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 .
DETAILED ACTION
1. Applicant’s preliminary amendment filed on November 28, 2023 is acknowledged. Claims 2-3, 12, 20, 24-25, 27, and 29-40 have been canceled. Claims 4, 6-11, 13-19, 21-22, 26, and 28 have been amended. Claims 1, 4-11, 13-19, 21-23, 26, and 28 are currently pending and under examination.
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on May 13, 2025; February 12, 2025; and November 28, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. An initialed copy is attached hereto.
Claim Objections
3. Claim 19 is objected to because of the following informalities: Claim 19 appears to be grammatically incorrect by the use of the phrase “wherein the base functions to control a pH of the fermentation medium”. Perhaps Applicant intends that the base functions to control the pH of the fermentation medium. Appropriate correction is required.
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.
4. Claims 1 and 19 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 is rendered vague and indefinite by the use of parenthesis. Parenthesis are viewed in the same manner as ‘such as’, which is exemplary language and is not permitted in a claim. The ambiguity of scope is not clear as the Office does not know clearly what is included and what is to be excluded. As written, it is impossible to determine the metes and bounds of the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
5. Claim(s) 1, 4-6, 9-11, 13, 17-19, 21-23, 26 and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dietrich et al., WO 2019/160862 A1; Published: 8/22/19.
Independent claim 1 is drawn to a fermentation method for producing malonate, the method comprising:
a) culturing a microorganism in the presence of a fermentation medium, the fermentation medium comprising:
at least one carbon source;
calcium ions ranging from 0.05 g/L to 1.6 g/L; and
a base other than a calcium containing base; and
b) producing at least 40 grams/liter of malonate (for example, in a range of from 40 grams/liter to 200 grams/liter, from 60 grams/liter to 150 grams/liter, from 80 grams/liter to 150 grams/liter, from 90 grams/liter to 150 grams/liter, or from 100 grams/liter to 150 grams/liter malonate), wherein optionally, the malonate is produced at a rate of at least 0.3 g L−1 h−1 to 5 g L−1 h−1.
Dietrich discloses methods for the preparing malonate as well as purifying malonate or malonic acid derivatives from fermentation broth, the methods comprising: (a) culturing a host cell under conditions suitable for production of malonate, (b) and recovering (i.e., purifying) the malonate from fermentation broth. The method further relates to malonic acid derived from a fermentation broth of a microorganism that is able to produce malonic acid from a fermentable carbon source. Biosynthesized malonate can be produced intracellularly and/or secreted into the culture medium. Intracellularly produced malonate is typically secreted into the culture medium using a membrane transporter, as described above. If not secreted, malonate can be removed from the host cell by chemical, enzymatic, or mechanical cell lysis. Malonate can be recovered from the cells, from the fermentation broth, or both (see paragraph 00144; meets claim 1).
In some embodiments, the microbial culture (i.e., fermentation broth) may comprise a fermentable carbon source (e.g., glucose monohydrate), and, optionally, a source of nitrogen, phosphorous, and additional media components such as vitamins, salts, and other materials that can improve cellular growth and/or product formation, and water. These components may be fed into a fermenter to regulate or promote growth and sustenance of the microbial culture. In some embodiments, the microbial culture may be grown under aerobic conditions provided by sparging an oxygen containing gas (e.g., air or the like). In some embodiments, calcium hydroxide can be provided for pH control during the growth of the microbial culture (see paragraph 00149; meets claims 1, 4-6).
In some embodiments, the microbial culture may comprise microorganisms capable of producing malonic acid from fermentable carbon sources (e.g., glucose, sucrose, and/or other carbohydrate sugars). Representative examples of microorganisms include, but are not limited to, those selected from the group consisting of Pichia kudriavzevii (P. kudriavzevii), Saccharomyces cerevisiae, Escherichia coli , mixtures thereof and the like. A preferred microorganism is a Pichia kudriavzevii strain (see paragraph 00150; meets claim 1 and 21-23).
