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
The present application was filed 04/13/2022. Acknowledgement is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/EP2020/082687, filed 11/19/2020, which in turn claims foreign priority to GB1916961.4, filed 11/21/2019 with the European Patent Office.
Information Disclosure Statement
The information disclosure statements (IDS) filed 04/13/2022, 01/30/2024, and 08/28/2024 have been considered, initialed and are attached hereto.
Status of the Claims
Claims 1-14 are currently pending and examined below. Claims 1 and 3-14 are amended.
Claim Objections
Claims 2 and 7 are objected to because of the following informalities:
Claim 7 recites “a control unit configured to control the each cycle”. There appears to be a typographical error. It is suggested to replace “the each cycle” with ---each cycle---.
Claim 2 recites “wherein elution captured”. There appears to be a typographical error. It is suggested to replace “wherein elution” with ---wherein the elution---.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
A chromatography system being configured for cyclic purification performed on a sample […] each cycle of the purification process including:
Loading feed onto the separation unit,
Washing the separation unit, and
Eluting the target product from the separation unit by providing a flow of an elution fluid over the separation unit and selectively directing a fraction of the outlet flow from the separation unit containing the eluted target product to a subsequent production step (claims 1 and 7)
A control unit configured to control the each cycle of the purification process including:
Loading feed onto the separation unit,
Washing the separation unit, and
Eluting the target product from the separation unit by providing a flow of an elution fluid over the separation unit and selectively directing a fraction of the outlet flow from the separation unit containing the eluted target product to a subsequent production step, wherein the control unit is further configured to:
Determine trigger points for target product collection […] and also to
Set a first time period based on the trigger points […]
Evaluate timing of the captured elution to identify next time period;
Apply the timing to capture a fraction of the elution during the elution phase in the following cycle;
Collect the captured fraction of the elution in the following cycle; and
Repeat step b)-d) (claim 7)
Register the presence of the target product in the outlet flow from each column and determine start time and a stop time (claim 11)
Register the presence of the target product over time as an elution curve and the initiation of the elution phase is determined from the elution curve (claim 12)
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
Regarding the chromatography system being configured for cyclic purification performed on a sample” in claims 1 and 7-12, the originally filed specification refers to said chromatography system as illustrated in figure 3(b) (described at pages 7-8 of the specification). The specification describes what the system does and various components that are structural features of the system, however, fails to clearly identify structure specific for the recited functions (i.e., fails to identify corresponding structure, material, or acts responsible for performing the recited functions). For example, the specification fails to specify a particular structure as performing the functions of loading, washing and eluting as claimed.
The system is described in the specification starting on page 7, line 27 as a chromatography system comprising a source of elution buffer (Fig. 3b, 60), and a source of cleaning solution and buffer/wash buffer ((Fig. 3b, 70; page 7, line 28-page 8, line 1). The specification recites that the harvest is fed into the separation step which may include one or more steps of a downstream purification process (page 6, lines 1-3) and that the system comprises an inlet valve as (Fig. 3b, 80), an outlet valve (Fig. 3b,120), and a pump (Fig. 3b, 90) . However, even though the specification describes various elements of the system it does not describe the structure(s) for performing the claimed function but rather recites what the system does, such as that the harvest is fed into the separation step, and is silent of the structure that does the feeding into.
The specification further describes a chromatography column (Fig. 3b, 100), which is a microporous resin column, nanofiber device, membrane, monolith, etc. (page 8, lines 16-17). The specification recites on page 7 that each purification cycle comprises loading an amount of sample feed onto the column, washing the column and eluting the at least one captured product (page 7, lines 16-18). As explained previously above the specification fails to describe the structure that achieves the loading, the washing, and the eluting, but rather describes what the system does instead.
Regarding the described structure for performing the claimed functions, see at page 15 the originally filed specification recites the chromatography system comprising at least one affinity chromatography separation unit and a control unit, each of these further described at page 15 functionally (affinity chromatography separation unit configured for cyclic purification and a control unit to control each cycle of the purification process, control unit configured to perform the method). Each of “affinity chromatography separation unit” and “control unit” are non-structural terms.
