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
Applicant’s claim for the benefit of a prior-filed application (371 of PCT/EP2017/084478, filed 22 December 2017) under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority (GB1622342.2, filed 29 December 2016) under 35 U.S.C. 119 (a)-(d).
Response to Amendments
Applicant’s amendments filed 10 June 2026 have been entered.
No claims have been amended; Claims 2-4, 7, 9, and 10 were previously canceled; Claims 11-15 are withdrawn; new Claims 16 and 17 have been added. Claims 1, 5, 6, 8, and 11-17 are pending.
Response to Arguments
Applicant’s arguments filed 10 June 2026 have been fully considered.
Regarding “III. Rejections under 35 U.S.C. § 103” (pg. 7-9), with respect to the rejections of Claim(s) 1, 5, 6, and 8 under 35 U.S.C. 103 as obvious over BANGTSSON et al. (US 2012/0091063 A1) in view of THORSON et al. (US PGPub 2014/0033793 A1) and HODGE (US 2012/0118828 A1), Applicant argues BANGTSSON “does not teach or suggest identifying a deviating behavior based on a parameter crossing a predetermined threshold level or exhibiting a declining trend over multiple cycles” (pg. 7, par. 5). Applicant further argues that neither HODGE nor THORSON address trend analysis and therefore do not cure the deficiencies of BANGTSSON (par. spanning pg. 7-8; pg. 8, par. 1).
The Examiner respectfully disagrees. This instantly recited feature is not claimed in any of the pending claims of the rejections of Claims 1, 5, 6, and 8. At best, the only consideration of “deviating behavior” in these claims is recited in Claim 1, step (b): “performing… real time trend analysis over time… to identify a deviating behavior of the operational column capacity of each column based on the historical data and a relative comparison between the columns and/or an absolute comparison between cycles for each column”, and in Claim 5: “wherein multiple cycles for each of the at least four columns are performed… and the trend analysis in step b) is performed based on cycle number”. No recitation of “declining trend” or “crossing a predetermined threshold level” is made in these claims. 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). Regarding HODGE and THORSON, even if arguendo such instant limitations were recited, it is noted that the rejection is based on multiple references. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that one of ordinary skill would not be motivated to combine BANGTSSON and THORSON because BANGTSSON discloses compensating column differences during operation without requiring column replacement whereas THORSON addresses single column chromatography, i.e., one of ordinary skill “would not have combined these references because the intended purpose of Bangtsson is to avoid the need for identical columns or column replacement through real-time compensation” (pg. 8, par. 2).
The Examiner respectfully disagrees. Applicant has misconstrued the purpose of THORSON; THORSON is not restricted to only column malfunctions in single column systems. THORSON merely teaches a method whereby any column that is performing poorly as identified by low efficiency can be replaced with a new column. Such a step is not limited to single-column systems—indeed, there is no explicit teaching in THORSON restricting this practice to single-column systems—in fact, THORSON regularly references multiple columns throughout its disclosure.
Applicant argues BANGTSSON fails to teach or suggest the limitation of detecting “target product concentration in the sample introduced in each column of the continuous chromatography system” of Claim 1, arguing that “Bangtsson measures effluent concentration after the column… not target product concentration in the sample introduced in each column” (pg. 8, par. 3).
The Examiner respectfully disagrees. As noted in previous rejections, BANGTSSON explicitly discloses measuring feed concentration, i.e., p0045.
Finally, regarding new Claims 16 and 17, Applicant argues the prior art fails to teach or suggest such limitations.
The Examiner respectfully disagrees. As noted in the subsequent rejections, such limitations are indeed taught or made obvious by the prior art.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 5, 6, 8, 16, and 17 is/are rejected under 35 U.S.C. 103 as obvious over BANGTSSON et al. (US 2012/0091063 A1) in view of THORSON et al. (US PGPub 2014/0033793 A1) and HODGE (US 2012/0118828 A1).
