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 .
Status of Claims
Claims 37-44, 47-51, 55, 57-62, 67, and 69 are pending.
Priority
Claims 37-44, 47-51, 55, 57-62, 67, and 69 are a 371 of PCT/IB 2022/054287 filed on May 9, 2022, which has priority to PRO 63/186334 filed on May 10, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on November 10, 2023, was filed before the mailing of the First Office Action on June 6, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Claim Objections
Claim 38 is objected to for the following reasons:
Claim 38 recites “wherein the cell culture medium comprising one or more materials” should read as “wherein the cell culture medium comprises one or more materials”.
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 44, 51, 55, 61, 62, and 67 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 44 recites the limitation "cell mass" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 44 should read “to remove a cell mass”.
Claim 51 recites “cation exchange column and/or addition of an acid in step (3)”. As written the “and/or addition” is unclear. Based on the language, a person of ordinary skill in the art would not understand if the cation exchange column is in “addition” to the acid step. Is the cation exchange column limitation optional where a person of ordinary skill can perform one or the other?
Claim 51 recites the limitation "an acid" in line 2. There is insufficient antecedent basis for this limitation in the claim. The claim language should read “addition of the [[an]] acid”.
Claim 51 recites the limitation “step (3)” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 37 does not contain a “step (3)”.
Claim 61 recites the limitation “step (4)” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 37 does not contain a “step (4)”
Claim 62 recites “subjected to an anion exchange column and/or addition of base”. As written the “and/or addition” is unclear. Based on the language, a person of ordinary skill in the art would not understand if the cation exchange column is in “addition” to the base step. Is the cation exchange column limitation optional where a person of ordinary skill can perform one or the other?
Claim 62 recites the limitation “base” in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 62 should read “addition of a base”.
Claim 67 is rejected as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention. Claim 67 is dependent on claim 63 which has been cancelled. Because a dependent claim must refer back to and incorporate the limitations of a valid independent or dependent claim, claim 67 is rendered indefinite and is given no further consideration.
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.
Claims 37-44, 47-51, 55, 57-62, and 69 are rejected under 35 U.S.C. §103 as being unpatentable over Nakai et al. [EP 3591030 A1], in view of Luo and Wan (Hereinafter Luo) [Effects of pH and salt on nanofiltration – a critical review, Journal of Membrane Science, 2013], in view of Torres et al. [Process and metabolic engineering perspectives of lactate production in mammalian cell cultures, Current Opinion in Chemical Engineering, 2018], in view of Waymouth [Osmolality of mammalian blood and of media for culture of mammalian cells, In Vitro, 1970], in view of Reiss et al. [Cell sources for cultivated meat: applications and considerations throughout the production workflow, International Journal of Molecular Sciences, 2021], in view of Kwon et al. [Continuous removal of small nonviable suspended mammalian cells and debris from bioreactors using inertial microfluidics, Royal Society of Chemistry, 2018], in view of Wikipedia [Blood fractionation, 2020], in view of Allan et al. [Bioprocess design considerations of cultured meat production with a focus on the expansion bioreactor, Front. Sustain Food Syst., 2019].
Regarding claim 37, Nakai et al. teaches every element through step b) that includes recycling a culture medium [¶ 0004], removing a cell culture medium from a bioreactor [¶ 0003], and filtering the cell culture medium to obtain waste medium for further processing and a concentrate medium for recirculation where the waste medium is essentially devoid of cells and large proteins [¶ 0005]. However, Nakai et al. does not teach parts c) acidifying the waste medium and d) subjecting the acidified waste medium to nanofiltration where further removing waste material resulting in a “rejuvenated” medium that is essentially devoid of at least one waste material.
Regarding the limitations of c) and d) listed in claim 37, Luo teaches that the efficiency and selectivity of nanofiltration processes are highly dependent upon pH of the feed solution given pH directly affects solute ionization, molecular charge state, electrostatic interactions, and membrane rejection behavior [Abstract, Graphical Abstract]. Luo further explains that adjusting solution pH can enhance the separation of ionic and low molecular weight compounds by altering their dissociation characteristics and transport across nanofiltration membranes [Practical Advice & 5.2. Chemical Cleaning]. Given this, there would have been a reasonable expectation of success for a person of ordinary skill in the art to combine the teachings of Nakai et al. with the teachings of Luo given that acidification would have been recognized as a viable path in order to modify ionic strength and solute charge interactions in a manner that enhances membrane separation efficiency during the nanofiltration step recited in step d). This would have allowed the removal of charged waste metabolites, salts, ammonium-containing particulates, lactate, and other contaminants that would be viewed as interfering with cell expansion.