Although the specification does indicate “methods described…may be implemented in a computer program for controlling a bioprocess purification system”, neither of the “chromatography system” or the “control unit” are identified as a computer/processor or programmed computer/processor.
The specification does not provide any structure specific to the system such to explain what/how the system achieves the functions of the loading, washing, and eluting steps. As such there is insufficient structure for performing the recited steps.
Regarding the “control unit”, see as discussed previously above, the specification supports that the control unit is a structure included as part of the “chromatography system (the system includes each of an affinity chromatography separation unit and a control unit), and while the specification does indicate methods described above may be implemented in a computer program for controlling a bioprocess purification system, the specification fails to identify corresponding structure, material, or acts responsible for performing the recited functions.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-14 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.
Claim 1 recites the limitations “the outlet flow” in line 8, "the elution phase" in line 12, and “the elution” in line 15. There is no prior recitation of an outlet flow, an elution phase, or an elution and as such, there is insufficient antecedent basis for this limitation in the claim. Claim 1 further recites an “affinity chromatography separation unit” (line 2) and a “separation unit” (line 5). It is unclear whether the affinity chromatography separation unit is the same as the separation unit or if the separation unit comprises the affinity chromatography separation unit. Additionally, there is no prior recitation of the phrase “separation unit” and therefore there is insufficient antecedent basis for this limitation in the claim.
Claim 7, similarly recites the limitations “the outlet flow” in line 8, "the elution phase" in line 12, and “the elution” in line 14. There is no prior recitation of an outlet flow, an elution phase, or an elution and as such, there is insufficient antecedent basis for this limitation in the claim.
Claims 1, 7, and 12 are further indefinite because they recite “a chromatography system […] being configured for cyclic purification […] including: loading feed onto the separation unit, washing the separation unit, and eluting the target product […] determining trigger points” (claim 1) and “control unit” (claim 7). Claim 12 further recites “wherein the control unit is further configured to register the presence of the target product”. There is insufficient structure for performing the recited steps. See as discussed previously above, the claims appear to limit the structure by what it does rather than what it is, for the reasons explained previously above under 35 U.S.C. 112(f), there is insufficient structure for performing the claimed functions and therefor the claims are indefinite.
Regarding the interpretation under 35 U.S.C. 112(f):
Claim 1 further recites a “chromatography system being configured for cyclic purification”, but the specification does not provide any structure specific to the system such to explain how, or by what structure, it is configured for cyclic purification (fails to recite structure specific to the recited functions of the cyclic purification” and therefore the claim is indefinite.
Claim 7 recites a chromatography system configured “for cyclic purification process […] including: loading feed […], washing the separation unit […], eluting the target […], wherein the control unit is further configured to: determine trigger points”. It is unclear which the corresponding structures are that actually perform the functions recited in the claim and therefore the claim is indefinite.
Regarding claims 7 and 9, the claims recite “control the each cycle of the purification process including […]” and the specification further teaches that the outlet valve is controlled by a combined algorithm (specification, page 15, lines 23-26), but the specification does not provide any structure to explain how, or by what structure, the “each cycle of the purification process” is controlled or what structure controls the algorithm to control the outlet valve and therefore the claim is indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 13 and 14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to” we first look to whether the claim recites:
Any judicial exceptions, including certain groupings of abstract ideas (i.e. mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
Additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “’inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent eligible application of the judicial exception. Alice, 573 U.S.at 2221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
Adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d); or
Simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims do not fall within at least one of the four categories of patent eligible subject matter because the broadest reasonable interpretation of a “computer program for controlling fraction collection […] comprising instructions which, when executed on at least one processor, cause the at least one processor to carry out the method” of claim 13 and “a computer program for controlling fraction collection” of claim 14 encompasses software per se. The specification states that “the methods described above may be implemented in a computer program for controlling a bioprocess purification system. The computer program comprises instructions which, when executed on at least one processor, cause the at least one processor to carry out the method according to the different variations described […] the program for controlling the bioprocess purification system may be stored on and carried by a computer readable storage medium” (page 15, lines 17-22) which clearly includes propagating electromagnetic waves. The further recitation of “instructions” in claim 13 only serves to limit the content carried by the electromagnetic waves. As understood in light of the specification, the broadest reasonable interpretation of claims 13 and 14 encompasses signals which are not within one of the four statutory categories of invention. See MPEP 2106.03(I).
