cofactor selected from NAD+ and/or NAD(P)H take place in a transformed E. coli cell in which the E. coli cell has been transformed with a nucleic acid encoding a xylonate dehydratase
Thus Frost teaches a method for obtaining oxidation products from a mixture of n sugars selected from the group consisting of C5 and C6 sugars comprising a mixture of sugars contains xylose and arabinose, the process comprising: enzymatically oxidizing the sugars xylose and arabinose to xylonic acid and arabonic acid, respectively, by means of one or more dehydrogenase(s) using an oxidized redox cofactor selected from NAD+ and/or NADP+; regenerating the redox cofactor selected from NAD+ and/or NADP+ by an enzymatic cofactor regeneration system, wherein the enzymatic cofactor regeneration system uses an enzyme selected from NAD(P)H oxidases; and enzymatically converting arabonic acid which has formed and xylonic acid which has formed further into 2-keto-3-deoxysugar acids by means of a dehydratase.
Frost teach that the methods and apparatus of this invention afford benefits over methods and apparatus among those known in the art. Such benefits include reduced production of byproducts from the production of D,L-1,2,4-butanetriol and decreased cost by substituting microbially produced D,L-1,2,4-butanetriol as the precursor for 1,2,4-butanetriol trinitrate for nitroglycerin.
Frost does not teach the use of a enzymatic cofactor regeneration system using an NAD(P)H oxidase whereby oxygen is consumed as co-substrate wherein the NAD(P)H oxidase is from Clostridium aminovalericum.
Ertl et al. (WO 2013/117584) teach methods for enzymatically regenerating the redox cofactors NAD+/NADH and NADP+/NADPH in a one-pot reaction. Ertl et al. (WO 2013/117584) teach that in said method, one of the two redox cofactors is obtained in the reduced form thereof while the other redox cofactor is obtained in the oxidized form thereof as a result of at least two additional enzymatically catalyzed redox reactions (product forming reactions) taking place in the same reaction batch. The disclosed method is characterized in that a) oxygen or a compound of general formula R1C(O)COOH is reduced during the regeneration reaction converting the reduced cofactor back into the original oxidized form thereof, and b) a compound of general formula R2CH(OH)R3 is oxidized during the regeneration reaction converting the oxidized cofactor back into the original reduced form thereof, R1, R2, and R3 in the compounds having different meanings. Ertl et al. (WO 2013/117584) teach that the enzyme which catalyzes the regeneration of the redox cofactors NAD+/NADH and NADP+/NADPH is a NADH oxidase from Clostridium aminovalericum, which may be used as a protein overexpressed recombinantly by E. coli.
One of ordinary skill in the art before the effective filing date would motivated to combine both xylose and arabinose to the starting culture medium and then use for the methods taught by Frost of enzymatically oxidizing the sugars xylose and arabinose to xylonic acid and arabonic acid, respectively, by means of one or more dehydrogenase(s) using an oxidized redox cofactor selected from NAD+ and/or NADP+; and enzymatically converting arabonic acid which has formed and xylonic acid which has formed further into 2-keto-3-deoxysugar acids by means of a dehydratase as a means of combining the methods taught by Frost of xylose catabolism and arabinose catabolism for benefits of greater production of end products. Such benefits include reduced production of byproducts from the production of D,L-1,2,4-butanetriol and decreased cost by substituting microbially produced D,L-1,2,4-butanetriol as the precursor for 1,2,4-butanetriol trinitrate for nitroglycerin. The expectation of success is high based upon the high level of skill in the art as taught by both Frost who teach all that is necessary to practice the obvious methods.
One of ordinary skill in the art before the effective filing date would been further motivated to combine the enzymatic cofactor regeneration system comprising a NADH oxidase from Clostridium aminovalericum taught by Ertl et al. to the E. coli host cells in the methods taught by and obvious over Frost of enzymatically oxidizing the sugars xylose and arabinose to xylonic acid and arabonic acid, respectively, by means of one or more dehydrogenase(s) using an oxidized redox cofactor selected from NAD+ and/or NADP+; and enzymatically converting arabonic acid which has formed and xylonic acid which has formed further into 2-keto-3-deoxysugar acids by means of a dehydratase as a means of increasing enzymatic cofactor regeneration for increased xylose catabolism and arabinose catabolism for benefits of greater production of end products (even though the use of the enzymatic cofactor regeneration system comprising a NADH oxidase from Clostridium aminovalericum taught by Ertl et al. is no longer required by the claimed method). Such benefits include reduced production of byproducts from the production of D,L-1,2,4-butanetriol and decreased cost by substituting microbially produced D,L-1,2,4-butanetriol as the precursor for 1,2,4-butanetriol trinitrate for nitroglycerin. The expectation of success is high based upon the high level of skill in the art as taught by both Frost and Ertl et al. who teach all that is necessary to practice the obvious methods.
Applicants Response:
Applicants submit that regarding claim 42, applicants submit that the enzymes used are obtained from cell lysates or are purified. Applicants submit that thus the recited methods are distinct from the fermentative processes of Frost.
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however, is found non-persuasive for the reasons previously stated and for those reasons repeated herein.
In response to applicants submission that the enzymes used are obtained from cell lysates or are purified, which applicants submit are distinct from the fermentative processes of Frost, this is not found persuasive for the reasons stated previously and repeated herein. As stated above , applicants amendment of claim 42 is indefinite as to whether applicants are limiting the enzymes in a product by process manner or whether applicants are limiting the method steps (i)-(iii) themselves. Accordingly the claimed methdos are given their broadest reasonable interpretation which is that while the enzymes used in steps (i)-(iii) are obtained from cell lysates or are purified, however the method steps themselves (i)-(iii) are not limited as such.
Thus, claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Frost (US 2006/0234363) as evidenced by Auriol et al. (PNAS Vol 108, No 4, pp 1278-1283, January 2011), Wirtz et al. (WO 2014/076012, for an English translation see US 2015/0291988, all citations herein refer to the US document) and Ertl et al. (WO 2013/117584).
Examiner Comment:
In review of the application file the examiner notes that applicants Abstract and Summary state that it is the object of the present invention to fractionate the very complex sugar mixture resulting in a non-equimolar ratio of at least two sugars in the mixture that is subsequently enzymatically oxidized. It is noted that no such fractionation of a complex sugar mixture or no non-equimolar ratio of sugars in the sugar mixture is reflected in applicants claims.
Remarks
No claim is allowed.
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 RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached 6-3 EST Mon-Fri.
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rgh
10/14/2025
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652