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 .
Priority
This application is a 371 of PCT/US2019/024132 filed 03/26/2019 which claims benefit of provisional application 62/648, 752 filed 03/27/2018 and claims benefit of provisional application 62/667,250 filed 05/04/2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/21/2025 complies with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 4, 8, 21, 61, 63 and 72 are amended. Claims 10, 18, 60 and 73-75 are cancelled. Claims 77-82 are new.
Claims 1, 4, 5, 7-9, 21, 61-63, 70-72 and 76-82 are pending (claim set filed 08/21/2025) and are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 04/08/2024 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
A previously applied objection to specification has been withdrawn necessitated by Applicant's amendment of specification.
Maintained/Modified Rejections
The following rejections are maintained and/or modified taking into consideration amendment to claims filed on 08/21/2025.
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4-5, 7-9, 21, 61-63, 72, 77 and 80 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more. Claim 1 recites a method of purifying a target protein comprising steps of setting up a harvest skid, measuring the UV signal, automatically transferring the UV signal into the target protein titer using a model and collecting the target protein. Claim 1 recites formulas I and II for the model, including mathematical equations and coefficients which is an abstract idea/mathematical concept. Thus, claim 1 recites judicial exception, i.e. abstract idea/mathematical concept.
The judicial exception is not integrated into a practical application because in addition to mathematical formulas, the claim also includes steps of setting up a harvest skid, measuring and automatically transferring the UV signal into the target protein titer based on mathematical models and automatic control system that automatically starts and stops collection of the target protein depending on the titer and collecting the target protein. The whole process appears to be automated including measuring the UV signal with a sensor and collecting the target protein which is automatically controlled and does not require any active intervention from the user except the initial setting up a harvest skid. The harvest skid is described in the specification as a system comprising different sensors including UV sensor (paragraphs 0057, 00139 and 00140). The setting up a harvest skid is recited at high level of generality and adds insignificant extra solution to the judicial exception. The method is directed to purifying a target protein which is the intended use of the process and thus describes the purpose of the process and not the actual method steps. The claim recites that the process is performed during filtration based cell culture harvesting process and production of the target protein in cell culture comprising mammalian cells. These processes are recited at high level of generality and add insignificant extra solution to the judicial exception.
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because steps of setting up the harvest skid and automatic control of the protein production and collection of the target protein are recited at high level of generality and are routine and conventional as evidenced by Sulya (WO 2015010097 A2). Sulya teaches a method of fully automated protein production controlled by monitoring in real-time a target protein concentration by UV absorbance during all steps of protein production including filtration during cells harvesting (Abstract, paragraphs 021-028, 079 and 083). Konstantinov (US 20140255994 A1) teaches system for continuous manufacturing of therapeutic proteins utilizing dynamic UV monitoring and including bioreactor, filtration system and chromatography system (Abstract, paragraphs 0305, 0009, 0015). Konstantinov discloses disposition of the entire system on a skid (paragraph 0115) that corresponds to setting up a harvesting skid.
Based on the above, claim 1 is rejected as ineligible.
Dependent claims 4-5, 7-9, 21, 61-63 and 72 describe different aspects of the protein production process which do not add significantly more to markedly alter judicial exception. Dependent claims 4, 5, 7, 21 and 72 describe protein titers including titers for the start and stop of protein collection which are calculated based on the mathematical models and do not change the judicial exception of mathematical concept and additionally are routine and conventional as evidenced by Konstantinov teaching protein titers between 0.05 mg/ml and 100 mg/ml during protein production (paragraph 0151). Dependent claim 8 recites increase in protein yield production which is routine and conventional for the automated process as evidenced by Konstantinov describing from 2-fold to 10-fold increase in protein production (paragraph 0212). Dependent claim 9 recites the cell density for cell culture used for protein harvesting which is routine and conventional as evidenced by Konstantinov teaching the cell density during harvest at 50-60 x 106 cells/mL (paragraph 0223). Claims 61 and 63 describe protein filtration as depth filtration and different aspects of depth filtration process which is routine and conventional as evidenced by Yamada (Yamada et al. J. J. Chromatogr., 2017, 1061-1062, 110-116). Yamada teaches purification of monoclonal antibodies using depth filtration, including combination of two filters and flushing and chasing the depth filtration (Abstract, p. 112, right column, 1st paragraph, p. 111, left column, 4th and 5th paragraphs). Dependent claim 62 is described at high generality as routine operation of the bioreactor with the control system modulating the flow rate and sample loading and are conventional as evidenced by Konstantinov teaching continuous process of protein production including multiple pumps to regulate the flow (paragraph 0148) and monitoring protein titer after loading protein to filtration (paragraph 0151).