Embodiments of the methods provided herein may comprise the step of fermenting a microorganism capable of producing malonic acid in the presence of a fermentable carbon source and an alkaline earth metal base under suitable fermentation conditions to obtain an aqueous fermentation broth that comprises an insoluble alkaline earth metal malonate salt (i.e., the salt formed between the alkaline earth metal and malonic acid). In some embodiments, seed crystals can be added at the start of the fermentation (i.e., before the cells begin producing malonic acid) or at any point during the fermentation. The microorganism can be any microorganism capable of producing malonic acid (see paragraph 00168; meets claim 1). In some such embodiments, the concentration of alkaline earth metal malonate salt in the fermentation broth may be at least 75 g/l, at least 100 g/l, at least 110 g/l, at least 120 g/l, at least 130 g/l, at least 140 g/l, or at least 150 g/l (see paragraph 00190; meets claim 1b). As it pertains to claim 26, the fermentation method is capable of producing 40 g/L to 200 g/l of malonate over a time in a range of 15 hours to 200 hours, absent evidence to the contrary.
In some embodiments, the method comprises the following steps: (1) fermenting a microorganism capable of producing malonic acid in the presence of a fermentable carbon source and an alkaline earth metal base under suitable fermentation conditions to obtain a fermentation broth that includes an insoluble alkaline earth metal malonate salt; (2) separating the insoluble alkaline earth metal malonate salt from the fermentation broth such that the isolated alkaline earth metal malonate salt is substantially free of cells; (3) converting the isolated alkaline earth metal malonate salt to soluble malonic acid; and crystallizing said soluble malonic acid; and (4) synthesizing diester derivatives of malonic acid (see paragraph 00151; meeting the limitation of not a calcium base-claim 1).
Embodiments of the methods provided herein may comprise the step of fermenting a microorganism capable of producing malonic acid in the presence of a fermentable carbon source and an alkaline earth metal base under suitable fermentation conditions to obtain an aqueous fermentation broth that comprises an insoluble alkaline earth metal malonate salt, for example calcium malonate and can be added at the start of the fermentation (i.e., before the cells begin producing malonic acid) or at any point during the fermentation (see paragraph 00168-69; meets claim 4). Moreover, typically the cation is added to the fermentation broth (or lysate) as a salt (meets claim 4). Various calcium salts ( e.g. , calcium hydroxide, calcium carbonate, calcium chloride) can be used in accordance with this disclosure to precipitate malonate from fermentation broth (see paragraph 00147; meets claim 5). The nitrogen source may be any assimilable nitrogen sources include ammonia (see paragraph 00172; meets claim 13).
The disclosure provides recombinant host cells wherein the host cell is a recombinant host microorganism and can produce malonate (see 00103, meets claim 21). In various embodiments, the host is eukaryote and is a yeast selected from Issatchenki (Issatchenki orientalis) and Pichia (see paragraph 00105; meets claim 22-23). Dietrich discloses that suitable temperatures for fermenting typically depend on the choice of microorganism used (see paragraph 00174). Thus, a suitable fermentation pH depends on both the choice of the microorganism used (i.e., its ability to grow and produce malonic acid at a lower fermentation pH) and the concentration of fully protonated malonic acid in solution (see paragraph 00177).
The addition of the alkaline earth metal base to the fermentation is also of focus. Said base may be added to the fermentation as a slurry, and in these cases, maximizing the concentration of the alkaline earth metal base used in the slurry may improve yield. Use of a dilute base can result in the addition of excess water to the fermentation and can hinder isolation of the alkaline earth metal malonate salt. In some embodiments, in which the alkaline earth metal base is a calcium base, at least a 1M, at least a 2M, at least a 3M, at least a 4M, or at least a 5M solution of Ca(OH)2, CaC03, or CaO are used to control the fermentation pH (meets claim 19). In other embodiments in which the alkaline earth metal base is a calcium base, the calcium base is added dry (i.e., substantially free of water) to the fermentation (see paragraph 00187; meets claim 6 and 10). Further, the alkaline earth metal base can be added to the fermentation broth at any one or multiple times of the fermenting, including at the start (i.e., before the microorganism begins producing malonic acid), during, or at the end of the fermenting ( i.e. ., prior to separation of insoluble alkaline earth metal malonate salt from the fermentation broth) (see paragraph 00189; meets claim 9 and 10).
