DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Claims 1-20 were entered on Oct. 31, 2024.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on Ot. 31, 2024 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 2-3 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.
The phrase “substantially consistent” in claims 2 and 3 is a relative phrase which renders the claim indefinite. The phrase is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The metes and bounds for determining whether the airflow or stirring is “substantially consistent” is not defined by the claims or specification. Thus, it is unclear how to define substantially consistent; therefore appropriate clarification is required to overcome the rejection.
The term “enhanced” in claim 2 is a relative term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The metes and bounds for determining whether the enhanced airflow is not defined by the claims or specification. Thus, it is unclear how to define enhanced airflow as opposed to unenhanced airflow; therefore appropriate clarification is required to overcome the rejection.
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.
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.
5. Claims 1-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Hopkins (US Patent 4,883,759 published Nov. 1998; priority to July 1983) in view of Yousef et al., (US 20110245152 published 2011-10-06; priority to 2007-09-28).
The claims are drawn to a method for obtaining a metabolite, the method comprising the steps of: conducting a bioreaction with a selected microorganism, thereby resulting in the production of at least one metabolite, wherein: the bioreaction is conducted in a bioreactor having a bulk liquor and a headspace above the bulk liquor;
the selected microorganism is provided in the bulk liquor; and the bioreaction is conducted under conditions for inducing a persistent foam at an interface between the bulk liquor and the headspace above it; removing the persistent foam from the bioreactor; allowing the persistent foam to break, thereby giving condensed foam liquid; and isolating at least one metabolite from the condensed foam liquid.
Hopkins teach a process for the production of microbial cells by fermentation of carbonaceous material in a foam fermenter containing an oxygen-enriched nutrient medium. The process uses a source of carbon which is assimilable by the microorganism for the production of the microbial cells. The microbial cells are separated and removed from the foam fermenter for use as a food product high in protein content. The process includes the controlled release of a quantity of the constituents of a portion of the microorganism within the fermenter to increase the maintenance of the source of carbon and the nutrient medium in a foamed condition at a predetermined level in the fermenter [abstract]. The process of the present invention can be generally characterized as the aerobic fermentation of a suitable carbon source assimilable by a microorganism in fermentors which operate under essentially foam-filled conditions. Suitable sources of carbon material include any feed which can be used to make organisms or their bio-products by a high-cell density foam fermentation process, and include, for example, alcohols, glucose, sucrose (molasses), etc [Description]. It has been found that fermentation carried out in a foam-filled fermentor in certain fermentation processes is highly efficient when carried out in a continuous process. The foamed contents of the fermentor can be described as the dispersion of the gaseous phase within the liquid phase, or occasionally may be described as an emulsified gaseous phase or simply as an emulsion of the gaseous and liquid phases wherein increased surface area contact is effected between the gas and liquid phases for enhancing the fermentation process. Specifically, it has been found that the fermentation productivity (grams of cells per liter of mixture per hour) is significantly higher when using the foam fermentor than when a conventional paddle stirred tank fermentor is employed [Description]. the formation and maintenance of foam in foam fermentation processes is enhanced by suitably treating a portion of the microorganisms in the fermentation vessel so as to release or cause the release of the constituents of said thus treated microorganisms [Description].
Hopkins teach a foam fermenter apparatus. The apparatus comprises a closed fermentation vessel [Figure 4]. A draft tube is disposed within the vessel and provides a flow path for the medium contained within the vessel to help induce circulation. A heater is mounted on the lower end portion of the vessel and is provided with a heating element; thereby meeting the limitation of arranged for maintaining and controlling temperature in the reactor vessel. A suitable foam level transducer 34 is mounted at the upper and provides means for sensing the level of foam within the vessel and providing a suitable signal output in response to the thus sensed level of the foam. A foam breaker is positioned within the upper end portion of the vessel and functions to break foam which might otherwise accumulate in the upper portion of the vessel. Thus Hopkins teach breaking the received foam into a condensed foam liquid.