Step 2A, Prong 2
The above recited steps (namely controlling fraction collection) are insufficient to integrate into a practical application. Specifically, a computer program for controlling fraction collection is themselves the judicial exception and not a practical application thereof. Dependent claim 14 comprises “a computer-readable storage medium carrying a computer program for controlling fraction collection” and does not comprise any active steps. Neither of these claims further applies, relies on or uses the judicial exceptions in a manner to integrate into a practical application thereof.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN “INVENTIVE CONCEPT”
Further, the additional elements of the claims (the active method steps/limitations recited in addition to the judicial exceptions themselves) do not add significantly more to the judicial exception(s); the additional recited claim elements are recited at a high level of generality, and do not constitute any additional active steps.
For these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
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.
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.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Rose MH, US 11,498,941 B2, PCT filed 07/16/2018, in view of Gilby et al., US 6,997,031 B2, 02/14/2006.
Regarding claim 1, Rose teaches a process for the purification of a product biomolecule from a feedstock comprising the steps of loading feed from the feedstock to a chromatography matrix (loading feed onto the at least one chromatography separation unit; Rose, column 4, lines 41-45), washing the matrix after loading is complete (Rose, column 6, lines 65-66), eluting the product biomolecule from the chromatography matrix in an eluate by applying an elution solution to the chromatography matrix (eluting target providing a flow of an elution fluid over the separation unit) and collecting the first fraction separately from the second fraction (selectively directing a fraction to a subsequent production step; Rose, column 4, lines 47-58). Rose further teaches that preferably the chromatography matrix is selected from a list comprising an affinity chromatography matrix (Rose, column 26, lines 52-56). Rose further teaches that at least one fraction of the eluate following the one or more first fraction(s) are re-loaded to the same chromatography matrix and this can be repeated several times until the product is exhausted (repeating steps/cyclic purification; Rose, column 5, lines 58-60 and Figure 2). Rose further teaches that step b) of Rose (eluting the product biomolecule), step c) of Rose (holding the second fraction in one or more container(s)), and step d) of Rose (loading the second fraction from the container to the chromatography matrix) are repeated (repeating steps during the purification process to capture a fraction in the elution phase of the following cycle; Rose, column 9, lines 33-54). Rose further teaches that fractions of the eluate pass through a detector which analyses discrete volumes of the eluate (Rose, column5, lines 20-22).
Rose further teaches that any suitable means can be used to determine the identity of the fractions of the eluate to be (re)-loaded to the chromatography matrix of the processes of the invention. For example, the fractions to be (re)-loaded can be identified by determining the volume of eluate obtained or the run time of the method, based on pre-learned knowledge of the characteristics of the first and second factions. Alternatively, the fractions to be (re)-loaded can be identified based on measurements taken during the course of the method (Rose, column 11, lines 54-63). As such, Rose teaches a method for controlling fraction collection in a system including at least one affinity chromatography unit, the system being configured for cyclic purification.
Rose does not specifically teach a method comprising determining trigger points for target collection in relation to presence of target product in the outlet flow during the initiation of the elution phase and wherein the method for controlling fraction collection of the target product further comprises setting a first time period based on the trigger points within which a fraction of the elution in the first cycle is captured, evaluating timing for the captured elution to identify the next time period, and applying the timing to capture a fraction of the elution during the elution phase in the following cycle.
