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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/30/2025 has been entered.
Response to Amendment
The amendment filed 06/30/2025 has been entered. Claims 1, 4-15 and 19-20 remain pending in the application, with previous claims 21-28 being withdrawn. Applicant’s amendments to the Specification and Claims have addressed nearly every objection and 112(b) rejection previously set forth in the Non-Final Office Action mailed 05/06/2025.
Response to Arguments
Applicant's arguments filed 06/30/2025 have been fully considered but they are not persuasive.
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., “having fewer than two columns”) 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).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1, 4-15 and 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 11 recite “d) repeating steps a-d, wherein sample feed is directed to at most one separation column and one guard column during loading time”
Specification p 7 ln 1 supports “using several columns in sequence”
Specification p 7 ¶2 and p 12 ¶5 support “one single column, or alternatively several columns coupled in parallel”
The original specification does not distinguish a separation column or a guard column, nor is it disclosed that sample feed is directed to one separation column and/or directed to one guard column during loading time.
For the purpose of compact prosecution, Examiner interprets “at most one separation column and one guard column during loading time” as “at most two columns during the loading time”.
Claims 4-10, 12-15 and 19-20 depend from Claims 1 and 11, and are also rejected.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-15 and 19-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 11 recite
“loading of the sample feed onto the column during a loading time …
c) determining the loading time of the subsequent cycle according to the following three scenarios:
c-1) reducing the loading time in the subsequent cycle if breakthrough is detected,
c-2) maintaining the same loading time in the subsequent purification cycle if breakthrough is both not detected in the current purification cycle, and has not been detected in a number of cycles that is less than a predetermined number [*Claim 11 recites 25], or
c-3) increasing the loading time in the subsequent if breakthrough is both not detected in the current purification cycle, and has not been detected in a number of purification cycles that is equal to or greater than a predetermined number [*Claim 11 recites 25]; and
d) repeating steps a-d, wherein sample feed is directed to at most one separation column and one guard column during loading time”
Using “or” to separate C-1), C-2), and C-3) makes it unclear whether “C)… according to the following three scenarios” means according to one of the following scenarios.
There is no antecedent basis for the subsequent cycle in step c).
It is unclear whether “subsequent cycle” in C-1) means “subsequent purification cycle”
It is unclear whether “a number of cycles” in C-2) means “a number of purification cycles”
Performing “a number of cycles” more than one purification cycle is not positively recited in the steps prior to step C).
There is no antecedent basis for the current purification cycle in step c-2).
There is no antecedent basis for the subsequent in step c-3).
It is unclear whether “the subsequent” in C-3) means “subsequent purification cycle”
Step d) is self referential and thus indefinite.
It is unclear whether “sample feed” of step d) is the same as “the sample feed of step a)”.
It is unclear whether “loading time” of step d) is the same as “the loading time” of step c).
Step D recites: “sample feed is directed to at most one separation column and one guard column during loading time”.
It is unclear whether either/both of one guard column or one separation column is equivalent to the column of step A, which recites : “loading of the sample feed onto the column during a loading time”.
It is unclear whether “directed to” of Step D is akin to “loading” of Step A, or if “directed to” is considered a separate action.
For the purpose of compact prosecution, Examiner interprets breakthrough detection scenarios in step C and the repetition in step D in the following manner, drawing from Step A and from a rearranged Step B for consistent language and clarity of interpretation of Step C), and in light of Specification p 8 ¶2 for step D):
Step A)
performing a purification cycle..
Step B)
during the purification cycle, measuring at least one parameter indicative of breakthrough of the at least one product during the loading time
Step C)
determining the loading time of a subsequent purification cycle as a function of/in response to the at least one parameter indicative of breakthrough such that:
C-1)
the loading time of the subsequent purification cycle is reduced if breakthrough is detected.
