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 .
Response to Amendment
The amendment filed 05/05/2026 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 Claims 1, 4-15 and 19-20 remain pending in the application, with previous claims 21-28 being withdrawn.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 02/05/2026.
Response to Arguments
Applicant's arguments filed 05/05/2026 have been fully considered but they are not persuasive.
Applicant argues “Chromacon teaches loading sample directly onto two columns at once. In fact, this is the core innovation of Chromacon: To direct breakthrough from a first capture column to a second capture column in order to minimize product loss. See Chromacon, Figure 1, line 3”
Examiner notes that directing breakthrough from one column to the next is not parallel but is a sequential process, as depicted in Fig. 1 line 3, and is in concert with Instant Claim 1 reciting “columns arranged in a sequence”.
Note: For Remarks discussing column exhaustion, See Section 112 a.
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 recites
“b) measuring at least one parameter indicative of breakthrough of the at least one product during the loading time;
c) for a subsequent purification cycle, switching the active column to another column if the parameter indicates the active column is exhausted”
Specification p 13 last paragraph supports “only switching to the use of another chromatography column should the first become exhausted.”
The specification does not define what is meant to “become exhausted”, nor does the original disclosure indicate correlation between breakthrough and column exhaustion.
For the purpose of compact prosecution, Examiner interprets in claim 1 that “the parameter” is “at least one parameter indicative of breakthrough”, such that “the parameter indicates the active column is exhausted” becomes “the at least one parameter indicative of breakthrough indicates the active column is exhausted”. Therefore, Examiner interprets indication of breakthrough and indication of exhaustion to be interchangeable for claim 1.
Claim 11 recites
“b) measuring at least one parameter indicative of breakthrough of the at least one product during the loading time; and measuring at least one additional parameter during the purification cycle indicative of an amount of the at least one product during elution);
c) for a subsequent purification cycle, switching the active column to another column if the parameter and the additional parameter indicate the active column is exhausted”
Specification p 13 last paragraph supports “only switching to the use of another chromatography column should the first become exhausted.”
The specification does not define what is meant to “become exhausted”, nor does the original disclosure indicate correlation between column exhaustion and the combined indications of breakthrough and eluted product amount.
For the purpose of clarity of record, Examiner interprets in claim 11:
“the parameter” is “at least one parameter indicative of breakthrough”, such that “the parameter indicates the active column is exhausted” becomes “the at least one parameter indicative of breakthrough indicates the active column is exhausted”.
“at least one additional parameter during the purification cycle indicative of an amount of the at least one product during elution” in light of Specification p 9 ln 8-10“at least one additional parameter measured during elution of the at least one captured product …is indicative of purification capacity”
Therefore, Examiner interprets the combination of indication of breakthrough and indication of changes in purification capacity to be interchangeable with the indication of exhaustion for claim 11.
Additionally,
Claims 1 and 11 recite “switching the active column to the next column in the sequence if the parameter… indicate(s) the active column is exhausted, and otherwise continuing with the active column”
Specification p 13 last paragraph supports “only switching to the use of another chromatography column should the first become exhausted.”
Fig. 6b Elements 65 b to 69 supports “capacity less than lower threshold” [Wingdings font/0xE0] “Replace column with new column”
The original specification does not indicate replacing the active column with the next column in the sequence.
For the purpose of compact prosecution, Examiner interprets “next column in the sequence” as “another column”
Claims 4-10, 12-15 and 19-20 depend on 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 recites
“the column capture chromatography system is configured for cyclical repetitive purification performed on a sample feed comprising at least one product configured to be captured in a column during loading …
a) performing a purification cycle comprising: loading the sample feed onto the column during a loading time, washing the column and eluting the at least one product, wherein, during the loading time of the purification cycle, sample feed is loaded onto only a single active column and not directly onto any other column”
It is unclear whether the column is equivalent to only a single active column and not any other column.
Examiner interprets “the column” being loaded with the sample feed during the loading time of the purification cycle is “an active column”.
“b)...one parameter during the purification cycle indicative of breakthrough of the at least one product during the loading time”
“c)…switching the active column to the next column in the sequence if the parameter indicates the active column is exhausted”
It is unclear whether “the active column is exhausted” is equivalent to indication of breakthrough, which is the only parameter defined in claim 1.
“ d) repeating steps a-d”
Step d) is self-referential and thus indefinite.
For the purpose of compact prosecution:
Examiner interprets breakthrough detection as indication of exhaustion of the column
Examiner interprets d) repeating steps a-c.