Regarding Claim 1, BANGTSSON discloses a method for determining the binding capacities of a chromatography column via real-time measurements of a continuous chromatography process (i.e., a method for monitoring operational status in a continuous chromatography; p0002, p0005). As shown in FIG. 3, the chromatography system comprises three columns 39, 47, 59 (i.e., a continuous chromatography system configured to operate with… columns; providing the continuous chromatography system, wherein the continuous chromatography system comprises… columns) connected in series with multiple detectors 33, 45, 53, 65, which are connected to determining unit 71 and control unit 73 for continuously monitoring a feed line and effluent from each column (p0031, p0033). The method is repeated whereby a target sample is continuously purified over subsequent cycles (i.e., configured for continuous purification in a cyclic operation wherein the continuous purification is performed on a sample comprising a target product; p0032-0044). Furthermore, as shown in FIG. 6 and as indicated throughout the disclosure, the taught columns are monitored in real-time for multiple cycles (203, 205, 207, and 209) spanning up to 800 minutes; UV absorbance measurements are made to determine concentrations of solutes eluting from the multiple columns (Claim 7). It is noted that BANGTSSON further provides an embodiment wherein four columns 107, 109, 111, 113 are utilized under the same setup as the embodiment utilizing three columns (i.e., wherein the continuous chromatography system comprises at least four columns; FIG. 5; p0048).
Regarding step (a), as is well-known to one of ordinary skill in the art, each chromatography process relies on a breakthrough curve that is determined based on how much solute that can bind at any given time and flow conditions, i.e., a breakthrough curve relates the concentration capacity a column can have against time (or volume or mass loaded) (p0003). Thus, given this breakthrough curve relationship between binding capacity and time, the amount of solute that binds can be calculated if provided the column run-time (i.e., residence time), flow rate, and volume. Because BANGTSSON discloses monitoring column performance continuously in real-time (i.e., “determining the breakthrough point and the saturation point… could be done automatically in real time… since the feed signal is automatically compensated for”, p0027), BANGTSSON discloses determining the breakthrough point (i.e., a predetermined capacity) based on residence time (i.e., step (a), detecting at least one parameter indicative of the operational column capacity of each column… wherein said parameter comprises a time of sample for each column to reach a predetermined capacity). BANGTSSON further discloses the monitored variable is feed/effluent concentration (i.e., the detected at least one parameter is a target product concentration in the sample introduced in each column of the continuous chromatography system; p0045). BANGTSSON further discloses an embodiment where UV detectors are utilized to monitor the absorbance of MAb feed and effluent (i.e., MAb concentration) in the columns (p0048). As shown in FIG. 2 and in p0025-0026, BANGTSSON discloses how Deltasignal and Deltasignalmax are used to calculate the breakthrough point and further relate how Deltasignal is dependent on both the feed concentration measured at feed signal 21 and the effluent concentration measured at effluent signal 23.
Regarding step (b), BANGTSSON discloses that the system is able to detect changes in real-time and compensate for such changes by automatically adjusting the breakthrough and saturation switching points between columns, e.g., “these determinations of binding capacities… are used for automatically controlling the start and stop of the different chromatography process steps, i.e. when a certain breakthrough or saturation point level has been reached a control system can control the chromatography system to proceed to the next process step” (i.e., step (b), performing…real time trend analysis over time, of each of the at least one detected parameter to identify a deviating behavior of the operational column capacity of each column based on a relative comparison between the columns and/or an absolute comparison between cycles for each column; p0028).
Regarding step (c), BANGTSSON discloses “any differences in [column] binding capacities and/or flow rates can be compensated for” (p0029) (i.e., step (c), initiating… at least one action to eliminate or reduce the effect of the identified deviating behavior…whereby the eliminating or reducing the effect of the identified deviating behavior causes performance of the continuous chromatography system to be maintained; p0027-0029; p0045). Regarding the limitation that step (c) is performed “in response to determining that the identified deviating behavior is not attributable to a start-up process of a first cycle”, the claim language utilizes open-ended transitional language (e.g., “comprises”) and does not exclude process steps whereby corrective actions are taken to eliminate or reduce deviating behavior during start-up cycles. BANGTSSON discloses that the aforementioned compensating process is practiced during the entire “process time” of the system – they note that these differences are based on a priori knowledge of expected feed composition and flow rates over the process time of the system (p0029) based on “Deltasignal” and “Deltasignalmax” measurements (p0045). These measurements are made continuously by detectors in the feed line and effluent from each column (p0031-0033). Because BANGTSSON teaches this compensating process is continuously performed during all processing times, BANGTSSON inherently discloses initiating the at least one action in response to deviating behavior not attributed to a start-up process of a first cycle, i.e., as discussed in p0057, when an unexpected loss of antibodies is discovered during elution from a column (i.e., a non-start-up process), corrective actions are implemented. Thus, one of ordinary skill in the art prior to the effective filing date of the claimed invention would have found obvious the limitation of “initiating… in response to determining that the identified deviating behavior is not attributable to a start-up process of a first cycle”. (Furthermore, the phrase “not attributable to a start-up process” is overly broad and could be reasonably interpreted to be any point in time after a process has started). Finally, BANGTSSON discloses that “any differences… can be compensated for by automatically adjusting breakthrough and saturation switching points…” (p0045). As shown in the sole example, mass loading onto separate columns was adjusted in response to identified differences, i.e., the process was reconditioned to capture/elute different amounts of product (i.e., wherein the at least one action comprises one or both of reconditioning or column replacement; p0057). It is further noted that the added limitation wherein “the at least one action includes one or both of reconditioning or column replacement” is obvious to one of ordinary skill in any art. If a part of a system is malfunctioning or showing deviating behavior, it would be wholly obvious to fix that part or entirely replace that part, i.e., “column replacement”.