Gilby teaches a method and apparatus for controlling fraction collection in an eluent stream flowing from a liquid chromatography column (Gilby, ‘Abstract’, lines 1-2). Gilby further teaches that a triggering detector recognizes the presence of a target substance above a predetermined threshold level according to characteristics of chromatographic peaks in the eluent stream (trigger points within which a fraction of the elution is captured; Gilby, column 3, lines 56-59). Gilby further teaches a setup process by which the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely (setting a time period based on trigger points), the setup process comprising detecting the signal exceeding a predetermined threshold on the waste detector chromatogram indicating the point on the peak where the fraction collector stopped collecting and comparing the trace to a reference chromatogram obtained by the waste stream detector after allowing a peak to pass uncollected by the fraction collector (Gilby, column 7, lines 45-57). Gilby further teaches that a waste stream carries the remainder of the eluent stream away from the fraction collector and that characteristics of chromatographic peaks from the target sample components are detected in the waste stream and a calibrated delay time for actuating the fraction collector is computed according to the characteristics of peaks detected in the waste stream (evaluating timing of the captured elution to identify next time period). The fraction collector timing is adjusted to effect optimum fraction collection (applying timing Gilby, column 4, lines 15-23). Gilby further teaches making a second injection with the fraction collector delay time set based on the tsetup, i.e. the timing detected during the setup process (applying timing to capture fraction the following cycle), and further teaches that setting the fraction collector delay time to tsetup causes the fraction collector to start collecting before the peak reaches is, diverting mobile phase into the collection vial plus the leading portion of the peak (Gilby, column 8, lines 5-12). Gilby further teaches that the method optimizes the timing of a fraction collector to minimize the loss of target sample components and allows for continuous recalibration of the fraction collector timing (Gilby, column 5, lines 48-54).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification method comprising an affinity chromatography column of Rose, wherein the fractions to be (re)-loaded can be identified based on measurements taken during the course of the method, with the method of controlling fraction collection, as taught by Gilby, by continuously recalibrating fraction collector timing, based on trigger points determined in the first cycle because of the teaching of Gilby that the method optimizes the timing of a fraction collector and minimizes the loss of target sample components.
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of controlling fraction collection as taught by Gilby to the purification method of Rose, because both Rose and Gilby teach collecting fractions and analyzing them in a chromatography system and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection would not interfere with the cyclical purification method of Rose.
Regarding claim 2¸ Rose and the prior art above teaches a method of controlling fraction collection of a target product in a chromatography system substantially as claimed.
Rose teaches that at least one fraction of the eluate following the one or more first fraction(s) are re-loaded to the same chromatography matrix and this can be repeated several times and product is exhausted (Rose, column 5, lines 58-60 and Figure 2).
Rose does not teach that the elution captured in the first cycle is used for calibration purposes for the following cycle.
Gilby teaches a setup process by which the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely (use first cycle for calibration purposes), the setup process comprising detecting the signal exceeding a predetermined threshold on the waste detector chromatogram indicating the point on the peak where the fraction collector stopped collecting and comparing the trace to a reference chromatogram obtained by the waste stream detector after allowing a peak to pass uncollected by the fraction collector (Gilby, column 7, lines 45-57). Gilby further teaches making a second injection with the fraction collector delay time set based on the tsetup, i.e. the timing detected during the setup process (determine timing of elution for the following cycle), and further teaches that setting the fraction collector delay time to tsetup causes the fraction collector to start collecting before the peak reaches is, diverting mobile phase into the collection vial plus the leading portion of the peak (Gilby, column 8, lines 5-12). The fraction collector timing is adjusted to effect optimum fraction collection (applying timing Gilby, column 4, lines 15-23). Gilby further teaches that the method optimizes the timing of a fraction collector to minimize the loss of target sample components and allows for continuous recalibration of the fraction collector timing (Gilby, column 5, lines 48-54). Gilby further teaches that the method also eliminates fraction collector timing errors introduced by reliance on a calibrant that may be different from flow characteristics of a component at a later time in the eluent stream (Gilby, column 6, lines 17-21).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification method of Rose with the method of Gilby of using one cycle to calibrate timing of the next cycle because of the teaching of Gilby that this optimizes timing of a fraction collector and minimizes loss of target sample components. The artisan having ordinary skill in the art would be motivated to do so because of the teaching of Gilby that the method eliminates timing errors by reliance on a calibrant that may be different from flow characteristics of a component at a later time in the eluent stream.
