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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 20 October 2025 has been entered.
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).
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, and 8 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).
Response to Amendments/Arguments
Applicant’s amendments filed 20 October 2025 and 17 September 2025 have been fully considered.
Regarding the rejections of Claims 1 and 5-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, Applicant’s amendments to Claim 1 filed 17 September 2025 are sufficient; these rejections have been withdrawn.
Regarding the rejection of Claim 1 under 35 U.S.C. 103 as obvious over BANGTSSON et al. (US 2012/0091063 A1) in view of HODGE (US 2012/0118828 A1), Applicant’s amendments to Claim 1 incorporating the limitations of Claims 7 and 9 in the amended claims filed 17 September 2025 and the subsequent amended claims filed 20 October 2025 persuasive; the rejection has been withdrawn. However, upon further consideration new grounds of rejection for Claim 1 have been made 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 the rejection of Claim 1 under 35 U.S.C. 103 as obvious over BANGTSSON et al. (US 2012/0091063 A1) in view of HODGE (US 2012/0118828 A1), Applicant’s amendments to Claim 1 in the amended claims filed 20 October 2025 have been fully considered and are not persuasive; the updated rejection of Claim 1 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) is sustained.
In the response filed 17 September 2025, Applicant argues that the limitations of Claim 1 (now amended to recite the subject matter of Claims 7 and 9), are not taught or suggested by BANGTSSON, HODGE, and/or THORSON (pg. 5-6). Applicant argues that the Examiner’s conclusion that “the replacement of a faulty or failing element is an obvious step” ignores the fact that BANGTSSON explicitly teaches that its determination of binding capacities allows a user to determine the role of a column and therefore, “does not require or call for replacement or removal of a column” (pg. 5-6). Applicant argues that THORSON fails to disclose a system that includes more than one column and therefore, THORSON's disclosure of a faulty column replacement with a new column is not applicable to BANGTSSON's teaching of redirecting flow through other non-faulty columns (pg. 6).
The Examiner respectfully disagrees.
BANGTSSON explicitly discloses redirecting flow away from the faulty column so that the faulty column issues can be addressed; such actions include column wash steps to recondition the column resin (p0028, p0031). This effectively removes the column from the chromatography cycle. Further, Applicant’s argument that BANGTSSON explicitly teaches that its determination of binding capacities allows a user to determine the role of a column and therefore, “does not require or call for replacement or removal of a column” (pg. 5-6) is a complete mischaracterization of BANGTSSON and unnecessarily extrapolates BANGTSSON’s disclosure to a draw a conclusion that is not explicitly taught or even suggested by BANGTSSON. Nowhere does BANGTSSON disclose or exclude column replacement. One of ordinary skill in the art, in finding a faulty or inoperable equipment, would find it obvious to disconnect that faulty or inoperable equipment and either refurbish or replace that equipment. In this case, when presented with an inoperable or low efficiency column, an operator would find it obvious to take the column off-line and recondition the affected column or replace with an operable, efficient column. The most obvious immediate advantage of reconditioning the affected column would be the significant cost savings from procuring a new expensive column; however, when an operator is unable to recondition a column—which inevitably occurs for every column over prolonged use—the most obvious next step is to replace the affected column.
Regarding Applicant’s arguments with respect to THORSON, THORSON teaches that if a user observed that a column is not operating as expected, one solution is to simply replace the column. Such a teaching is certainly compatible with BANGTSSON's disclosure where a defective column is being addressed. THORSON doesn't teach replacing multiple columns. THORSON simply teaches the replacement of a defective column. BANGTSSON teaches addressing defective individual columns as well. Applicant's argument that THORSON fails to teach multiple columns is also ignoring the fact that Applicant has claimed column replacement for a single column (i.e., "the particular column"). 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). A system with multiple columns is taught by BANGTSSON; remedying a defective single column is noted by BANGTSSON, and a solution by replacement is provided by THORSON.
In the response filed 20 October 2025, Applicant cites the added limitation to as-amended Claim 1, i.e., “wherein the detected at least one parameter is a target product concentration in the sample introduced in each column of the continuous chromatography system”, and the teaching of BANGTSSON in paragraph 0027 that “[0027] One advantage with this approach of determining the breakthrough point and the saturation point is that this could be done automatically in real time and it is independent of the feed concentration since the feed signal is automatically compensated for” (emphasis Applicant’s own). Thus, Applicant argues that “the detecting of a “feed concentration” or a “target product concentration” in a feed or “sample”, is not taught or suggested by Bangtsson” (pg. 6, top) and as a result, none of the cited prior art teach or suggest Applicant’s amended claims.
The Examiner disagrees.
Applicant has ignored the phrase following their emphasized line: “since the feed signal is automatically compensated for”. While the Applicant-highlighted/underlined phrase certainly seems to indicate BANGTSSON ignores feed concentration, this is not the case. In the previous paragraphs p0025-0026 and as shown in FIG. 2, BANGTSSON explicitly explains the calculations by which the breakthrough point and saturation point are determined, highlighting the fact that the feed input signal 21 is used to calculate “Deltasignal”:
[AltContent: textbox (Deltasignalmax)][AltContent: textbox (Effluent signal)][AltContent: textbox (Breakthrough point)][AltContent: textbox (Exemplary Deltasignal)][AltContent: textbox (Feed signal)][AltContent: textbox (Time delay)]
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“The feed signal 21 measures the feature (in one embodiment UV absorbance) for both non binding and binding components of the feed” – this indicates that the concentrations of the feed are measured (i.e., by UV absorbance), which already indicates that BANGTSSON’s disclosed method is dependent on feed concentration (p0025). Further, in p0026, BANGTSSON discloses that “a Deltasignalmax 27 is calculated which is defined to be the feed signal 21 minus the signal level for the effluent signal 23 when it is in the plateau 25. This Deltasignalmax 27 can then be used for defining suitable levels for the breakthrough point and the saturation point”. BANGTSSON explicitly discloses that Deltasignalmax is used to calculate breakthrough and that Deltasignalmax is dependent on both feed signal 21 and effluent signal 23, i.e., BANGTSSON’s disclosed method is not independent of feed concentration as argued by Applicant and is in fact wholly dependent on the feed concentration. Applicant’s interpretation of p0027 has conveniently cherry-picked phrases and ignored the paragraph as a whole (especially the phrase “since the feed signal is automatically compensated for”) and ignored BANGTSSON’s actual disclosure as a whole (especially FIG. 2 and p0025-0026).
Conclusion
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.
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/Ryan B Huang/Primary Examiner, Art Unit 1777