C-2)
the loading time of the subsequent purification cycle is maintained if the purification cycle performed number less than x cycles and breakthrough is not detected in any of the purification cycle performed, wherein x is a predetermined number [Claim 11: wherein x is 25], or
C-3)
the loading time of the subsequent purification cycle is increased if the purification cycle performed number greater than or equal to x cycles and breakthrough is not detected in any of the purification cycle performed, wherein x is a predetermined number [Claim 11: wherein x is 25], and
Step D)
repeating steps a-c until a desired amount of product has been produced, wherein the sample feed is directed to at most two columns during the loading time.
Claims 4-10, 12-15 and 19-20 depend from Claims 1 and 11, and are also rejected.
Claims 8 and 14 recite “the amount of sample feed”
There is no antecedent basis for this limitation.
Claim 10 recites “The method according to claim 1, wherein the cyclical repetitive purification is performed on sample feed”
It is unclear whether sample feed is the same as the sample feed recited in claim 1.
Claim 20 recites “The method according to claim 11, wherein the cyclical repetitive purification is performed on a sample feed”
It is unclear whether a sample feed is the same as the sample feed recited in claim 11.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4-15 and 19-20 is/are rejected under 35 U.S.C. 103 as being obvious over WO2014/166799Al, hereinafter Chromacon.
Regarding Claim 1, Chromacon teaches a method for monitoring operational status in a column capture chromatography system (“methods of chromatographic purification…in particular
using affinity chromatography, and in particular for capture chromatography…and to methods for the control of such processes”, p 1 ln 5-7) configured for cyclical repetitive purification performed on a sample feed comprising at least one product (“a chromatographic purification method for the isolation of a desired product fraction from a mixture using 2 chromatographic columns, it relates to methods for setting up such a process, and it also relates to control and/or monitoring and/or optimization processes in this context. The method comprises, within one cycle to be carried out at least once, Abstract; Fig. 1) configured to be captured in a column during loading (“Affinity materials offer a very high selectivity for the target molecules as they are based on immobilized ligands that bind specifically to the target molecules while letting impurities pass by unaffected”, p 1 ln 15-18), wherein the method comprises:
a) performing a purification cycle comprising: loading the sample feed (Fig. 1: Feed) onto the column (Fig. 1: 1 and/or 2), washing the column (Fig. 1: wash) and eluting the at least one product (Fig. 1: Elu[Wingdings font/0xE0] P),
b) during the purification cycle, measuring at least one parameter indicative of breakthrough of the at least one product (“The monitoring and control method is based on the comparison of at least the peak areas …The method is capable of monitoring column capacity and feed concentration changes in a cycle-to-cycle manner, and to derive control actions from the measured areas.”, p 23 ln 2-7- column capacity is indicative of breakthrough) during the loading time (“the breakthrough areas of the downstream columns in the interconnected loading phase”, p 22 ln 25-26); Alternatively, “a more generalized control, monitoring and optimization process for a chromatographic separation process…wherein downstream of at least one…column, a detector is located capable of detecting the desired product and/or impurities when passing the detector…Measuring the area confined by the breakthrough curve and a horizontal baseline…in a product load position…using the detector(s) at the column(s) outlet(s)… if this area is larger than zero … the load should be reduced”, p 27 ln 4-32);
c) determining the loading time of a subsequent purification cycle as a function of the at least one parameter indicative of breakthrough (“if needed, applying a process control strategy using the same detector to record the relevant signals for the control”, p 4 ln 24-25; “Measuring the area confined by the breakthrough curve and a horizontal baseline… if this area is larger than zero …the load should be reduced”, p 27 ln 4-32)
such that:
c-1) the loading time of the subsequent purification cycle is reduced if breakthrough is detected. (“Possible control actions for adapting the load in the subsequent chromatography cycles or cycle phases include, but are not limited to, changes of the feed flow … The yield is adapted by changing the load… obtain a higher yield, the load L must be lowered”, p 23 ln 16-20), and
d) repeating steps a-c until a desired amount of product has been produced, (“The method is capable of monitoring column capacity and feed concentration changes in a cycle-to-cycle manner, and to derive control actions from the measured areas.”, p 23 ln 5-7), wherein the sample feed is directed to at most two columns during the loading time (“using 2 chromatographic columns, Abstract).