In the operation of the apparatus, a suitable amount of nutrient medium and alcohol is fed into the vessel via inlet. An inlet communicates with the interior of the upper portion of the vessel and provides means for delivery of portions of the nutrient medium used in the fermentation process. Thus the first conduit as disclosed by Hopkins as an inlet.
An outlet communicates with the interior of the upper end portion of the vessel at a point above the foam breaker and provides means for exhausting gaseous effluent from the fermentation process being carried on within the vessel. An outlet communicates with the interior or the lower end portion of the vessel and provides means for drawing off a portion of the contents of the vessel for further processing. Hopkins’ inlet and outlet disclose a fraction collector unit, arranged for withdrawing and analyzing samples from the reactor vessel wherein the second conduit as disclosed by Hopkins as an outlet.
Hopkins disclose the instantly claimed control console as a control unit. During the fermentation process, an output signal to be generated by the transducer and transmitted via conduit to control unit. When the foam within the vessel regains electrically conductive contact with the foam a transducer generates another signal which is transmitted to the control unit. In response to the second signal, the control unit will cause the heater to turn off thus deactivating the heater element. Thus Hopkins disclose a system arranged for controlling temperature. A conduit extends through the wall of the vessel and downwardly through the draft tube terminating at a point adjacent the turbine. The conduit provides means for introducing a source of oxygen, such as free oxygen, air, or air supplemented by free oxygen, into the medium.
Hopkins disclose a suitable amount of nutrient medium and alcohol is fed into the vessel. Hopkins disclose a sonicator being activated by the control unit, the sonication probe transmits by vibrations to the contents of the vessel. Therefore, the apparatus comprises a means for agitating the bulk liquor. Hopkins disclose a suitable amount of oxygen is injected through the conduit to the lower portion of the draft tube to further enhance foam formation.
When the desired level of foam generation is achieved within the vessel, the interior of the vessel is inoculated with a desired microorganism to initiate fermentation therein. Thus teaching the suspension of microorganisms including bacteria as recited by the claims. During the fermentation process, the heater is mounted on the lower end portion of the vessel and is provided with a heating element. Hopkins provides a means for exhausting gaseous effluent from the fermentation process being carried on within the vessel. Thus teaching an opening to vent gas pressure as recited by the claims. The foam beaker meets the limitation of a foam collector, arranged to receive a foam formed at an interface of the bulk liquor and the headspace and to break the received foam into a condensed foam liquid. While Hopkins teach the claimed method, Hopkins does not teach Paenibacillus polymyxa strain, OSY-DF or other bacterial species.
Yousef et al., teach a novel Paenibacillus polymyxa strain, OSY-DF, and its bioactive mutants. Also provided is a method for using a novel antimicrobial peptide, paenibacillin, isolated from the bacterial strain OSY-DF, and its bioactive variants or fragments. The invention also relates to antimicrobial compositions containing same and methods of their use [abstract]. Thus teaching peptide isolation and claims 13-14. Live cultures of Paenibacillus polymyxa strain OSY-DF, fermentates derived from these cultures, or their crude extracts are useful in various applications [para 50]. “Fermentate” refers to a microorganism plus the medium in which the microorganism (e.g., P. polymyxa OSY-DF or its mutant) has grown and secreted its metabolites. The metabolites of interest in the present invention are the antimicrobial agents discussed above. Fermentate refers to the cultured strain (that is after inoculation of strain in a medium and incubation) which includes both the live biomass and the metabolites, i.e. antimicrobial agents [para 60]. The “bacterial compositions,” containing a