The rate at which oxygen is transferred into the fermentation broth, expressed as mmol-02/l/hr., describes the oxygenation of the fermentation broth. In many embodiments of the present disclosure, the fermentation OTR is at least 5 mmol/l/h, at least 10 mmol/l/hr., at least 20 mmol/l/hr., at least 30 mmol/l/hr., at least 40 mmol/l/hr., or at least 50 mmol/l/hr. (see paragraph 00176; meets claim 11).
The fermentation pH can be controlled by the addition of various inorganic bases at the beginning and/or throughout the course of the fermentation, and the choice of the fermentation base affects the pKa values for the two carboxylic acid groups. In the presence of a monovalent cation (for example, a sodium cation when sodium hydroxide is used as a base) the two carboxylic acid pKa values are about 2.83 and 5.69. Thus, when sodium hydroxide is used as a base the fermentation pH will often be greater than or equal to pH 5.69 (see paragraph 00181; meets claim 13). In some embodiments, the preferred pH of the fermentation is kept around pH 5.0 (see paragraph 00178; meets claim 17-18)
As it pertains to claim 28, the malonate of the prior art has been produced using the same method steps as claimed, said malonate necessarily comprises the compound of formula I, absent evidence to the contrary.
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.
6. Claim(s) 7-8 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Dietrich et al., WO 2019/160862 A1; Published: 8/22/19.
Independent claim 1 is drawn to a fermentation method for producing malonate, the method comprising:
a) culturing a microorganism in the presence of a fermentation medium, the fermentation medium comprising:
at least one carbon source;
calcium ions ranging from 0.05 g/L to 1.6 g/L; and
a base other than a calcium containing base; and
b) producing at least 40 grams/liter of malonate (for example, in a range of from 40 grams/liter to 200 grams/liter, from 60 grams/liter to 150 grams/liter, from 80 grams/liter to 150 grams/liter, from 90 grams/liter to 150 grams/liter, or from 100 grams/liter to 150 grams/liter malonate), wherein optionally, the malonate is produced at a rate of at least 0.3 g L−1 h−1 to 5 g L−1 h−1.
Dependent claim 7 is drawn to the fermentation method of claim 5, wherein the calcium ion is provided to the fermentation medium at a concentration in a range of 0.1 g/L to 1.2 g/L.
Dependent claim 8 is drawn to the fermentation method of claim 6, wherein the calcium ion is provided to the fermentation medium at a concentration in a range of 0.1 g/L to 0.5 g/L.
Dietrich et al., teach the limitations set forth supra.
Dietrich et al. do not specifically teach that their calcium ion is provided to the fermentation medium at a concentration in a range of 0.1 g/L to 1.2 g/L, as recited in claim 7; nor does it specifically teach that their the calcium ion is provided to the fermentation medium at a concentration in a range of 0.1 g/L to 0.5 g/L, as recited in claim 8.
It would have been obvious before the effective filing date of the presently claimed invention to employ the fermentation medium at, for instance, a concentration in the range as claimed with a reasonable expectation of success. This modification may be viewed as a limitation of optimizing experimental parameters. The skilled artisan would have been motivated to make this modification because the amount of calcium ions needed depends largely upon the specific microorganism, microbial culturing, and for cell culture.
Regarding the specific concentrations listed in the instant claims, MPEP 2144.05 states, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).”
Limitations such as administration, weight ratios and the base ranges as recited in claims 15-16 are being viewed as limitations of optimizing experimental parameters. Accordingly, the subject matter of the rejected claims would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
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Conclusion
7. No claim is allowed.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAKIA J JACKSON-TONGUE whose telephone number is (571)272-2921. The examiner can normally be reached Monday-Friday 930AM-530PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary B Nickol can be reached at 571-272-0835. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAKIA J JACKSON-TONGUE/Examiner, Art Unit 1645 November 25, 2025
/BRIAN GANGLE/Primary Examiner, Art Unit 1645