An embodiment of Chromacon provides further motivation for optimization to maximize load and throughput of the process: “Another embodiment of the invention relates to an optimization method to maximize load and throughput of the process. This approach is relevant in process development in order to maximize the productivity of the process and to appropriately size the equipment when scaling up the process” (p 23 ln 21-24).
Chromacon is considered analogous art because Chromacon addresses the same problem of monitoring and optimizing cyclic capture chromatography purification.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to utilize the combined method and motivation of Chromacon to continuously control and optimize purification results (“methods for design, setup, control and optimization of sequential countercurrent loading chromatography processes”, Chromacon p 4 ln 20-21). Doing so would be relevant to “maximize the productivity of the process and to appropriately size the equipment when scaling up the process” (p 23 ln 21-24).
Regarding Claim 4, Chromacon teaches the measured parameter in step b) is a signal from a UV detector mounted after the column (“Detectors are located at the outlet of each column… e.g. be UV detectors.”, p 7 ln 15-16).
Regarding Claim 5, An embodiment of Chromacon teaches the method further comprises monitoring at least one additional parameter measured during elution of the at least one captured product indicative of purification capacity of the column and increasing the amount of sample feed loaded during the loading time in the next purification cycle if the purification capacity is declining without an indication of breakthrough (“the sequential loading process can be optimized by increasing the load successively and by monitoring and evaluating the areas under the signal curves corresponding to the positions of potential product loss. The effect of a load increase control action becomes evident in the following cycle…the optimization method can also be applied if the feed concentration changes or the column capacity is different among the columns and/or the capacity of the columns is decreasing”, p 48 ln 18-25).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to incorporate the flow rate profile of Chromacon to reduce loading time towards the end of loading. By doing so “the sequential loading process can be optimized” (Chromacon p 48 ln 18-20).
Claim(s) 6-9 depend(s) on claim 5 and are also rejected.
Regarding Claim 6, Chromacon teaches prior to step c) evaluating the at least one additional parameter (“the sequential loading process can be optimized by … evaluating the areas under the signal curves corresponding to the positions of potential product loss. The effect of a load increase control action becomes evident in the following cycle.”, p 48 ln 18-22); and cleaning the column (“Following the loading step, the column is washed, eluted and cleaned, even though the
stationary phase has not been fully utilized”, p 2 ln 21-24; Fig. 1: CIP).
Claim(s) 7-9 depend(s) on claim 6 and are also rejected.
Regarding Claim 7, an embodiment of Chromacon teaches the evaluation is a trend analysis of the measured at least one additional parameter over time (“As outlined in example 6,
AICiu and Apeaki experience certain trends in response to feed concentration and column capacity changes”, p 43 ln 11-12; “The above cases show that the effects of column capacity deterioration and feed concentration change in the periodic countercurrent loading process can be controlled by changing only the load. Summarizing the above control actions, if Apeaki decreases beyond the specified limits the load should be increased (see constraint below) and if Apeaki increases beyond the specified limit the load should be reduced”, p 44 ln 9-14).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to incorporate the evaluation techniques of the embodiment of Chromacon to optimize and control the loading process (Chromacon p 44 ln 10-14).
Claim(s) 8 depend(s) on claim 7 and are also rejected.
Regarding Claim 8, Chromacon teaches the additional parameter is an elution peak area measured when eluting the at least one captured product in relation to the sample feed loaded onto the column (“As outlined in example 6, AICiu and Apeaki experience certain trends in response to feed concentration and column capacity changes”, p 43 ln 11-12; “The above cases show that the effects of column capacity deterioration and feed concentration change … if Apeaki decreases beyond the specified limits the load should be increased (see constraint below) and if Apeaki increases beyond the specified limit the load should be reduced”, p 44 ln 9-14).
