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 .
Claim Status
Claims 1-3, 5-14, and 16-24 are pending.
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.
Claim 2 is 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 2 recites the limitation "a first time interval” and “a second time interval”. There is insufficient antecedent basis for this limitation in the claim. These terms have previously been defined.
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 1-2, 5, 10-13, 16, 18, 21-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US 2012/0264920) in view of Johnson et al (“Adapting viral safety assurance strategies to continuous processing of biological products”).
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With regard to Claims 1, 2, 5, and 10, Wang et al (Wang) discloses a method for purifying a protein (Abstract). Wang discloses a method for purifying an antibody from a sample comprising one or more impurities including viral particles ([0004]). Wang discloses the method comprises providing a sample including the antibody (Abstract, [0004]).
Wang discloses loading the sample to a hydrophobic interaction chromatography (HIC) column (Figure 1, step 4, [0047], after steps 1-3, the sample may be loaded into an intermediate/final polishing step, which may be a hydrophobic interaction chromatography column). The Examiner notes that the instant specification does not have a special definition for “sample”, and also refers to eluates as samples; see e.g., “HIC pool sample” at [0064] and “output sample” at [0029].
Wang discloses that the HIC column is coupled to a virus retentive filtration (VRF) system, wherein flowthrough of the HIC column is loaded to the VRF system (Figure 1, step 5, [0059], following the intermediate/final polishing chromatography step, the eluate pool may be subjected to a nanofiltration step; the nanofiltration step is accomplished via one or more nanofilters or viral filters, such as Sartorius Virosart® filters; [0035], the specific methods for the chromatography capture step are typically provided by the manufacturers or are known in the art, and can include the process of flowing or passing a sample through chromatography column and shall include a continuous flow through each mechanism (wherein flowthrough of the HIC column is loaded to the VRF system)). Wang discloses wherein the VRF system comprises at least two filter trains in parallel ([0059], a filter train comprised of a prefilter and a viral filter; two filter trains in parallel with two prefilters and two viral filters).
Wang discloses that the HIC column and the VRF system are part of a series of recovery, capture, and purification steps ([0062]). Wang discloses that the economics of large-scale protein purification are important, particularly for therapeutic antibodies ([0003]).
However, Wang is silent to wherein the HIC column and the VRF system are connected inline in a continuous processing system, and wherein each of the at least two filter trains is scheduled to operate at different time intervals, wherein at a first time internal, the flowthrough of the HIC column is scheduled for filtering through a first filter train, and wherein at a second time interval after the first time interval, the flowthrough of the HIC column is scheduled for filtering through a second filter train, wherein the VRF system is operated under externally driven feed flow (Claim 5), wherein the viral reduction capability of the method is at least 4 LRV (logarithmic reduction value (Claim 10).
Johnson discloses that there has been a recent drive in commercial large-scale production of biotechnology products to convert current batch mode processing to continuous processing manufacturing (Abstract). Johnson discloses that continuous processing is particularly advantageous for the immediate capturing of the protein of interest, which confers considerable product stability advantages over allowing long holding periods of raw harvest in tanks (Page 21/Introduction and Problem Statement). Continuous processing also promises to reduce facility size by reducing the size of tanks, bioreactors, and columns (Page 21/Introduction and Problem Statement).
