DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, encompassed by claims 1-13, drawn to a process for producing optically active (R)-3-hydroxybutyrate and (R)-3-hydroxyvalerate mixtures from biomass containing poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHB-co-HV), in the reply filed on April 17, 2026 is acknowledged.
Applicant has not pointed to any errors in Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant further elected the following species, without traverse, as described below:
A single alcohol: Applicant elects ethanol;
A single base: Applicant elects NaOH;
A single central nervous system disorder: Applicant elects Alzheimer’s disease.
Applicant has not pointed to any errors in Examiner’s analysis of the different species. The requirement is still deemed proper and is therefore made FINAL.
In the claims as filed on 12/27/2023, applicants have amended claims 1, 3, 5-8, 14, 19-32; cancelled no claims; and added no new claims. Claims 14-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Therefore, claims 1-32 are currently pending, and claims 1-13 are presently under examination.
Priority
The instant application is a 35 U.S.C. § 371 International Application PCT/US2022/034675, filed June 23, 2022, which claims the benefit of U.S. Provisional Application No. 63/215,711 filed on June 28, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 12/27/2023, 11/14/2024, and 02/19/2025 are in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Specification
Acknowledgement is made of the drawings received December 27, 2023.
The drawings are objected to because:
In FIGs. 1-3, the x- and y-axes, as well as the graph titles, are illegible. As recited in 37 CFR 1.84:
(l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. This requirement applies to all lines however fine, to shading, and to lines representing cut surfaces in sectional views. Lines and strokes of different thicknesses may be used in the same drawing where different thicknesses have a different meaning.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: for consistency of verb tense, claim 1, step (f) should read “…and forming a distilled mixture…” (emphasis added). In step (h), the word “of” should be added to read “…final mixture of (R)-3-hydroxybutryate…” (emphasis added). Appropriate correction is required.
Claim 2 is objected to because of the following informalities: as claim 2 presently reads, it is unclear what “…PHB-co- HV (a)…” means. Furthermore, there is an additional space between the “co-” and “HV” of the claim. For clarity, the word “used” should be replaced with “added”. Last, for consistency with claim 1, step (a), the “precursors” should read “precursor compounds” and the “fermentative phase” should read “fermentation phase”. Altogether, the claim 2 objections would be overcome if it recited, “…where the precursor compounds added in the fermentation phase, step (a), of the synthesis of PHB-co-HV are chosen from…” (emphasis added). Appropriate correction is required.
Claim 3 is objected to because of the following informalities: as claim 3 presently reads, it is unclear what “…from the biomass (b)…” means. For clarity, Applicant should amend the claim to read, “…in the extraction, step (b), of PHB-co-HV from the biomass are…”. For clarity, the word “used” should be replaced with “added” so as to read, “…where the proteolytic enzymes added…”. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: as claim 4 presently reads, it is unclear what “…and trans-esterification (c)…” means. For clarity, Applicant should amend the claim to read, “…and trans-esterification step (c)…”. Appropriate correction is required.
Claim 7 is objected to because of the following informality: there is an additional space in “10 %” of the claim, which should recite “10%”. Appropriate correction is required.
Claim 9 is objected to because of the following informality: for clarity, Applicant should amend the claim to read, “…from the trans-esterification reaction, step (f), is removed…” (emphasis added). Appropriate correction is required.
Claim 11 is objected to for the recitation of “sodium, potassium, calcium, or magnesium hydroxides”. It is unclear if Applicant is claiming sodium metal, potassium metal, or calcium metal; or if Applicant is claiming sodium hydroxide, potassium hydroxide, calcium hydroxide, or magnesium hydroxide. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: the charge in “H+” should be superscripted to read “H+”. In addition, each (R)-3-hydroxybutyrate and (R)-3-hydroxyvalerate can only have one counter-ion, not multiple, so counter-ions should be singular. The word “of” should be added between “counter-ion” and “sodium”. For clarity, it would be easier to understand the claim if the formed compounds were recited as (R)-3-hydroxybutyric acid and (R)-3-hydroxyvaleric acid. Altogether, the claim 13 objections would be overcome if it recited, “…so that the counter-ion of sodium, potassium, magnesium, and/or calcium is replaced by H+, forming (R)-3-hydroxybutyric acid and (R)-3-hydroxyvaleric acid.” (emphasis added). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1, 4-7, 9-12 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.