Regarding Claim 9, An embodiment of Chromacon teaches the step of evaluating the at least one additional parameter further comprises replacing the column with a new column (“Since column cleaning is a major cause for stationary phase degradation the column packing has to be replaced after a certain number of cycles”, p 2 ln 22-24- stationary phase degradation leads to decrease in purification capacity; “In practice both columns and detectors are significantly different, thus in most cases the areas AIC1u and AIC2u are significantly different and the areas Apeak1 and Apeak2 are significantly different from each other. This is confirmed by the ratio AK2ν/AK1ν (table 4, column 5) calculated for every single cycle… In the case of different areas it is very important to determine if the difference is due to a detector with different properties, e.g. amplification, or if it is due to a column with different, potentially deteriorated capacity. Making a judgment based on the different areas alone may lead to the erroneous replacement of a column that actually had an acceptable capacity.” p 37 ln 26- p 38 ln 2) if the purification capacity is below a lower predetermined threshold while break through is detected.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to incorporate the ratio evaluation of Chromacon to clearly distinguish relevant differences in peak area and signals coming from the detectors. Doing so “is very important to determine if the difference is due to a detector with different properties, e.g. amplification, or if it is due to a column with different, potentially deteriorated capacity” (Chromacon p 37 ln 31-33).; an inaccurate assessment in this regard “may lead to the erroneous replacement of a column that actually had an acceptable capacity” (Chromacon p 38 ln 1-2).
Regarding Claim 10, Chromacon teaches the cyclical repetitive purification is performed (“these cycles, in case of continuous feed, can be carried out continuously and repeatedly”, p12 ln 6-7) on the sample feed continuously provided from a cell culture reactor (“Based on this principle, for the purification of therapeutic proteins from cell culture harvest, a number of multicolumn sequential loading processes have been described”, p 3 ln13-14).
Alternatively, Chromacon Example 2 teaches “capture of an IgG monoclonal antibody from clarified cell culture harvest” (p 33 ln 21-22) and “After the initial startup phase the purification process was run continuously” (p. 34 ln 6-7).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to utilize the combined methods and motivating rationale of Chromacon to continuously control and optimize purification results (“methods for design, setup, control and optimization of sequential countercurrent loading chromatography processes”, Chromacon p 4 ln 20-21). Doing so would be relevant to “maximize the productivity of the process and to appropriately size the equipment when scaling up the process” (p 23 ln 21-24).
Regarding Claim 11, Chromacon teaches a method for monitoring operational status in a column capture chromatography system (“methods of chromatographic purification…in particular using affinity chromatography, and in particular for capture chromatography…and to methods for the control of such processes”, p 1 ln 5-7) configured for cyclical repetitive purification performed on a sample feed comprising at least one product (“a chromatographic purification method for the isolation of a desired product fraction from a mixture using 2 chromatographic columns, it relates to methods for setting up such a process, and it also relates to control and/or monitoring and/or optimization processes in this context. The method comprises, within one cycle to be carried out at least once, Abstract; Fig. 1) configured to be captured in a column during loading (“Affinity materials offer a very high selectivity for the target molecules as they are based on immobilized ligands that bind specifically to the target molecules while letting impurities pass by unaffected”, p 1 ln 15-18), wherein the method comprises:
a) performing a purification cycle comprising: loading the sample feed (Fig. 1: Feed) onto the column (Fig. 1: 1 and/or 2), washing the column (Fig. 1: wash) and eluting the at least one product (Fig. 1: Elu[Wingdings font/0xE0] P),