Johnson discloses that one method to adapt viral filtration into a continuous process is an automated parallel switch-in and -out system filtration scheme between old and fresh filters before they reach a validated total volumetric throughput (Page 28/Viral Filtration). The concept of staging them in parallel allows switch-out as they foul which enables them to be in a continuous process (Page 28/Viral Filtration). The input stream to the VRF system will be held and mixed in a surge tank to control the flowrate via a pump (i.e., externally driven feed flow) into the cyclic filtration system (Page 28/Viral Filtration, Page 29/Figure 2A) (Claim 5, wherein the VRF system is operated under externally driven feed flow). An in-house proof-of-concept study showed that this automated parallel flow filtration system was able to clear bacteriophage models at >= 4 LRVs with and without protein content (Page 28, Column 2) (Claim 10, wherein the viral reduction capability of the method is at least 4 LRVs). Johnson teaches programmed control logic (Figure 1, Figure 2; controller, control loop, control inputs which control the time periods and flow rates).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention for wherein the HIC column and the VRF system are connected inline in a continuous processing system, and wherein each of the at least two filter trains is scheduled to operate at different time intervals, wherein at a first time internal, the flowthrough of the HIC column is scheduled for filtering through a first filter train, and wherein at a second time interval after the first time interval, the flowthrough of the HIC column is scheduled for filtering through a second filter train, wherein the VRF system is operated under externally driven feed flow (Claim 5), wherein the viral reduction capability of the method is at least 4 LRV (logarithmic reduction value (Claim 10), as taught by Johnson, in order to adapt the viral filters of Wang into a continuous process, and since continuous processing is particularly advantageous for the immediate capturing of the protein of interest, which confers considerable product stability advantages over allowing long holding periods of raw harvest in tanks, and since continuous processing also promises to reduce facility size by reducing the size of tanks, bioreactors, and columns.
With regard to Claim 11, Wang discloses further comprising a step of single-pass tangential flow filtration and/or a prefiltration ([0059], prefilters before viral filters).
With regard to Claims 12, 13, 16, and 21, Wang et al (Wang) discloses a method for purifying a protein (Abstract). Wang discloses a system for purifying an antibody from a sample comprising one or more impurities including viral particles ([0004]). Wang discloses the system comprises a hydrophobic interaction chromatography (HIC) column, wherein the sample is loaded to the HIC column (Figure 1, step 4, [0047], after steps 1-3, the sample may be loaded into an intermediate/final polishing step, which may be a hydrophobic interaction chromatography column). The Examiner notes that the instant specification does not have a special definition for “sample”, and also refers to eluates as samples; see e.g., “HIC pool sample” at [0064] and “output sample” at [0029].
Wang discloses that the system comprises a virus retentive filtration (VRF) system, wherein flowthrough of the HIC column is loaded to the VRF system (Figure 1, step 5, [0059], following the intermediate/final polishing chromatography step, the eluate pool may be subjected to a nanofiltration step; the nanofiltration step is accomplished via one or more nanofilters or viral filters, such as Sartorius Virosart® filters; [0035], the specific methods for the chromatography capture step are typically provided by the manufacturers or are known in the art, and can include the process of flowing or passing a sample through chromatography column and shall include a continuous flow through each mechanism (wherein flowthrough of the HIC column is loaded to the VRF system)). Wang discloses wherein the VRF system comprises at least two filter trains in parallel ([0059], a filter train comprised of a prefilter and a viral filter; two filter trains in parallel with two prefilters and two viral filters).
Wang discloses that the HIC column and the VRF system are part of a series of recovery, capture, and purification steps ([0062]). Wang discloses that the economics of large-scale protein purification are important, particularly for therapeutic antibodies ([0003]).
However, Wang is silent to wherein the HIC column and the VRF system are connected inline in a continuous processing system, wherein each of the at least two filter trains is configured to operate at different time intervals according to a schedule, wherein according to the schedule, the flowthrough of the HIC column is configured for filtering through a first filter train at a first time interval, and wherein the flowthrough of the HIC column is configured for filtering through a second filter train at a second time interval after the first time interval, wherein the VRF system is operated under externally driven feed flow (Claim 16), wherein the viral reduction capability of the system is at least 4 LRV (logarithmic reduction value) (Claim 21).
Johnson discloses that there has been a recent drive in commercial large-scale production of biotechnology products to convert current batch mode processing to continuous processing manufacturing (Abstract). Johnson discloses that continuous processing is particularly advantageous for the immediate capturing of the protein of interest, which confers considerable product stability advantages over allowing long holding periods of raw harvest in tanks (Page 21/Introduction and Problem Statement). Continuous processing also promises to reduce facility size by reducing the size of tanks, bioreactors, and columns (Page 21/Introduction and Problem Statement).