As referenced earlier, BANGTSSON further discloses the chromatography system continuously monitors certain parameters, e.g., breakthrough and saturation points, for each column and detects any unexpected changes such that variations in feed or effluent concentrations can be compensated for by adjusting changes in feed concentration/mass (i.e., when the operational status of a particular column indicates that action is needed to maintain performance of the continuous chromatography system; p0045). Such steps include bypassing columns (e.g., by redirecting flow) that have exceeded these parameters and subjecting them to column wash steps for eventual addition back to the chromatography cycle (i.e., removing the particular column from the at least four columns used by the continuous chromatography system for continuous purification; performing actions to reinstate the operational status of the particular column; p0028, p0031).
BANGTSSON is deficient in disclosing that when the operational status indicates a particular column has to be replaced, the action performed in step c2) comprises removing the particular column from the continuous chromatography and replacing the particular column with a new column.
THORSON discloses methods for maintaining the quality of a chromatography system (abstract). THORSON discloses that when a column efficiency is determined to be too low, the column can be replaced with a new “good” column (p0158). Advantageously, this column exchange would address any deficiently-performing columns and thereby increase the effectiveness of a chromatography system. Thus, at the time of the filing of the invention, one of ordinary skill in the art would have found it obvious to remove a particular column and replaced with a new column if the particular column was indicated to require replacement as taught by THORSON in the method for monitoring the operational status of a chromatography system made obvious by modified BANGTSSON.
Modified BANGTSSON is deficient in explicitly disclosing processing circuitry used for performing real-time trend analysis over time and is also deficient in disclosing accessing, by processing circuitry, historical data of the at least one detected parameter in a database and performing, by the processing circuitry, real time trend analysis over time, of each of the at least one detected parameter to identify a deviating behavior of the operational column capacity of each column based on the historical data.
HODGE discloses a system and method for variable feedback control in chromatography processes (abstract). Such a system is designed for monitoring a process condition and in real time, adjust a chromatographic operating parameter (p0010). The system comprises a sensor positioned in a main downstream effluent path configured to detect at least one signal indicative of the presence or absence of a component in the effluent of a chromatography column; a controller operably connected to the sensor; and a pump operably controlled by the controller (p0010). The sensor sends signals to the controller, and the controller analyzes the signal (p0016-0017) to control the rate of pumping of fluid to regulate residence time in the column (p0018). The controller is a programmable logic controller and is connected via circuitry to the pump and sensor (p0031-0032). The sensor and pump operate in a feedback loop to optimize the chromatography process using a PID control to establish a control set-point utilizing “historical trending data” (i.e., performing, by the processing circuitry, real time trend analysis over time, of each of the at least one detected parameter; p0035). Although HODGE is deficient in explicitly disclosing “a database”, the disclosure of utilizing “historical trending data” suggests the presence of a database for holding such data, i.e., the claimed database and its access are inherent in the prior art (i.e., accessing, by processing circuitry, historical data of the at least one detected parameter in a database). Advantageously, this method greatly increases the efficiency of a chromatography process (p0028). Thus, prior to the effective filing date of the claimed invention, one of ordinary skill in the art would have found it obvious to provide the disclosed processing circuitry to access historical data in a database to perform real time trend analysis over time as taught by HODGE for the method made obvious by modified BANGTSSON.