b) during the purification cycle, measuring at least one parameter indicative of breakthrough of the at least one product (“The monitoring and control method is based on the comparison of at least the peak areas …The method is capable of monitoring column capacity and feed concentration changes in a cycle-to-cycle manner, and to derive control actions from the measured areas.”, p 23 ln 2-7- column capacity is indicative of breakthrough) during the loading time (“the breakthrough areas of the downstream columns in the interconnected loading phase”, p 22 ln 25-26); Alternatively, “a more generalized control, monitoring and optimization process for a chromatographic separation process…wherein downstream of at least one…column, a detector is located capable of detecting the desired product and/or impurities when passing the detector…Measuring the area confined by the breakthrough curve and a horizontal baseline…in a product load position…using the detector(s) at the column(s) outlet(s)… if this area is larger than zero … the load should be reduced”, p 27 ln 4-32);
c) determining the loading time of a subsequent purification cycle as a function of the at least one parameter indicative of breakthrough (“if needed, applying a process control strategy using the same detector to record the relevant signals for the control”, p 4 ln 24-25; “Measuring the area confined by the breakthrough curve and a horizontal baseline… if this area is larger than zero …the load should be reduced”, p 27 ln 4-32)
such that:
c-1) the loading time of the subsequent purification cycle is reduced if breakthrough is detected. (“Possible control actions for adapting the load in the subsequent chromatography cycles or cycle phases include, but are not limited to, changes of the feed flow … The yield is adapted by changing the load… obtain a higher yield, the load L must be lowered”, p 23 ln 16-20), and
d) repeating steps a-c until a desired amount of product has been produced, (“The method is capable of monitoring column capacity and feed concentration changes in a cycle-to-cycle manner, and to derive control actions from the measured areas.”, p 23 ln 5-7), wherein the sample feed is directed to at most two columns during the loading time (“using 2 chromatographic columns, Abstract).
Although Chromacon does not specify 25 consecutive cycles, an embodiment of Chromacon provides motivation for optimization to maximize throughput of the process: “Another embodiment of the invention relates to an optimization method to maximize load and throughput of the process. This approach is relevant in process development in order to maximize the productivity of the process and to appropriately size the equipment when scaling up the process” (p 23 ln 21-24).
MPEP 2144.05 (III)(A) states “Where the issue of criticality is involved, the applicant has the burden of establishing his position by a proper showing of the facts upon which he relies”
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to utilize the combined methods and motivating rationale of Chromacon to continuously control and optimize purification results (“methods for design, setup, control and optimization of sequential countercurrent loading chromatography processes”, Chromacon p 4 ln 20-21). Doing so would be relevant to “maximize the productivity of the process and to appropriately size the equipment when scaling up the process” (p 23 ln 21-24).
Regarding Claim 12, An embodiment of Chromacon teaches prior to step c) evaluating the at least one additional parameter (“In practice both columns and detectors are significantly different, thus in most cases … the areas Apeak1 and Apeak2 are significantly different from each other. This is confirmed by the ratio AK2ν/AK1ν (table 4, column 5) calculated for every single cycle… In the case of different areas it is very important to determine if the difference is due to a detector with different properties, e.g. amplification, or if it is due to a column with different, potentially deteriorated capacity. Making a judgment based on the different areas alone may lead to the erroneous replacement of a column that actually had an acceptable capacity.” p 37 ln 26- p 38 ln 2); and cleaning the column (“Following the loading step, the column is washed, eluted and cleaned, even though the stationary phase has not been fully utilized”, p 2 ln 21-24; Fig. 1: CIP).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to incorporate the evaluation of different peak areas of Chromacon to clearly distinguish relevant differences in peak area coming from different columns and/or detectors. Doing so “is very important to determine if the difference is due to a detector with different properties, e.g. amplification, or if it is due to a column with different, potentially deteriorated capacity” (Chromacon p 37 ln 31-33).; an inaccurate assessment in this regard “may lead to the erroneous replacement of a column that actually had an acceptable capacity” (Chromacon p 38 ln 1-2).
Claim(s) 13-14 depend(s) on claim 12 and are also rejected.