Johnson discloses that one method to adapt viral filtration into a continuous process is an automated parallel switch-in and -out system filtration scheme between old and fresh filters before they reach a validated total volumetric throughput (Page 28/Viral Filtration). The concept of staging them in parallel allows switch-out as they foul which enables them to be in a continuous process (Page 28/Viral Filtration). The input stream to the VRF system will be held and mixed in a surge tank to control the flowrate via a pump (i.e., externally driven feed flow) into the cyclic filtration system (Page 28/Viral Filtration, Page 29/Figure 2A) (Claim 16, wherein the VRF system is operated under externally driven feed flow). An in-house proof-of-concept study showed that this automated parallel flow filtration system was able to clear bacteriophage models at >= 4 LRVs with and without protein content (Page 28, Column 2) (Claim 21, wherein the viral reduction capability of the method is at least 4 LRVs). Johnson teaches programmed control logic (Figure 1, Figure 2; controller, control loop, control inputs which control the time periods and flow rates).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention for wherein the HIC column and the VRF system are connected inline in a continuous processing system, and wherein each of the at least two filter trains is configured to operate at different time intervals (Claim 12), wherein according to the schedule, the flowthrough of the HIC column is configured for filtering through a first filter train at a first time interval, and wherein the flowthrough of the HIC column is configured for filtering through a second filter train at a second time interval after the first time interval, wherein the VRF system is operated under externally driven feed flow (Claim 16), wherein the viral reduction capability of the system is at least 4 LRV (logarithmic reduction value (Claim 21), as taught by Johnson, in order to adapt the viral filters of Wang into a continuous process, and since continuous processing is particularly advantageous for the immediate capturing of the protein of interest, which confers considerable product stability advantages over allowing long holding periods of raw harvest in tanks, and since continuous processing also promises to reduce facility size by reducing the size of tanks, bioreactors, and columns.
With regard to Claim 22, Wang discloses further comprising a step of single-pass tangential flow filtration and/or a prefiltration ([0059], prefilters before viral filters).
With regard to Claim 24, modified Wang discloses all the limitations in the claims as set forth above. However, modified Wang is silent that the first predetermined time interval is greater than one day.
As the method efficiency and purification parameters are variables that can be modified, among others, by adjusting said time interval length, the time interval length would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed time interval length cannot be considered critical. Accordingly, one of ordinary skill in the art at the time the invention was made would have optimized, by routine experimentation, the time interval length in the method of modified Wang obtain the desired balance between the method efficiency and purification parameters (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Claims 3, 7, 14, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2012/0264920) in view of Johnson et al (“Adapting viral safety assurance strategies to continuous processing of biological products”), as applied to the claims above, and in further view of Kleindienst et al (“Continuous processing: challenges and opportunities of virus filtration”).
With regard to Claims 3 and 14, modified Wang discloses all the limitations in the claims as set forth above.
However, modified Wang is silent to wherein the VRF system is operated under constant flow or constant pressure (Claim 3), wherein the VRF system is configured to operate under constant flow or pressure (Claim 14).
Kleindienst et al (Kleindienst) discloses that virus filtration is a crucial downstream processing operation that must be carefully considered when implementing continuous bioprocesses to ensure patient safety (Page 2/Batch vs. continuous virus filtration). Kleindienst discloses that because continuous virus filtration is operated at much lower flow rates, longer filtration times often involve longer pressure releases than are observed with batch filtration (Page 3/Filtration parameters). Continuous filtration is often run at constant flow rather than constant pressure, but may be run at constant pressure for ease of experimentation (Page 3/Filtration parameters).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention for wherein the VRF system of modified Wang is operated under constant flow or constant pressure (Claim 3), wherein the VRF system is configured to operate under constant flow or pressure (Claim 14), as taught by Kleindienst, since continuous filtration is often run at constant flow rather than constant pressure, but may be run at constant pressure for ease of experimentation.
With regard to Claims 7 and 18, modified Wang discloses all the limitations in the claims as set forth above. However, modified Wang is silent to wherein each of the at least two filter trains is scheduled at a time point for priming, equilibration, filtration, flushing, integrity testing, sanitization, neutralization, or storage (Claim 7), wherein for each of the at least two
parallel filter trains, the schedule includes a different time interval for priming, equilibration, filtration, flushing, integrity testing, sanitization, neutralization or storage (Claim 18).