live culture of Paenibacillus polymyxa OSY-DF, a live culture of a bioactive mutant of OSY-DF, or a fermentate or crude extract of a live culture of Paenibacillus polymyxa OSY-DF or its bioactive mutants [para 69]. Thus teaching claim 16. Paenibacillin exhibits a relatively broad antimicrobial spectrum, showing activity against a panel of Gram-positive bacteria including spore- and nonspore-formers, and pathogenic and spoilage bacteria. This peptide is quite stable at the temperatures tested [para 76]. Other useful compositions of the invention can include the peptides of the invention together with another active agent, i.e., another lantibiotic or a known antibiotic. Example of suitable lantibiotics are Nisin and subtilin. The combination of ingredients can be quite effective when applied together to kill or inhibit the growth of bacteria, especially gram-positive bacteria [para 100]. The OSY-DF strain or its bioactive mutants offer promise for use as a control preparation or biocontrol agent because OSY-DF is active against many Gram-positive and/or Gram-negative bacteria. Such compositions are relatively inexpensive to mass produce because they are grown in large volume fermenters and require little or no downstream processing other than, in some embodiments, drying [para 145]. The isolated bacterial strain, OSY-DF, was propagated on tryptic soy agar supplemented with 0.6% yeast extract (TSAYE) at 30° C. For stock preparation, the culture was cultivated overnight at 30° C. in TSBYE mixed with sterile glycerol (final concentration of 20%) and stored at —80° C. The indicator strains and media used in this study are listed in Table 1 [para 157]. Thus teaching claim 15. Table 1 includes strains E. coli K12, Listeria innocua, B. subtilis and L. lactis [para 158]. The lantibiotics produced by lactic acid bacteria have been tested as biopreservatives in a number of food products, with nisin being the most prominent member of these bacteriocins. For decades, nisin has been used worldwide [para 7]. Other useful compositions of the invention can include the peptides of the invention together with another active agent, i.e., another lantibiotic or a known antibiotic. Example of suitable lantibiotics are Nisin and subtilin [para 100]. Thus teaching claims 19-20.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Yousef et al’s bacteria and associated ingredients, to Hopkins’ method for producing a target metabolite in a bioreaction, in order to prevent pressure build-up inside biogeneration chamber, and provides a method for using paenibacillin and other antibiotics. One of ordinary skill in the art would have a reasonable expectation of success by incorporating components in order to prevent excessive foaming can cause the biogeneration chamber to overflow through the vent line, causing loss of nutrients, water and cell count, thereby slowing the desired bacterial growth.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results" and there is no change in the respective function of the components, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim Rejections - 35 USC § 103
6. Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Hopkins (US Patent 4,883,759 published Nov. 1998; priority to July 1983) and Yousef et al., (US 20110245152 published 2011-10-06; priority to 2007-09-28) as applied to claims 1-17 above, and further in view of Gerst et al., (Genome Announc. 2017 Oct 12;5(41):e01046-17).
Hopkins et al., in view of Yousef et al., teach a method for obtaining a metabolite, the method comprising the steps of: conducting a bioreaction with a selected microorganism, thereby resulting in the production of at least one metabolite, wherein: the bioreaction is conducted in a bioreactor having a bulk liquor and a headspace above the bulk liquor; the selected microorganism is provided in the bulk liquor; and the bioreaction is conducted under conditions for inducing a persistent foam at an interface between the bulk liquor and the headspace above it; removing the persistent foam from the bioreactor; allowing the persistent foam to break, thereby giving condensed foam liquid; and isolating at least one metabolite from the condensed foam liquid. However neither teach the inclusion of Bacillus velezensis GF610.