Regarding Claim 13, an embodiment of Chromacon teaches the evaluation is a trend analysis of the measured at least one additional parameter over time (“Apeak experience certain trends in response to feed concentration and column capacity changes”, p 43 ln 11-12; “This is confirmed by the ratio AK2ν/AK1ν (table 4, column 5) calculated for every single cycle” p 37 ln 26- 30; “the effects of column capacity deterioration and feed concentration change in the periodic countercurrent loading process can be controlled by changing only the load. Summarizing the above control actions, if Apeaki decreases beyond the specified limits the load should be increased (see constraint below) and if Apeaki increases beyond the specified limit the load should be reduced”, p 44 ln 9-14).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to incorporate the evaluation techniques of the embodiment of Chromacon to optimize and control the loading process (Chromacon p 44 ln 10-14).
Claim(s) 14 depend(s) on claim 13 and is also rejected.
Regarding Claim 14, Chromacon teaches the additional parameter is an elution peak area measured when eluting the at least one captured product in relation to the sample feed loaded onto the column (“Apeak experience certain trends in response to feed concentration and column capacity changes”, p 43 ln 11-12; “The above cases show that the effects of column capacity deterioration and feed concentration change … if Apeaki decreases beyond the specified limits the load should be increased (see constraint below) and if Apeaki increases beyond the specified limit the load should be reduced”, p 44 ln 9-14).
Regarding Claim 15, An embodiment of Chromacon teaches the step of measuring the at least one additional parameter further comprises replacing the column with a new column if the purification capacity is below a lower predetermined threshold while breakthrough is detected (“Since column cleaning is a major cause for stationary phase degradation the column packing has to be replaced after a certain number of cycles”, p 2 ln 22-24- stationary phase degradation leads to decrease in purification capacity; “In practice both columns and detectors are significantly different, thus in most cases the areas AIC1u and AIC2u are significantly different and the areas Apeak1 and Apeak2 are significantly different from each other. This is confirmed by the ratio AK2ν/AK1ν (table 4, column 5) calculated for every single cycle… In the case of different areas it is very important to determine if the difference is due to a detector with different properties, e.g. amplification, or if it is due to a column with different, potentially deteriorated capacity. Making a judgment based on the different areas alone may lead to the erroneous replacement of a column that actually had an acceptable capacity.” p 37 ln 26- p 38 ln 2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to incorporate the ratio value measurement of Chromacon to clearly distinguish relevant differences in peak area and signals coming from the detectors. Doing so “is very important to determine if the difference is due to a detector with different properties, e.g. amplification, or if it is due to a column with different, potentially deteriorated capacity” (Chromacon p 37 ln 31-33); an inaccurate assessment in this regard “may lead to the erroneous replacement of a column that actually had an acceptable capacity” (Chromacon p 38 ln 1-2).
Regarding Claim 19, Chromacon teaches the measured parameter in step b) is a signal from a UV detector mounted after the column (“Detectors are located at the outlet of each column… e.g. be UV detectors.”, p 7 ln 15-16).
Regarding Claim 20, Chromacon teaches the cyclical repetitive purification is performed (“these cycles, in case of continuous feed, can be carried out continuously and repeatedly”, p12 ln 6-7) on the sample feed continuously provided from a cell culture reactor (“Based on this principle, for the purification of therapeutic proteins from cell culture harvest, a number of multicolumn sequential loading processes have been described”, p 3 ln13-14).
Alternatively, Chromacon Example 2 teaches “capture of an IgG monoclonal antibody from clarified cell culture harvest” (p 33 ln 21-22) and “After the initial startup phase the purification process was run continuously” (p. 34 ln 6-7).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effectively filed date, to utilize the combined methods and motivating rationale of Chromacon to continuously control and optimize purification results (“methods for design, setup, control and optimization of sequential countercurrent loading chromatography processes”, Chromacon p 4 ln 20-21). Doing so would be relevant to “maximize the productivity of the process and to appropriately size the equipment when scaling up the process” (p 23 ln 21-24).
Conclusion
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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MARRIAH ELLINGTON
Examiner
Art Unit 1773
/RICHARD C GURTOWSKI/ Primary Examiner, Art Unit 1773 02/03/2026