Therefore claims 4-5, 7-9, 21, 61-63 and 72 are rejected as ineligible.
Dependent claims 77 and 80 are directed to building the model which is an abstract idea/mental process. Thus, claims 77 and 80 recite judicial exception, i.e. abstract idea/mental process. The judicial exception is not integrated into a practical application and claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because in addition to building the model, claim 77 also includes step of adjusting the UV sensor pathlength and claim 80 excludes step of chromatography. Adjusting the UV sensor pathlength is not a physical step but a mental step of including additional parameter in the model and hence does not modify the judicial exception to make it markedly different. Exclusion of chromatography in claim 80 does not add anything to judicial exception of building the model. Therefore, claims 77 and 80 are rejected as ineligible.
Claims 70, 71, 76, 78, 79, 81 and 82 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more. Claims 70 and 7 recites a method of purifying a target protein comprising steps of setting up a harvest skid, measuring the UV signal, automatically transferring the UV signal into the target protein titer using a model and collecting or stopping collection of the target protein. Claims 70 and 71 recite formulas for the model, including mathematical equations and coefficients which are an abstract idea/mathematical concept. Thus, claims 70 and 71 recite judicial exception, i.e. abstract idea/mathematical concept.
These judicial exceptions are not integrated into a practical application because in addition to mathematical model, the claims also include steps of setting up a harvest skid, measuring and automatically transferring the UV signal into the target protein titer based on mathematical models and automatic control system that automatically starts and stops collection of the target protein depending on the titer and collecting the target protein. The whole process appears to be automated including measuring the UV signal with a sensor and collecting the target protein which is automatically controlled and does not require any active intervention from the user except the initial setting up a harvest skid. The harvest skid is described in the specification as a system comprising different sensors including UV sensor (paragraphs 0057, 00139 and 00140). The setting up a harvest skid is recited at high level of generality and adds insignificant extra solution to the judicial exception. The methods are directed to purifying a target protein which is the intended use of the process and thus describes the purpose of the process and not the actual method steps. The claim recites that the process is performed during filtration based cell culture harvesting process and production of the target protein in cell culture comprising mammalian cells. These processes are recited at high level of generality and add insignificant extra solution to the judicial exception.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because steps of setting up the harvest skid and automatic control of the protein production and collection of the target protein are recited at high level of generality and are routine and conventional as evidenced by Sulya (WO 2015010097 A2). Sulya teaches a method of fully automated protein production controlled by monitoring in real-time a target protein concentration by UV absorbance during all steps of protein production including filtration during cells harvesting (Abstract, paragraphs 021-028, 079 and 083). Konstantinov (US 20140255994 A1) teaches system for continuous manufacturing of therapeutic proteins utilizing dynamic UV monitoring and including bioreactor, filtration system and chromatography system (Abstract, paragraphs 0305, 0009, 0015). Konstantinov discloses disposition of the entire system on a skid (paragraph 0115) that corresponds to setting up a harvesting skid.
Based on the above, claims 70 and 71 are rejected as ineligible.
Dependent claim 76 describes protein titers for the start and stop of protein collection that does not add significantly more to a markedly alter judicial exceptions. The protein titers are calculated based on the mathematical model and do not change the judicial exceptions of mathematical concept and additionally are routine and conventional as evidenced by Konstantinov (US 20140255994 A1) teaching protein titers between 0.05 mg/ml and 100 mg/ml during continuous protein production (paragraph 0151). Therefore claim 76 is rejected as ineligible.
Dependent claims 78, 79, 81 and 82 are directed to building the model which is an abstract idea/mental process. Thus, claims 78, 79, 81 and 82 recite judicial exception, i.e. abstract idea/mental process. The judicial exception is not integrated into a practical application and claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because in addition to building the model, the claims 78 and 79 also include step of adjusting the UV sensor pathlength and claims 81 and 82 exclude step of chromatography. Adjusting the UV sensor pathlength is not a physical step but a mental step of including additional parameter in the model and hence does not modify the judicial exception to make it markedly different. Exclusion of chromatography in claims 81 and 82 do not add anything to judicial exception of building the model. Therefore, claims 78, 79, 81 and 82 are rejected as ineligible.