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of calibrating timing of fraction collection as taught by Gilby to the purification method of Rose, because both Rose and Gilby teach collecting fractions and analyzing them in a chromatography system and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection as taught by Gilby would not interfere with the cyclical purification method of Rose.
Regarding claim 3, Rose teaches that the one or more of the first fractions are collected and removed from the process as product (Rose, column 5, lines 51-56 and Figures 2-7).
Regarding claim 4, Rose teaches loading feed to a chromatography matrix (step a), eluting the product, holding the second fraction in one or more containers and loading the second fraction to the chromatography matrix (step e) and further teaches that the chromatography matrix in steps a and e is the same chromatography matrix. As such Rose teaches a chromatography system using a single chromatography column (Rose, column 9, lines 21-48 and Figure 1).
Regarding claim 5, Rose and the prior art above teaches a method of controlling fraction collection of a target product in a chromatography system substantially as claimed.
Rose does not teach registering the target product from outlet flow over time and determining start time and a stop time for target product collection.
Gilby teaches that a triggering detector recognizes the presence of a target substance above a predetermined threshold level according to characteristics of chromatographic peaks in the eluent stream (Gilby, column 3, lines 56-59). As discussed previously in detail above, Gilby teaches a setup process by which the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely (start time and stop time; Gilby, column 7, lines 45-57). Gilby further teaches that the fraction collector timing is verified and if necessary adjusted according to characteristics of peaks detected in the in the waste stream, periodically or each time the fraction collector is actuated (target product is registered over time; Gilby, column 5, lines 32-36). Gilby further teaches that the method optimizes the timing of a fraction collector to minimize the loss of target sample components and allows for continuous recalibration of the fraction collector timing (Gilby, column 5, lines 48-54).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification method of Rose with the method of Gilby of timing the collection before a peak reaches it and stop collection before the peak has passed completely verifying the fraction detector timing periodically because of the teaching of Gilby that this allows the timing to begin collection before a peak reaches the fraction collector and to stop collecting before the peak has passed completely. One of ordinary skill in the art would have been motivated to do so because the method allows for continuous recalibration of the fraction collector timing and therefore minimizes loss of target sample components.
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of controlling fraction collection as taught by Gilby to the purification method of Rose, because both Rose and Gilby teach collecting fractions in a chromatography system and analyzing them and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection as taught by Gilby would not interfere with the cyclical purification method of Rose.
Regarding claim 6, Rose and the prior art above teaches a method of controlling fraction collection of a target product in a chromatography system substantially as claimed.
Rose teaches recording chromatograms during multiple cycles of fraction collection (register target product over time as elution curve; Rose, column 6, lines 54-56 and Figures 8-14).
Rose does not teach that the initiation of the elution phase is determined from the elution curve.
Gilby teaches that the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely and that the optimum fraction collector delay time can be found by comparing the trace to a reference chromatogram obtained by the waste stream detector after allowing a peak to pass uncollected by the fraction collector (Gilby, column 7, lines 45-56). Gilby further teaches that this is a way the signature of the waste stream detector can be used to establish the fraction collector delay time (Gilby, column 7, lines 57-59).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification method of Rose with the method of Gilby of comparing the chromatogram obtained from the waste stream detector to a reference chromatogram because this would allow the user to establish the fraction collector delay time, and one of ordinary skill in the art would be motivated to do so because this would be advantageous in order to begin collection before a peak reaches it and to stop collecting before the peak has passed completely (i.e., won’t miss the target, one would appreciate this improves accuracy because the collection wouldn’t’ be missed due to poor timing).