Claim 1 recites the limitation "the 3-hydroxyvalerate" and “the PHB-co-HV polymer” in step (a). There is insufficient antecedent basis for these limitations in the claim. Claim 1 is rejected as vague and indefinite for its usage of “0 and 40%” in step (a). It is unclear what the units are for this percentage. Is it “0 and 40%” by mass percentage (%w/w), by volume percentage (%v/v), mass-volume percentage (%w/v), or some other percentage measurement? Furthermore, how can the 3-hydroxyvalerate content be as low as 0% (non-existent) when it is present in the PHB-co-HV polymer? Additionally, claim 1 is rejected as vague for the recitations of “sugars” in step (a). The specification provides Example 1 (page 21) to exemplify step (a), which is an experimental procedure that includes “inverted cane molasses”, “molasses”, and “reducing sugars” so it is unclear what the sugars are referring to in step (a) of claim 1.
Claim 1 recites the limitation "the mixture of “(R)-3-hydroxybutryate/(R)-3-hydroxyvalerate esters" in step (f). There is insufficient antecedent basis for this limitation in the claim. Additionally, claim 1 is rejected as vague for its usage of a slash in step (f) in the recitation of “(R)-3-hydroxybutryate/(R)-3-hydroxyvalerate esters” (emphasis added). Does the slash mean “and” or does it mean “or”, or does it mean both?
Claim 1 recites the limitation "the final mixture of (R)-3-hydroxybutyrate and (R)-3-hydroxyvalerate" and “the PHB-co-HV polymer” in step (h). There is insufficient antecedent basis for these limitations in the claim.
Claim 4 recites the limitation "the step hydrolyzing the polymer chain and trans-esterification”. There is insufficient antecedent basis for these limitations in the claim. Furthermore, since the trans-esterification step is never named as such in claim 1, it is unclear if the trans-esterification is occurring in step (c) or step (d).
Claim 5 recites the limitation "the ester”. There is insufficient antecedent basis for this limitation in this claim. Step (c) of claim 1 forms a suspension, according to the claim, not an ester. Claim 5 is rejected as vague and indefinite for its usage of “a stoichiometrically amount for the formation of an ester”. What is the stoichiometrically necessary amount? Is it 2, 3, 4, 5, 10, 100, 1000 equivalents, or some other value? The confusion is compounded by the fact that the claim then recites adding “2 to 10 times” this unknown “stoichiometrically necessary amount”.
Claim 6 recites the limitation "the trans-esterification step”. There is insufficient antecedent basis for these limitations in the claim. Regarding claim 6, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 7 is vague for its usage of “…of added PHB-co-HV”. Examiner is not aware of any added PHB-co-HV in independent claim 1. There is the initial PHB-co-HV from the biomass and there is also an extracted PHB-co-HV from step (c) of claim 1, but there is no “added PHB-co-HV”.
Claim 9 recites the limitation "the trans-esterification reaction”. There is insufficient antecedent basis for this limitation in this claim.
Claim 9 is vague for its usage of referring to “(f)” in “…wherein the excess alcohol from the trans-esterification reaction, (f)…” is removed by distillation. The removal of excess alcohol occurs in step (f) of claim 1, while the trans-esterification step, while not explicitly defined as such, occurs in step (c) or step (d). Note: It is unclear from the claims at which point the trans-esterification step is occurring. So, what is the “(f)” referring to: the removal of excess alcohol step, or the trans-esterification step?
Claim 9 is vague for its usage of “the process”. At which point of the process is the excess alcohol being returned? Claim 1 recites steps (a) through (h). By way of example to highlight the confusion, both step (c) denotes the addition of alcohol, and step (a) refers to precursor compounds, which can be chosen from isopropanol, n-propanol, and n-pentanol.