Based on the above claims 1, 4-5, 7-9, 21, 61-63, 70-72 and 76-82 are rejected as directed to ineligible subject matter.
Response to Arguments
Applicant's arguments filed 08/21/2025 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 10-12 of the Remarks) that: “Step 2A-prong two of Office's guidance provides that if the claims recite additional steps or elements that integrate the recited judicial exceptions into a practical application, then the claims as a whole are not directed to the judicial exception. For instance, M.P.E.P. § 2106.04(d)(l) provides that "[o]ne way to demonstrate such integration is when the claimed invention improves the function of a computer or improves another technology or technical field." … Accordingly, a skilled artisan reading the present application would recognize that the present claims can greatly improve harvest robustness and protein yield in a method of purifying a target protein from a sample mixture without requiring a chromatography.”, these arguments are not persuasive because:
Independent claims 1, 70 and 72 are silent about improvement of harvest robustness, protein yield and purification without requiring a chromatography. Besides, since the method steps are recited with transitional phrase “comprising”, additional steps such as chromatography are not excluded as downstream processing. The increase of the yield of the target protein is recited in claim 8 as between about 1 and about 20% increase which is not superior to Konstantinov teaching describing from 2-fold to 10-fold increase in volumetric productivity of the recombinant therapeutic protein produced by continuous manufacturing with dynamic UV monitoring of protein titers (paragraphs 0212, 0305). Therefore, based on the claims and prior art, the artisan in the art would not recognize the great improvement of protein purification identified by present application. The judicial exception is not integrated into a practical application since the steps of measuring the UV signal, transferring the UV signal into target protein titer and collecting protein are performed automatically and the only active step of setting up the harvest skid is recited at high level of generality and is routine and conventional as evidenced by Konstantinov teaching the disposition of the entire system for continuous manufacturing of therapeutic protein on a skid (paragraph 0115). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because steps are recited at high level of generality and are routine and conventional as described in the rejection above. Therefore, the 35 U.S.C. 101 rejection is maintained and modified necessitated by amendment of claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4, 5, 7-9, 21, 62, 70-72 and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Sulya (WO 2015010097 A2) in view of Konstantinov (US 20140255994 A1) and Rudt (Rudt et al. Biotechnol. And Bioengineer., 2017, 114, 368-373).
Regarding claims 1, 70 and 71, Sulya teaches systems and methods of automated operation for production of biologics: “…systems, methods, and devices for monitoring and controlling bioprocess parameters. The systems and methods enable automated operation with real-time analysis of process conditions and analyte or biologic production” (Abstract). Sulya describes systems including a growth vessel, a sampling system, a filtration system, a pumping system, a chromatography system, a detection system, a collector and a processor (paragraphs 006-017). Sulya teaches that the described system can measure in real-time analyte concentrations, transfer the data to a server and adjust system parameters based on the collected data (paragraphs 021-028). Sulya mentions that the described system can measure produced protein drug on all the steps of production: “…the device can measure a drug from start to finish of the batch.” (paragraph 094). The protein concentration is measured by the absorbance spectra of the sample corrected for the background: “… the system can comprise a flow through absorbance analyte detector, which can use the corrected absorbance, Ac, calculated from the difference between the absorbance at a wavelength that the analyte absorbs (e.g. 280 nm), Aabs, and one that it does not absorb, Aref, (e.g.320 nm) Ae= Aabs- Aref = ɛbc.” (paragraph 083). Depending on the protein concentration the amount of protein collected after filtration and loaded on the column is regulated by the processor through the pump: “The pump can control the time, flow rate and volume of how much filter sample is loaded onto the stationary phase, which can control the mass of the biologic loaded onto the cartridge. The processor can be used to control the pump.” (paragraph 079). Sulya mentions growing mammalian cells, including CHO cells for protein production (paragraph 070).