For claim 38 where the cell culture medium is made up of one or materials selected from a Markush listing, Nakai et al. discloses a cell culture medium that is made up of cells, nutrients, and other biological materials necessary for cell cultivation [¶ 0007-0008], and although Nakai et al. does not specifically disclose the exact listing of components found in Claim 38, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the current application that conventional cell culture media used in mammalian cell culture and perfusion bioreactor systems routinely include components such as cells, tissue, nutrients, supplements, feeds, amino acids, peptides, proteins, vitamins, polyamines, etc. These components represent well known components of biological cel culture media used in maintaining cell growth, proliferation, differentiation, metabolism, and protein production.
For claim 39 where the culture medium contains blood cells, Wikipedia describes blood fractionation as a routine and well-established method for separating blood into plasma and cellular components based on different densities [Plasma protein fractionation].
For claim 40 where the waste materials interfere with desired growth and/or differentiation of cells, Nakai et al. teaches that waste products discharged in large amounts can improve cell growth, i.e. desired growth and/or differentiation [¶ 0008].
For claim 41 where the cell culture medium comprises tissues cultured for antibody production or cultured meat production, Nakai et al. discloses antibody production using cells such as CHO cells which were originally isolated from tissue [¶ 0038]. Additionally, Reiss et al. discloses tissue derived from animals as the source of pluripotent cells, that are then used for culturing meat [Figure 1]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Nakai et al. with the additional teachings of Reiss et al. where a person of ordinary skill would have a reasonable expectation to chose a culture media that is appropriate for culturing mammalian cells that included such things as cells, tissues, nutrients, supplements, feeds, amino acids, etc. in order to provide a culture environment that is capable of sustaining mammalian cellular growth and to ensure that the medium is refreshed in some manner that could include removal of waste products to further promote cellular growth and proliferation. Additionally, it is prima facie obvious that in order to promote antibody production and/or cultured meat production, a person of ordinary skill would understand that the starting cells would need to be derived from tissues that are capable of supporting such production.
For claim 42 where the cell culture medium is filtered through at least one hollow fiber with pore cutoff up to 60 kDa in step b), Nakai et al. discloses the use of an ultrafiltration membrane where the molecular cutoff is between 30 and 70 kDa [¶ 0021].
For claim 43 where the hollow fiber has a pore density at least 10% of the inner wall surface of the hollow fiber, Nakai et al. teaches the use of hollow fiber configurations for the continuous removal of waste products from cell culture medium [¶ 0003 and 0005]. Furthermore, it would be considered routine optimization for a person of ordinary skill in the art to choose a hollow fiber configuration with routine porosity and pore density characteristics given that such parameters are well-known parameters that determine the desired separation performance in bioreactor systems.
For claim 44 where the cell culture medium is filtered continuously centrifugation to remove cell mass form the bioreactor, Kwon et al. discloses the continuous removal of waste in a bioreactor cell suspension is viable and is capable of removing small nonviable cells and debris from bioreactors [Abstract]. Although Kwon et al. does not specifically cite the use of centrifugation as the means for waste removal, centrifugation is a well-known method for separating cellular debris, and other particles from culture media. Additionally, Nakai et al., citing JP 2015-053892 A, discloses a semicontinuous culture device that includes a spin filter which is disposed in the culture tank and separates bacterial bodies from culture solution [¶ 0005].
For claim 47 where the molecular waste has a molecular weight of no greater than 60 kDa, the selection of a molecular weight of no greater than 60 kDa as an upper limit cutoff reflects a predictable adjustment of membrane cutoff properties in order to achieve a desired separation efficiency. Because of this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Nakai et al. to select a molecular weight threshold of no greater than 60 kDa by means of routine optimization of known membrane separation parameters.
For claims 48 and 49 where at least one waste material comprises ammonia, lactate, etc., Torres et al. teaches lactate is a known waste material in mammalian cell-based cultures [Introduction ¶ 1].