Gerst et al., teach Bacillus species are known to produce potent antimicrobial compounds. Bacillus velezensis GF610 was isolated from garden soil originating in Dunlap, IL, USA. A bacterial cell extract of B. velezensis was effective against Listeria innocua and 11 strains of Listeria monocytogenes (M. Gerst and A. Yousef, unpublished data). A lantibiotic, amyloliquecidin GF610, was identified in the crude extract using matrix-assisted laser desorption ionization-time of flight mass spectrometry and Fourier transform ion cyclotron resonance mass spectrometry [Genome Announcement]. Bacillus spp. are known to produce these compounds. For example, B. velezensis LM2303 produces surfactin, iturin, fengycin, bacillaene, and macrolactin. Strains of Bacillus amyloliquefaciens were found to produce difficidin, macrolactin, fengycin, bacillaene, surfactin, bacillibactin, and bacilysin [Genome Announcement]. Therefore, Bacillus velezensis GF610 is a producer of potent anti-Listeria agents including amyloliquecidin GF610.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Gerst et al’s bacteria, to Hopkins and Yousef et a’s method for producing a target metabolite in a bioreaction, in order to produce potent antimicrobial compounds. One of ordinary skill in the art would have a reasonable expectation of success by incorporating the Bacillus velezensis GF610 bacteria of Gerst et al., when Yousef already taught Bacillus bacteria producing antimicrobial metabolites.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results" and there is no change in the respective function of the components, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Pertinent Art
7. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO 2008091416 teach a live culture of Paenibacillus polymyxa OSY-DF, a live culture of a bioactive mutant of OSY-DF, or a fermentate or crude extract of a live culture of Paenibacillus polymyxa OSY-DF or its bioactive mutants. Isolated OSY-DF lantibiotic or peptides or bioactive fragments thereof are free of contaminating proteins from the same bacteria from which the lantibiotic or peptides are derived. Typically, such lantibiotic and peptides are produced by extraction from the culture of the bacteria which produces them. The starter culture for safer fermented products. The lantibiotics produced by lactic acid bacteria have been tested as biopreservatives in a number of food products, with nisin being the most prominent member of these bacteriocins. For decades, nisin has been used worldwide as a food additive, and it is the only lantibiotic approved by the World Health Organization as a food preservative [para 7].
WO 2011017420 teaching a multi-phase, gas-lift bioreactor device for digestion and production of biogas or biofuel from organic material, as well as methods of use thereof.
Donaldson et al., (US 20150252389) teach a recombinant microorganism having an engineered isobutanol biosynthetic pathway [para 8]. The present process employs a batch method of fermentation. Fed-Batch fermentation processes are also suitable in the present invention and comprise a typical batch system with the exception that the substrate is added in increments as the fermentation progresses. Fed-Batch systems are useful when catabolite repression is apt to inhibit the metabolism of the cells and where it is desirable to have limited amounts of substrate in the media. Measurement of the actual substrate concentration in Fed-Batch systems is difficult and is therefore estimated on the basis of the changes of measurable factors such as pH, dissolved oxygen and the partial pressure of waste gases such as CO2. Batch and Fed-Batch fermentations are common and well known in the art [para 179].
Kiplinger et al., (US Patent Pub 20010051371 published Dec 2001). Kiplinger et al., teach method for cultivating bacteria in a fluid medium and thereafter selectively discharging the fluid medium, wherein an initial supply of the selected strain or strains of bacteria is combined with nutrients and water in a biogenerator in the presence of air to promote mixing and bacterial cultivation. The disclosed system and method utilize a vortex created by recirculation of the fluid medium to achieve aeration and mixing without substantial foaming [abstract].
RU 2580646 teaching fermentation apparatus for methane- assimilating microorganisms.
WO2017165244 teaching microorganisms and bioprocesses are provided that convert gaseous C1 containing substrates, such as syngas, producer gas, and renewable H2 combined with CO2, into nutritional and other useful bioproducts.
US7598075 teaching apparatus and methods for the growth of cells to high density, products therefrom and uses thereof.
US Patent 4,211,645 teach the steps of adding a nutrient medium, adjusting the pH to mildly acid or neutral condition, feeding the mixture to a fungal culture inoculated fermentor with agitation and with aeration, resulting in foaming of the mixture, said foam carrying with it the fungi and sludge resulting from the fermentation, the suspended solids content of the foam when collapsed being generally not more than half the suspended solids content of the fermentor broth, said foam being processed so as to separate the components into a sludge and a clarified effluent, said sludge being recycled to the fermentor vessel and the clarified effluent prepared for discharge or additional processing. Under optimum operating conditions as much as 85 to 90% BOD removal from spent sulfite liquor is accomplished.