Thus, Sulya teaches a method of fully automated protein production controlled by monitoring in real-time a target protein concentration by UV absorbance during all steps of protein production including filtration during cells harvesting. Even though Sulya teaching includes automated control system, Sulya does not present it as a harvest skid. Sulya does not specify the set titers for starting and stopping collection of the protein and does not provide the model predicted titer.
Regarding claims 1, 70 and 71, Konstantinov teaches integrated continuous manufacturing of therapeutic proteins (Abstract). Konstantinov describes systems including multi-column chromatography systems (MCCS): “biological manufacturing system that include: a first multi-column chromatography system (MCCS) including an inlet; and a second MCCS including an outlet, where the first and second MCCSs are in fluid communication with each other…: (paragraph 0015, Figure 1: 16 and 8). Konstantinov discloses that the chromatography system can be periodic counter current chromatography system (PCCS). The described system utilizes dynamic UV monitoring to determine column switching time: “…Accurate determination of the column-switching time, which is based on the UV absorbance difference between the feed and column outlet, is one of the critical elements of each single PCC system real-time control strategy”. (paragraph 0305).
Konstantinov teaches that the manufacturing system can also include bioreactor: “Some embodiments of any of the systems described herein further include a bioreactor…” (paragraph 0015, Figure 1: 25) and a filtration system between the bioreactor and chromatography system: “Some embodiments of any of the methods described herein further include filtering the liquid culture medium before it is fed into the MCCS1.” (paragraph 0009, Figure 1: 27). Konstantinov mentions that any type of filtration can be used: “… any filtration means known in the art, can be used to filter the liquid culture medium containing the recombinant therapeutic protein before it is fed into the first MCCS.” (paragraph 0149).
Konstantinov teaches the disposition of the entire manufacturing system or its parts on a skid: “Any of the biological manufacturing systems described herein can be disposed on a skid.” (paragraph 0114) and “…the entire system can be disposed on a skid; …or a bioreactor containing a liquid culture medium containing a recombinant therapeutic protein can be disposed on its own skid.” (paragraph 0115).
Konstantinov teaches that the titers of the recombinant protein obtained after harvesting cell culture and filtration and before loading to chromatography column are between 0.05 mg/ml and 100 mg/ml, that determines the lower and the upper levels of collection of protein after harvesting and filtration and loading onto chromatography columns: “The liquid culture medium fed (loaded) into the first MCCS can contain, e.g., between about 0.05 mg/mL to about 100 mg/mL recombinant therapeutic protein” (paragraph 0151). Under broadest reasonable interpretation the upper and lower levels of protein titers are interpreted as titers to start and to stop, respectively, collection and loading protein to a column.
Regarding claims 1, 70 and 71, Rudt teaches real-time monitoring and control of the load phase of a protein A capture step (Title). Rudt describes partial list squares regression (PLS) modeling based on UV/Vis absorption spectra to quantify the amount of the target protein, mAb, which corresponds to protein titer, in the effluent from chromatography column (Abstract). The model was developed by loading different titers of mAb containing contaminants on the column and determining the amount of mAb in the column effluent by analytical chromatography. The recorded spectra were averaged according to fraction time and correlated with mAb concentration based on the PLS model (p. 369, right column, 1st paragraph). Rudt mentions that the estimated concentrations by the PLS model closely followed the measured values by offline analytics (p. 371, left column, 2nd paragraph, Figure 2). Model was evaluated by performing a real-time control of loading with the automatic termination of loading at two target concentrations of mAb in the effluent of 1.5 mg/ml and 0.15 mg/ml corresponding to 50% and 5% of the target product (p. 369, right column, 1st paragraph, p. 371, right column, Figure 3). Rudt describes that for the higher sensitivity the second model was further improved by subtracting the impurity background (p. 372, Figure 3). The two developed models predicted the mAb concentrations with the root mean square error of 0.06 mg/ml and 0.01 mg/ml, respectively (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Sulya teaching of automated production of protein with real-time UV monitoring and Konstantinov teaching on continuous protein manufacturing system disposed on a skid and involving measurement of specified protein titers for beginning and end of protein collection. One would have been motivated to do so since the specified protein titers will identify the range of protein concentrations for the most efficient protein production and provide necessary instructions. A skilled artisan would have reasonably expected success in the combination because both Sulya and Konstantinov provided methods of continuous production of therapeutic proteins.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Rudt teaching and develop a model for prediction of protein titers for different steps of production of protein with real-time UV monitoring based on Sulya and Konstantinov teachings. One would have been motivated to do so since Rudt described the process of developing a model by correlation of the UV absorbance with the titers of the target protein, calibration of the model and evaluation and demonstrated its application for automatic termination of the process at the desired protein titer. A skilled artisan would have reasonably expected success in the combination because Sulya, Konstantinov and Rudt teach methods of automated production of therapeutic proteins.