Claims 4-10 depend from Claim 1and are also rejected.
Claims 11 recites
“b)..one parameter during the purification cycle indicative of breakthrough of the at least one product during loading… one additional parameter during the purification cycle indicative of an amount of the at least one product during elution”
“c)…switching the active column to the next column in the sequence if the parameter and the additional parameter indicate the active column is exhausted”
It is unclear how “exhausted” is defined in claim 11, such as a potential threshold of the indication of a combination of loading breakthrough and some status dependent on product elution information.
Note: Claim 5 and/or Specification p 9 ln 8-10 may suggest one manner by which column exhaustion is determined by an additional parameter, although the solution claimed/disclosed is to increase sample feed, not switch columns: “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.”
“ d) repeating steps a-d”
Step d) is self-referential and thus indefinite.
Examiner interprets d) repeating steps a-c.
Given the above interpretation (See Section 112 a):
Examiner interprets the combined indications of breakthrough and changes in purification capacity to be interchangeable with the indication of exhaustion for claim 11.
However, it is unclear what changes in purification capacity would be necessary to qualify for exhausted column status.
Where there is a great deal of confusion and uncertainty as to the proper interpretation of the limitations of a claim, it would not be proper to reject such a claim on the basis of prior art. As stated in In re Steele, 305 F.2d 859, 134 USPQ 292 (CCPA 1962), a rejection under 35 U.S.C. 103 should not be based on considerable speculation about the meaning of terms employed in a claim or assumptions that must be made as to the scope of the claims. MPEP 2173.06 (II). As written, this claim is so unclear that it is not possible either to effectively search it or to determine whether prior art reads on it.
Claims 12-15 and 19-20 depend from Claim 11, and are also rejected.
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, and 5-10 is/are rejected under 35 U.S.C. 103 as being obvious over WO2014/166799A1, 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), wherein the column capture chromatography system is 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), wherein, during the loading time of the purification cycle (Fig. 1: Feed), sample feed is loaded onto only a single active column and not directly onto any other column (Fig. 1: Feed only directly enters one column at a time in the sequence),
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) for a subsequent purification cycle, switching the active column to another column if the parameter indicates the active column is exhausted, and otherwise continuing with the active column (Fig:1 “One Cycle-repeated after startup” indicates continuing with the active column for the subsequent purification cycle); and
d) repeating steps a-c (“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),.
Chromacon also teaches the method of Chromacon Fig. 1 is applicable to comprising more than two columns arranged in sequence (“The control method is …applicable to twin-, three- and multicolumn”, p 4 ln 30-32; “The monitoring and control method for a chromatographic multicolumn sequential loading process”, p 21 ln 26-27).
Chromacon is considered analogous art because Chromacon addresses the same problem of monitoring and optimizing cyclic capture chromatography purification.
It would have been obvious to one of ordinary skill in the art, before the effectively filed date, to apply the method to more than the two columns specifically depicted in Fig. 1 of Chromacon, given Chromacon teaches applicability of the method to at least two, including more than two columns (“The monitoring and control method for a chromatographic multicolumn sequential loading process with at least two columns”, Chromacon p 21 ln 26-27; “The control method is …applicable to twin-, three- and multicolumn”, Chromacon p 4 ln 30-32)
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… UV detectors.”, p 7 ln 15-16).
Regarding Claim 5, The recited embodiment of Chromacon in the rejection above is silent on additional parameter monitoring.
However, another 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).
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 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).
Regarding Claim 6, modified 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).
Regarding Claim 7, The recited embodiment of Chromacon is silent on trend analysis.
However, another 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).
Regarding Claim 8, modified Chromacon teaches the additional parameter is an elution peak area measured when eluting the at least one captured product in relation to an amount of 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, The recited embodiment of Chromacon is silent on the conditions for column replacement.
However, 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 sample feed used in the cyclical repetitive purification is continuously provided (“these cycles, in case of continuous feed, can be carried out continuously and repeatedly”, p12 ln 6-7) 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
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 20120091063 A1 teaches multi-column chromatography with binding and breakthrough capacity indicators.
US 20100176058 A1 teaches Mult adsorbent series, which may be columns, with breakthrough indication
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARRIAH ELLINGTON whose telephone number is (703)756-1061. The examiner can normally be reached Monday - Friday, 9:00 am - 4:00 pm EST.
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MARRIAH ELLINGTON
Examiner, Art Unit 1773
/BENJAMIN L LEBRON/Supervisory Patent Examiner, Art Unit 1773
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