Yousef et al., (US 20130164317 published 2013-06-27; priority to May 7, 2012).
Yousef et al., a biologically pure culture of Paenibacillus thiaminolyticus, identified as OSY-SE, as well as an antimicrobial agent isolated and/or purified from the culture [abstract]. An antimicrobial polypeptide prepared by a process comprising the steps of: (a) culturing Paenibacillus thiaminolyticus OSY-SE, Paenibacillus thiaminolyticus OSY-SE cells, or another organism, or host cell under conditions effective to produce the antimicrobial polypeptide [para 10]. The method comprises contacting at least one of (i) a microbe and (ii) a substrate capable of supporting microbial activity with at least one of: (a) the biologically pure culture; (b) the amino acid sequence; (c) the composition; and (d) the compound as described herein, wherein the at least one of the microbe and the substrate is contacted with at least one of (a)-(d) in an amount effective to affect microbial activity [para 14]. The recombinant cell comprises a gram positive bacterial cell. In some embodiments, the recombinant cell comprises a bacterial cell of the genus Paenibacillus [para 24]. Yousef et al., teach a recombinant bacterial host cell obtained from the Bacillus amyloliquefaciens alpha-amylase gene (amyQ) [para 84]. The method for producing an antimicrobial agent (e.g., paenibacterin), wherein the method comprises (a) cultivating a host cell under conditions that allow for production of the polypeptide; and optionally (b) purifying/isolating the polypeptide [para 100]. Typically cells are cultivated in a nutrient medium suitable for production of the antimicrobial agent (e.g., paenibacterin) using common techniques known in the art. For example, the cell may be cultivated by shake flask cultivation, small-scale or large-scale fermentation (including continuous, batch, fed-batch, or solid state fermentations) in laboratory or industrial fermentors performed in a suitable medium and under conditions allowing the polypeptide to be expressed and/or isolated. Any suitable nutrient medium (e.g., a medium comprising carbon and nitrogen sources, inorganic salts, etc.) can be used to cultivate the cells using procedures known in the art. In embodiments wherein the polypeptide is secreted from the cell into the nutrient medium, the polypeptide can be recovered directly from the medium [para 101].
Van Wezel et al., (US Patent 4,888,294 published 1989-12-19)
Van Wezel et al., teach cultivation tank for continuous cultivation of cells or micro-organisms, containing a rotating separating device for separating suspended cells from cultivation liquid supplied continuously through a supply and passed through the separating device from the outside to the inside, cell free liquid being continuously discharged from within the separating device, the rotating parts of the separating device being formed so that within the outer circumference a zone is formed of a vortex-free, vertical rotating column of cultivation liquid from which the cells are radially thrown out by centrifugal forces into the surrounding liquid through openings in the outlet circumference of the separating device are considerably greater than the size of the cells [abstract]. The rotating assemblies may be attached to the rotating shaft of the stirring element or attached to a separate rotating shaft which extends into the cultivation tank [Summary of Invention]. The outlet pipe debouches in the vicinity of the shaft inside the innermost cylindrical drum. Given rotary speed of the rotating shaft of the stirrer and a given medium in the tank, a vortex-free column of liquid is formed which rotates along with the cylinders in the annular space , in which column of liquid the cells or cell-carrying particles suspended therein are subjected to the centrifugal force generated therein and as a consequence are thrown back through the large pores in the wall of the cylinder into the medium situated in the tank. As a result of the continuous supply and removal of medium a continuous perfusion system is obtained which is not obstructed by the occurrence of filter material blockages [Detailed Description].
Conclusion
8. No claims allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/JANA A HINES/Primary Examiner, Art Unit 1645
Prosecution Insights