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of establishing the fraction collector delay time as taught by Gilby to the purification method of Rose, because Gilby teaches success establishing a fraction collector delay time for sample collection and both Rose and Gilby teach collecting fractions and analyzing them and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection as taught by Gilby would not interfere with the cyclical purification method of Rose.
Claims 7-14 are rejected under 35 U.S.C. 103 as being unpatentable over Rose MH, US 11,498,941 B2, PCT filed 07/16/2018, in view of Gilby et al., US 6,997,031 B2, 02/14/2006 and further in view of Rathore et al. US20220146416A1 (filed 03/22/2019).
Regarding claims 7 and 11, Rose teaches a setup for use in the process of affinity chromatography (a chromatography system), comprising tanks for various liquid components which are pumped via a valve through a chromatographic matrix and after emerging from the chromatography matrix, pass through a detector (Rose, column 5, lines 23). Rose further teaches a container for an elution buffer and additional buffers as well as load and a valve following the detector as well as a collection and a waste container (see Rose, Figure 1). Rose further teaches that preferable the chromatography matrix is selected from a list comprising an affinity chromatography matrix (Rose, column 26, lines 52-56).
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Rose further teaches the system applied to a process for the purification of a product biomolecule from a feedstock comprising the steps of loading feed from the feedstock to a chromatography matrix (loading feed onto the at least one chromatography separation unit; Rose, column 4, lines 41-45), washing the matrix after loading is complete (Rose, column 6, lines 65-66), eluting the product biomolecule from the chromatography matrix in an eluate by applying an elution solution to the chromatography matrix (eluting target providing a flow of an elution fluid over the separation unit) and collecting the first fraction separately from the second fraction (selectively directing a fraction to a subsequent production step; Rose, column 4, lines 47-58). Rose further teaches that at least one fraction of the eluate following the one or more first fraction(s) are re-loaded to the same chromatography matrix and this can be repeated several times and product is exhausted (repeating steps/cyclic purification; Rose, column 5, lines 58-60 and Figure 2). Rose further teaches that step b) of Rose (eluting the product biomolecule), step c) of Rose (holding the second fraction in one or more container(s)), and step d) of Rose (loading the second fraction from the container to the chromatography matrix) are repeated (repeating steps during the purification process to capture a fraction in the elution phase of the following cycle; Rose, column 9, lines 33-54). Rose further teaches that fractions of the eluate pass through a detector which analyses discrete volumes of the eluate (Rose, column5, lines 20-22). As such, Rose teaches a method for controlling fraction collection in a system including at least one affinity chromatography unit, the system being configured for cyclic purification.
Rose does not teach a control unit configured to control each cycle of the purification process and further does not teach the cycle comprising a method for controlling fraction collection wherein the method comprises determining trigger points for target collection in relation to presence of target product in the outlet flow during the initiation of the elution phase and wherein the method for controlling fraction collection of the target product further comprises setting a first time period based on the trigger points within which a fraction of the elution in the first cycle is captured, evaluating timing for the captured elution to identify the next time period, and applying the timing to capture a fraction of the elution during the elution phase in the following cycle.