Thus, Sulya, Konstantinov and Rudt teachings render claims 1, 70 and 71 obvious.
Regarding claims 4, 5, 7, 72 and 76, Konstantinov teaches that titers of the recombinant protein obtained after harvesting cell culture and filtration and before loading to chromatography column are between 0.05 mg/ml and 100 mg/ml: “The liquid culture medium fed (loaded) into the first MCCS can contain, e.g., between about 0.05 mg/mL to about 100 mg/mL recombinant therapeutic protein” (paragraph 0151). That covers limitations of claims 4, 5, 7 and 72-76. Therefore, Konstantinov teaching in combination with Sulya and Rudt teachings renders claims 4, 5, 7 and 72-76 obvious.
Regarding claim 8, Konstantinov teaches increase in the yield of the recombinant therapeutic protein production: “The processes described herein can result in an increased percentage of recovery of the recombinant therapeutic protein (e.g., increased percentage of yield of the recombinant therapeutic protein present in the liquid culture medium in the therapeutic protein drug substance).” (paragraph 0213). Although Konstantinov does not describe increase in percent of yield, Konstantinov teaches substantial increase in the volumetric productivity of the recombinant protein using system he described: “…the processes described herein can result at least a 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7- fold, 8-fold, 9-fold, and 10-fold increase in the volumetric productivity of the recombinant therapeutic protein present in the therapeutic protein drug substance.” (paragraph 0212). Thus, Konstantinov teaching in combination with Sulya and Rudt teachings renders claim 8 obvious.
Regarding claim 9, Konstantinov teaches the cell density during harvest: “The cells were allowed to grow to 50-60 x 106 cells/mL.” (paragraph 0223) that reads on limitations of claim 9. Thus, Konstantinov teaching in combination with Sulya and Rudt teachings renders claim 9 obvious.
Regarding claim 21, Konstantinov teaches target protein titer based on the amount of the recombinant protein expressed in mg/ml and target protein yield in percent (paragraphs 0213 and 0214) and not on volume. Sulya and Konstantinov do not teach the step of air blown down. Thus, Sulya, Konstantinov and Rudt teachings render claim 21 obvious.
Regarding claim 62, Konstantinov teaches measurement of protein titer before column chromatography after cell culture harvest and filtration and hence not before loading sample mixture to filtration system (paragraph 0151). Thus, Konstantinov teaching in combination with Sulya and Rudt teachings renders claim 62 obvious.
Claims 61 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Sulya (WO 2015010097 A2) in view of Konstantinov (US 20140255994 A1) and Rudt (Rudt et al. Biotechnol. And Bioengin., 2017, 114, 368-373) as applied to claims 1, 4-5 and 7 above, and further in view of Yamada (Yamada et al. J. J. Chromatogr., 2017, 1061-1062, 110-116).
Sulya, Konstantinov and Rudt teachings have been set forth above.
Sulya, Konstantinov and Rudt do not teach protein filtration to be a depth filtration, depth filtration to comprise primary and secondary filter and flashing and chasing depth filters with buffers.
Regarding claims 61 and 63, Yamada teaches purification of monoclonal antibodies using depth filtration (Abstract). Yamada mentions the advantages of depth filtration: “Depth filters are thought to remove particles and impurities not only by physical capture in narrow pore spaces but also by electrostatic and hydrophobic adsorptive interactions.” (p. 110, right column, 3rd paragraph). Yamada describes the entirely flow-through process of monoclonal antibody purification including depth filtration step: “Our results show that an entirely flow-through process focused on depth filtration is possible for antibody purification” (p. 115, right column, 2nd paragraph).