The limitation “to maintain the performance of the continuous chromatography system” is directed toward an intended result of the claimed method. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. A “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003); MPEP §2111.04). Where a reference discloses the terms of the recited method steps, and such steps necessarily result in the desired and recited effect, the fact that the reference does not describe the recited effect in haec verba is of no significance because the reference meets the claim under the doctrine of inherency. In this case, even if the prior art fails to explicitly disclose maintaining performance, such a desired result is inherent in every chromatography process—the claim to a “performance” does not define any standard or degree of performance, e.g., a “performance” can be as relaxed as effecting any separation to as stringent as requiring 99.99% purification or removal of targeted contaminants. Even if a “performance” level is specified, such a limitation would be wholly due to the execution of the chromatography process as claimed and would be considered based on the restrictions and limitations defining the process itself.
Regarding Claim 5, modified BANGTSSON makes obvious the method of Claim 1. BANGTSSON further discloses the chromatography system practices the disclosed method over multiple continuous cycles (i.e., wherein multiple cycles for each of the at least four columns are performed; p0044). Further, the loaded amounts of target molecule on each column is measured over time and calculated over each cycle to carefully monitor any potential propagating issues (i.e., the detected parameter in step a) is related to cyclic performance; the trend analysis in step b) is performed based on cycle number; p0057).
Regarding Claim 6, modified BANGTSSON makes obvious the method of Claim 1. BANGTSSON further discloses that the breakthrough or saturation point levels are monitored for each column in the chromatography system (i.e., wherein the detected parameter in step a) is load volume and/or time of sample for each column to [reach] a predetermined capacity; p0028; p0029). Further, BANGTSSON discloses the chromatography system monitors these parameters in real time and continuously for several cycles; and, as shown in FIG. 6, the recorded signals at each detector are compared (i.e., the trend analysis in step b) is performed by comparing load time[s] between columns present in the continuous chromatography; p0027-0029; p0032-0045).
Regarding Claim 8, modified BANGTSSON makes obvious the method of Claim 1. BANGTSSON further discloses column wash steps (i.e., the action performed in step c2) comprises running a conditioning process of the particular column; p0028, p0031). BANGTSSON further discloses column equilibration (i.e., a conditioning process) for each column in the chromatography system in each cycle (p0049).
Regarding Claim 16, modified BANGTSSON makes obvious the method of Claim 1. As indicating in the rejection of Claim 1, BANGTSSON discloses the monitored variable is feed/effluent concentration (i.e., the at least one detected parameter; p0045), e.g., UV detectors are utilized to monitor the absorbance of MAb feed and effluent (i.e., MAb concentration) in the columns (p0048). Further, as shown in FIG. 2 and in p0025-0026, BANGTSSON discloses how Deltasignal and Deltasignalmax are used to calculate the breakthrough point and further relate how Deltasignal is dependent on both the feed concentration measured at feed signal 21 and the effluent concentration measured at effluent signal 23. Thus, BANGTSSON discloses monitoring when excess Mab not captured by the column has reached the breakthrough point, e.g., Qb10 (i.e., a deviation of the at least one detected parameter from an expected level based on the at least one detected parameter crossing a predetermined threshold level).
Regarding Claim 17, modified BANGTSSON makes obvious the method of Claim 1. As noted in the rejections of Claims 1 and 16, BANGTSSON discloses the monitored variable is feed/effluent concentration (i.e., the at least one detected parameter; p0045), e.g., UV detectors are utilized to monitor the absorbance of MAb feed and effluent (i.e., MAb concentration) in the columns (p0048). Further, as shown in FIG. 2 and in p0025-0026, BANGTSSON discloses how Deltasignal and Deltasignalmax are used to calculate the breakthrough point and further relate how Deltasignal is dependent on both the feed concentration measured at feed signal 21 and the effluent concentration measured at effluent signal 23 (i.e., wherein the deviating behavior comprises a deviation of the at least one detected parameter from an expected level). BANGTSSON further discloses that the MAb concentration is further monitored through multiple cycles to assess the loss of MAb over time due to breakthrough (i.e., based on the at least one detected parameter exhibiting a declining trend over multiple cycles; p0057, Table 2).
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RYAN B HUANG whose telephone number is (571)270-0327. The examiner can normally be reached 9 am-5 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, In Suk Bullock can be reached at (571)272-5954. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Ryan B Huang/Primary Examiner, Art Unit 1772
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