Claim 10 recites the limitation "such mixture”. There is insufficient antecedent basis for this limitation in this claim. There are lots of potential mixtures in the process of claim 1.
Claim 11 is rejected as vague for its usage of multiple slashes in the recitation of “(R)-3-hydroxybutryate/esters/ (R)-3-hydroxyvalerate esters” (emphasis added). Does the slash mean “and” or does it mean “or”, or does it mean both?
Claim 11 recites the limitation "the breakdown”. There is insufficient antecedent basis for this limitation in this claim.
Claim 12 recites the limitation " the mixture of (R)-3-hydroxybutyrate and (R)-3-hydroxyvalerate salts”. There is insufficient antecedent basis for this limitation in this claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4-13 are rejected under 35 U.S.C. 103 as being unpatentable over Nonato (BR 102018074086-5 A2, published June 2, 2020)(hereinafter, ‘Nonato’) and Koller et al. (“Modern Biotechnological Polymer Synthesis: A Review”, published 2010)(hereinafter, ‘Koller’), as evidenced by Zimmerman et al. (“Brominations of Cyclic Acetals from α-Amino Acids and α - or β-Hydroxy Acids with N-Bromosuccinimide”, published July 8, 1987)(hereinafter, ‘Zimmerman’).
Nonato teaches a process for producing optically active (R)-3-hydroxybutryate alkyl esters (3HB-AE) from biomass containing polyhydroxybutyrate. In reference claim 1, reference steps (e) through (i), Nonato discloses the steps required to break the polymer into monomeric units:
e) Form a suspension with the PHB flakes, containing residual 3HB-AE, in anhydrous alcohol; f) Add a catalyst to the PHB flakes suspension: g) Heat the suspension with the PHB flakes at a temperature of 70 to 150 ° C and for a period of 12 to 24 hours, causing the PHB polymer chains to break and the formation of 3HB-AE; h) Neutralize the solution formed with an alkalizing agent; i) Remove excess unreacted alcohol from the 3HB-EA solution…
and teaches (para [039]):
the vapors from the evaporator were condensed and sent to a fractional distillation column, from which 1,190 kg of ethyl (R) -3 hydroxybutyrate with 98% purity were obtained.
Nonato teaches (para [007]) that several members of the polyhydoxyalkanoate (PHA) family have found industrial application, including poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHB-co-HV). Furthermore, Nonato also teaches (para [002]) that the R-isomer has wide application in the production of antibiotics, vitamins, pheromones, development of new drugs, and as a nutritional supplement (emphasis added). Indeed, the instant application is directed towards methods to produce (R)-3-hydoxybutyrate and (R)-3-hydroxyvalerate from PHB-co-HV. Thus, Nonato provides motivation to extend the purification technique of (R)-3-hydroxybutryate alkyl esters (3HB-AE) from biomass to the purification of (R)-3-hydoxybutyrate and (R)-3-hydroxyvalerate mixtures from biomass.
Nonato does not teach the fermentation protocols for producing optically active (R)-3-hydoxybutyrate and (R)-3-hydroxyvalerate from biomass containing PHB-co-HV polymer, does not teach the extraction of PHB-co-HV from biomass by the addition of one or more proteolytic enzymes (corresponding to instant claim 1, steps (a) and (b)) and does not teach the ester hydrolysis to form (R)-3-hydroxybutyric and (R)-3-hydroxyvaleric acid (corresponding to instant claim 1, steps (g) and (h)).