For claim 50 where the cell concentrate medium comprises cells and essential materials for cell growth and/or differentiation, Nakai et al. does not explicitly teach concentrate medium. However, Nakai et al. does teach that removal of waste products from the culture media improves cellular growth [¶ 0008]. Furthermore, Luo teaches that membrane-based separation processes, including nanofiltration and related filtration techniques are capable of selectively removing low molecular waste material while retaining higher molecular weight and biologically essential components based on membrane properties [Introduction]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Nakai et al. and Luo in a manner that after waste material removal using selected filtration, the resulting media, although not necessarily concentrated, would contain essential materials that aid in cellular growth and/or differentiation given the cellular media was originally selected as an appropriate culture medium for culturing mammalian cells.
For claim 51 where the waste medium is subjected to cation exchange, Nakai et al. discloses the use of chromatography columns in which cation exchange columns are a subset [¶ 0045].
For claim 55 where the acidified waste medium has a pH value of less than 4, although Luo does not specifically disclose a pH value of less than 4, Luo does teach that pH is a critical process parameter in nanofiltration and related membrane separation processes [Abstract]. Based on this, it would have been nothing more than routine optimization for determining acidification conditions within a known and conventional range.
For claim 57, Luo teaches that nanofiltration performance is strongly influenced by feed concentration, ionic strength, and concentration polarization, and that dilution of feed streams is routinely used to improve membrane flux and separation efficiency [Abstract, 2.1 Flux/permeability]. Furthermore, the addition of deionized water in the pre-dilution step is understood to reduce ionic strength and solute concentration in the acidified waste medium, thereby improving nanofiltration performance by mitigating concentration polarization and enhancing removal of low molecular waste species.
For claim 58 where the nanofiltration has a molecular weight cutoff from about 150 to about 300 Da, Luo discloses that nanofiltration is characterized by molecular weight cutoff values, e.g. effective pore size and charges [Introduction]. Furthermore, the recited range represents routine optimization of membrane cutoff selection in order to achieve the desired separation efficiency.
For claim 59 where the waste material is further isolated and recovered, Allan et al, discussing cultured meat production, describes where waste product is identified along with waste separation through electrodialysis and/or filtration, and finally waste valorisation/ up-scaling where the separated waste products can be used in feedstock for alternative process and/or industry [Figure 1].
For claim 60 where the rejuvenated media comprises fatty acids having a molecular weight greater than 150 Da and glucose, although not specifically cited in Nakai et al. and in view of general knowledge in the art of mammalian cell culture media, mammalian cell culture media necessarily contain glucose as a primary carbon and energy source, as well as lipid components or fatty acid species required for cellular metabolism and membrane biosynthesis [¶ 0043]. Furthermore, the rejuvenated medium would inherently require the presence of glucose and fatty acids as essential components in order to sustain mammalian cell cultures. With respect to glucose and fatty acids have a molecular weight greater than 150 Da merely reflects the inherent composition conventional cell culture media used in perfusion systems.
For claim 61 where the pH of the rejuvenated medium is further neutralized, Nakai et al. discloses recycling of culture medium in a perfusion bioreactor and returning the processed medium to support continued cell growth and viability [¶ 0008]. Furthermore, Luo teaches that acidification can be applied to biological feed streams to improve nanofiltration efficiency and separation of ionic species [Abstract]. Although neither reference specifically state “further neutralizing” the pH of the rejuvenated medium, a person of ordinary skill would understand the medium that is below the requisite pH level for sustaining mammalian cell cultures would need to be restored to a pH level that would maintain culture conditions. Because of this, a person of ordinary skill would understand that the rejuvenated culture media’s pH would have to brought back to neutral from an acidic state.
For claim 62 where the rejuvenated medium is subjected to an anion exchange column and/or the addition of a base, please see analysis for claim 61.
For claim 69 where the rejuvenated medium is adjusted to be less than 360 milliosmoles per kilogram of water, Waymouth teaches that for most species milliosmoles value falls within the range of 290 to 305 mOsm [Osmolalities’ of blood of mammals other than man]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Nakai et al. and Luo with the further teachings of Waymouth where it is disclosed that most non-human mammals maintain a milliosmole range between 290 and 305. Given this, there is a reasonable expectation of success that person of ordinary skill in the art would recognize the need to maintain a milliosmolarity range that would minimize membrane stress, prevent metabolic disruption, and/or result in apoptosis.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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