Kleindienst et al (Kleindienst) discloses that one possible process implementation for virus filtration in continuous processing is to use a set-up with two filtration lines that can be operated independently of each other in a preparation mode or operation mode (Page 6/Process implementation). Steps such as flushing, equilibration, filtration, buffer flush, wetting for integrity tests, and the integrity tests are performed in preparation mode, whereas the product filtration is performed in operation mode (Page 6/Process implementation).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention for wherein each of the at least two filter trains of modified Wang is scheduled at a time point for priming, equilibration, filtration, flushing, integrity testing, sanitization, neutralization, or storage (Claim 7), wherein for each of the at least two parallel filter trains, the schedule includes a different time interval for priming, equilibration, filtration, flushing, integrity testing, sanitization, neutralization or storage (Claim 18), as taught by Kleindienst, in order to prepare the filter during preparation mode before filtration in operation mode.
Claims 6 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2012/0264920) in view of Johnson et al (“Adapting viral safety assurance strategies to continuous processing of biological products”), as applied to the claims above, as evidenced by Sartorius (“Virosart® CPV”).
With regard to Claims 6 and 17, modified Wang discloses all the limitations in the claims as set forth above. Wang discloses that the viral filters may be Sartorius Virosart® CPV filters ([0059]). However, Wang does not explicitly state what type of filters these are.
Sartorius discloses that the Virosart® CPV filters are polyethersulfone membranes (Page 1). Therefore, the filter of Wang is a membrane filtration.
Claims 8, 9, 19, 20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2012/0264920) in view of Johnson et al (“Adapting viral safety assurance strategies to continuous processing of biological products”), as applied to the claims above, and in further view of Xenopoulos (US 2015/0133636).
With regard to Claims 8, 9, 19, and 20, modified Wang discloses all the limitations in the claims as set forth above. However, modified Wang is silent to wherein the VFR system is operated under constant flow at between about 10 LMH and about 100 LMH (Claim 8), wherein the VFR system is operated under constant flow at about 90 LMH (Claim 9), wherein the VRF system is configured to operate under constant flow at between about 10 LMH and 100 LMH (Claim 19), wherein the VRF system is configured to operate under constant flow at about 90 LMH (Claim 20).
Xenopoulos discloses improved processes and systems for purification of biological molecules, where the processes can be performed in a continuous manner (Abstract). Xenopoulos discloses that a lower flow rate through the virus filtration step results in a higher throughput of the virus filter ([0359]). Xenopoulos selected flow rates of 100 LMH and 200 LMH for experimentation ([0360]-[0361]).
As the throughput of the VRF system is a variable that can be modified, among others, by optimizing the flow rate, the precise flow rate would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed flow rate between about 10 LMH and about 100 LMH (Claims 8 and 19) or of about 90 LMH (Claims 9 and 20) cannot be considered critical. See Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989)(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.). Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, the flow rate in the method of modified Wang to optimize the throughput in the VRF system (KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007); Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969)), since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also MPEP §2144.05(II)(A).
With regard to Claim 23, modified Wang teaches the limitations as noted above. Wang teaches a buffer flush of the first filter train after the first predetermined time interval, wherein the post-use buffer flush enhances consistency of pool concentration for continuous ultrafiltration/diafiltration ([0037]; [0040]; [0060]; [0065]; [0090]; [0092]; [0094]; [0096]; [0098]).
Wang does not teach storing the first filter train in NaOH when the first filter train is not in use. Wang teaches rinsing the filters with salt after use ([0063]).
Xenopoulos teaches storing the first filter train in NaOH when the first filter train is not in use ([0362]; [0367]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to incorporate NaOH for soaking the filter train when not in use, as taught by Xenopoulos as it is a known filter cleaning and storage buffer.
Response to Arguments
Applicant's arguments filed 3/25/2026 have been fully considered but they are not persuasive.
In regard to the Applicant’s argument that Wang and Johnson do not teach a programmed control logic to subject each filter to operate at predetermined time intervals; the Examiner does not find this persuasive.
See updated rejection above in light of claim amendments.
Conclusion
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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/KARA M PEO/ Primary Examiner, Art Unit 1777
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