Koller teaches (page 23, col 2) the industrial process development for PHA production. Specifically, Koller teaches “When grown on glucose and various concentrations of propionic acid up to 5 g/L, A. latus produced poly(3HB-co-3HV) with the content of 3HV monomer in the PHA of up to 20 %” (emphasis added), where propionic acid is the so-called precursor compound of instant claim 1, step (a), and A. latus (Alcaligenes latus) is the enzyme required for fermentation. Elsewhere, Koller teaches (page 265, col 1) the use of proteolytic enzymes for the digestion of the non-PHA cellular material:
An enzymatic digestion method has been developed by Imperial Chemical Industries (ICl; London, UK) to recover PHB from C. necator by proteases. This process includes thermal treatment of PHA-rich biomass, enzymatic disintegration of the cell material, and washing with an anionic surfactant to dissolve the residual biomass.
Regarding claim 2: Koller teaches the precursor enzyme is propionic acid.
Regarding claim 4: Nonato teaches the alcohol is ethanol (para [038]).
Regarding claim 6: Nonato teaches the acidifying agent is HCl (para [038]).
Regarding claim 8: Nonato teaches the alkalizing agent is NaOH (para [038]).
Regarding claim 9: Nonato teaches the ethanol vapors were condensed and the recovered ethanol was sent for rectification (para [038]).
Regarding claims 11: Zimmerman teaches (page 1112, compound 19), that KOH was added dropwise to (R)-ethyl-3-hydroxypentanoate (from PHB/PHV) to form (3R)-3-hydroxypentanoic acid (otherwise known as (R)-3-hydroxyvaleric acid).
Regarding claims 5, 7, and 10, 12, and 13: The claim language around stoichiometry (claim 5), percent by weight (claim 7), and temperature and pressure (claims 10, 12, 13) is language around amounts and concentrations of reaction components. In these instances, modifying concentrations, quantities, temperatures, and pressures (result effective variables) would be obvious based on routine optimization (In re Aller), unless there is evidence to the contrary. Furthermore, the specification does not show that modification of said variables is critical to the claimed invention. The selection of reaction conditions is more optimization by more modification of routine experimentation and within one skilled in the art. Change in temperature, concentration, or both is not patentable modification in the absence of unexpected results which is different in kind and not degree. Therefore, the determination of workable stoichiometries, percent by weights, temperatures, and pressures would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the criticality of the claimed stoichiometries, percent by weights, temperatures, and pressures, the determination of the optimum or workable stoichiometries, percent by weights, temperatures, and pressures given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. It is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 U.S.P.Q. 33 (C.C.P.A. 1937). In re Russell, 439 F.2d 1228; 169 U.S.P.Q. 426 (C.C.P.A. 1971). Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Accordingly, claims 5, 7, and 10, 12, and 13 are rejected.
It would have been prima facie obvious to a person of ordinary skill in the art, at the time before the effective filing date of the claimed the invention, to practice the disclosed processes of Nonato and Koller, as evidenced by Zimmerman, because it is nothing more than combining prior art elements according to known methods to yield predictable results. All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art.
Claim(s) 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Nonato and Koller as evidenced by Zimmerman and in further view of Yanagita et al. (EP 1609868 B1, published November 11, 2015, cited on IDS filed on 12/27/2023)(hereinafter, ‘Yanagita’).
The previous 103 rejection is incorporated herein.
Regarding claim 3: Yanagita teaches that the separated PHA is treated with an enzyme and/or surfactant to solubilize or decompose impurities adhering to the PHA ([0018]). Yanagita teaches this method where the PHA is a homopolymer of 3-hydroxybutyrate or 3-hydroxyvalerate or in which two are more are copolymerized ([0023]-[00226]. Yanagita teaches ([0058]-[0062]) that the treatment with enzyme can be the following: (1) Proteolytic enzyme (protease), such as alcalase, pepsin, trypsin, papain, chymotrypsin, aminopeptidase, carboxypeptidase; (2) Lipid degrading enzymes, such as lipases, phospholipases, cholinesterases, phosphatases; (3) Cell wall degrading enzyme, such as lysozyme, amylase, cellulase, maltase, saccharase, α-glycosidase, β-glycosidase, N-glycosidase; and (4) DNA-degrading enzyme, such as ribonucleases.
Thus, said claims are obvious.
Conclusion
No claims are allowed.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
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/L.A.B./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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