Regarding claim 61, Yamada teaches that combination of two depth filters significantly improves the removal of host cell proteins (HCP): “These data indicate that it is advantageous to combine different types of depth filters to remove HCP efficiently…” (p. 112, right column, 1st paragraph). Table 2 shows that the second depth filtration (Step 2) significantly reduces the HCP and high molecular weight (HMW) content retaining high yield: “In step 2, the HCP concentration decreased from step 1 in all combinations. The most effective HCP removal was observed in Runs 2 and 3, which were combinations of A1HC and EXT” (p. 112, right column, 1st paragraph).
Regarding claim 63, Yamada describes equilibration of depth filters with buffer before loading cell culture supernatant: “The depth filters were equilibrated with 10 mM Tris -HCl (pH 8.0) before the sample was loaded.” (p. 111, left column, 4th paragraph). Yamada teaches chasing the depth filter with buffer after flow through: “The first depth filtration pool was prepared by mixing the flowthrough and the chase.” (p. 111, left column, 5th paragraph). A chase is performed with a buffer: “… a chase was performed with 10 L/m2 of 10 mM Tris-HCl (pH 8.0).” (p. 111, left column, 5th paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add Yamada teaching on application of depth filtration during therapeutic protein production to Sulya, Konstantinov and Rudt teachings on automated production of protein with real-time UV monitoring and select depth filtration for filtration of harvested cell culture following Yamada instructions of application of two depth filters, equilibrating depth filter with buffer before loading and chasing the depth filtration post loading. One would have been motivated to do so since Yamada demonstrated efficient production of monoclonal antibody using depth filtration. A skilled artisan would have reasonably expected success in the combination because Sulya, Konstantinov, Rudt and Yamada developed methods of continuous recombinant protein production. Thus, Yamada teaching in combination with Sulya, Konstantinov and Rudt teachings renders claims 61 and 63 obvious.
Claims 77-79 are rejected under 35 U.S.C. 103 as being unpatentable over Sulya (WO 2015010097 A2) in view of Konstantinov (US 20140255994 A1) and Rudt (Rudt et al. Biotechnol. And Bioengin., 2017, 114, 368-373) as applied to claims 1, 70 and 71 above, and further in view of Chmielovski (Chmielovski et al. J. Chromat., 2017, 1526, 58-69).
Sulya, Konstantinov and Rudt teachings have been set forth above.
Sulya, Konstantinov and Rudt do not teach the model comprising adjustment of the UV sensor path-length.
Chmielowski teaches the improved method of dynamic control of protein loading during antibody purification in continuous chromatography process. The method is based on UV absorbance monitoring and allows to control protein loading independent on cell culture background (Abstract). Chmielowski discloses determination of the difference in UV280 nm signal between the cell culture feed and monoclonal antibody at different pathlengths: “Impurity versus antibody absorbance levels for a variety of different UV pathlengths were evaluated and compared against theoretical calculations to determine the optimal pathlength for signal detection and control.” (p. 59, right column, 3rd paragraph). The UV280 nm measurements of the samples with and without antibody ranging from 3-41 g/L were performed at pathlengths from 0.05 to 2 mm (p. 60, right column 1st paragraph). 0.35 mm pathlength was selected as optimal pathlength to overcome background signal (Abstract). Chmielowski describes that: “ … an optimal UV path-length could be 0.35 mm to achieve a robust difference in ∆UV and also maintain linearity for HCCF titers from about 3–31 g/L.” (p. 64, right column, 1st paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Chmielowski teaching and include adjustment of UV sensor path-length during developing a model predicting protein titer and used for target protein purification based on Sulya, Konstantinov and Rudt teachings. One would have been motivated to do so since Chmielowski teaches that detection and control of protein signal depends on the detection pathlength and suggests the optimal pathlength of 0.35 mm to overcome background signal. A skilled artisan would have reasonably expected success in the combination because Sulya, Konstantinov, Rudt and Chmielowski developed methods of continuous recombinant protein production. Thus, Chmielowski teaching in combination with Sulya, Konstantinov and Rudt teachings renders claims 77-79 obvious.
Claims 80-82 are rejected under 35 U.S.C. 103 as being unpatentable over Sulya (WO 2015010097 A2) in view of Konstantinov (US 20140255994 A1) and Rudt (Rudt et al. Biotechnol. And Bioengin., 2017, 114, 368-373) as applied to claims 1, 70 and 71 above, and further in view of Eaton (WO 02095373 A1).
Sulya, Konstantinov and Rudt teachings have been set forth above.
Sulya, Konstantinov and Rudt do not teach model for method excluding the use of chromatography.
Eaton teaches infrared spectroscopy for on-line process control and endpoint detection (Title). Eaton describes that the concentration of the analyte can be determined using a mathematical model representing the relationship between the concentration of the analyte and the absorbance profile. The mathematical model can be developed by measuring the spectrum for a number of standard samples with known concentration and mathematically correlating the concentration as a function of absorbance profile. However, when the analyte is in a complex mixture, more powerful multivariant mathematical correlation techniques are applied referred as chemometrics (p. 17, lines 7-26). Eaton discloses that the preferred mathematical technique is PLS (Partial Least Squares) to model the spectra as a function of concentration. The concentration of the analyte being modelled in each standard is measured off-line by HPLC (p. 19, lines 11-13, 24-27). Eaton mentions that the developed chemometric model can be used to determine concentrations of analyte by spectroscopy in real-time during continuous process allowing for improved reaction control and more accurate and timely determination of the end point (p. 21, lines 21-32). Eaton does not use chromatography.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Eaton teaching and use PLS chemometrics for developing a model predicting concentration of protein as a analyte in a process excluding chromatography and apply it for target protein purification based on Sulya, Konstantinov and Rudt teachings. One would have been motivated to do so since Eaton teaches that the chemometric model can be used to determine concentrations of analyte by spectroscopy in real-time during continuous process allowing for improved reaction control and more accurate and timely determination of the end point. A skilled artisan would have reasonably expected success in the combination because Rudt and Eaton teach PLS technique for modeling analyte concentration and Sulya, Konstantinov and Rudt developed methods of continuous recombinant protein production. Thus, Eaton teaching in combination with Sulya, Konstantinov and Rudt teachings renders claims 80-82 obvious.
Response to Arguments
Applicant's arguments filed 08/21/2025 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 13-15 of the Remarks) that Sulya, Konstantinov and Rudt do not specifically disclose or suggest all the features of claims 1, 70 and 71, are silent on the formula recited in the claims. Applicant further argues that: “only through the present application would a skilled artisan have been able to recognize the superior technical effects of the current claims at issue, including improved yield and superior prediction of target protein titer. For example, the specification states that the "yield using the new harvest skid was 2-5% higher than that using the old method" … The predicted titers had a slope of fit that was very close to 1 and thus very close to the offline titer values. These arguments are not persuasive because:
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., improved yield and superior prediction of target protein titer) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Besides, Konstantinov teaches 2-fold to 10-fold increase in volumetric productivity of the recombinant therapeutic protein produced by continuous manufacturing with dynamic UV monitoring of protein titers (paragraphs 0212, 0305). Rudt teaches RMSE for prediction in PLS model of 0.01 mg/ml (p. 372, right column) and Figure 2 (p. 372) demonstrates very close correlation of the offline quantification for mAb and the predicted by PLS model protein titers.
Applicant argues (addressing p. 16 of the Remarks) that “none of the cited references provides any disclosure or suggestion related to formula (I) and (II). Accordingly, a skilled artisan reading Sulya, Konstantinov, Rudt, and Yamanda, alone or in combination, would not have had any reason to specifically include the formula (I) and (II) to calculate the model predicted titer when developing a method of purifying a target protein from a sample mixture, and certainly not with any reasonable expectation of success.”, these arguments are not persuasive because:
Although Sulya, Konstantinov, Rudt, and Yamada do not expressly teach formula (I) and formula (II), one would have been motivated to apply Rudt teaching to protein purification with real-time UV monitoring as taught by Sulya and Konstantinov and develop a PLS model for prediction of protein titer on different steps of purification based on UV signal since Rudt discloses that the estimated concentrations by the PLS model closely follow the measured values by offline analytics (p. 371, left column, 2nd paragraph). Besides Rudt described the development, calibration and evaluation of the PLS model and demonstrated its application for automatic termination of the process at the desired protein titer (p. 369, right column, 1st paragraph, p. 371, right column, Figure 3). Additionally, Sulya, Konstantinov and Rudt teach methods of automated protein purification and hence a skilled artisan would have reasonably expected success at the prior art combination.
Therefore the 35 U.S.C. 103 rejection is maintained and modified necessitated by amendment of claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653