Gilby teaches a method and apparatus for controlling fraction collection in an eluent stream flowing from a liquid chromatography column (Gilby, ‘Abstract’, lines 1-2). Gilby further teaches that a triggering detector recognizes the presence of a target substance above a predetermined threshold level according to characteristics of chromatographic peaks in the eluent stream (trigger points within which a fraction of the elution is captured; Gilby, column 3, lines 56-59). Gilby further teaches a setup process by which the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely (setting a time period based on trigger points), the setup process comprising detecting the signal exceeding a predetermined threshold on the waste detector chromatogram indicating the point on the peak where the fraction collector stopped collecting and comparing the trace to a reference chromatogram obtained by the waste stream detector after allowing a peak to pass uncollected by the fraction collector (Gilby, column 7, lines 45-57). Gilby further teaches that a waste stream carries the remainder of the eluent stream away from the fraction collector and that characteristics of chromatographic peaks from the target sample components are detected in the waste stream and a calibrated delay time for actuating the fraction collector is computed according to the characteristics of peaks detected in the waste stream (evaluating timing of the captured elution to identify next time period). The fraction collector timing is adjusted to effect optimum fraction collection (applying timing Gilby, column 4, lines 15-23). Gilby further teaches making a second injection with the fraction collector delay time set based on the tsetup, i.e. the timing detected during the setup process (applying timing to capture fraction the following cycle), and further teaches that setting the fraction collector delay time to tsetup causes the fraction collector to start collecting before the peak reaches is, diverting mobile phase into the collection vial plus the leading portion of the peak (Gilby, column 8, lines 5-12). Gilby further teaches that the method optimizes the timing of a fraction collector to minimize the loss of target sample components and allows for continuous recalibration of the fraction collector timing (Gilby, column 5, lines 48-54).
Rathore teaches a system for monitoring and control of concentration of a bio-molecule in a chromatography apparatus, the chromatography apparatus comprising a reservoir for storing a feed material, a continuous multi-column chromatography system, a plurality of fluid transmission channels, where each channel is connected to a control-system-operable pump at an inlet for regulating and controlling a flow of fluid within the channel, where the channel has control-system-operable pump at an inlet for feeding the feed material within the channel and each column having an inlet and an outlet, wherein the inlet is connected through one of a plurality of valves of the channels of the system to one of the control-system-operable pump and the outlet is connected through one of a plurality of valves to a plurality of outlet ports characterized by a first control system connected to the system for operating the plurality of the pumps and the valves of the apparatus. The system further comprises near infrared flow cells (sensors) for analyzing spectra of the feed material to measure concentration of bio molecule in the feed material and at the outlet of one or more of the columns (register presence of the target product in the outlet flow over time; claim 11) to determine breakthrough of the feed material and communicating to the chromatography system and the secondary control system the system further comprises a secondary control system in communication with the flow cells and the first control system for transferring spectroscopy data to the first control system for electronically or pneumatically actuating supply of the feed material from the reservoir to one of the column and the first control system continuously processing the data from the flow cells or the secondary control system to change valve configuration, pump actuation, flow rate of feed material or a fluid to carry out steps selected from the group consisting of loading, second-pass loading, wash, elution, cleaning , regeneration, and equilibration (control unit configured to control loading, washing, eluting) to increase resin utilization reduce idle time, or take control actions to handle system errors (Rathore, page 2, see entire paragraph [0012]). Rathore further teaches that the software layer of the first control system is able to control the flow rate of all pumps and the positions of all valves in the chromatography system in real time and that the pumps are used to supply the harvest and buffers and that outlet ports lead to the elution vessel, second-pass column and waste vessel. Rathore further teaches that that the timings and valve combinations for each step is programmed into the first control system with the option of dynamic time adjustment in the case of extreme deviations (determine start time and stop time as trigger points; claim 11). Rathore further teaches that every 3 seconds, upon receiving concentration data from the flow cells via second control system, the control algorithm decides whether or not to change the flowrate of the loading pump (Rathore, page 5, paragraph [0044], lines 6-22). Put another way the control unit of Rathore is capable of evaluating and adjusting timing of the valve combinations depending on the concentration data in the outlet flow. As such the control unit in the system of Rathore is capable of setting a time period based on the trigger points, evaluate the timing of the captured elution, apply the timing to capture a fraction of the elution, and collecting the captured fraction. Rathore further teaches that the system is able to handle extreme deviations when the concentration drops below the normal operating range by dynamically adjusting the times of the various steps of the method (Rathore, page 3, paragraph [0031], lines 9-12). Rathore further teaches the system is unique in its ability to simultaneously assure both targeted resin utilization and consistent elution times and that resin costs are minimized and predictability is granted to elution time and quality, which is essential for the control of processes further downstream. Rathore further teaches that the system is easily adaptable to any continuous chromatography system with multiple columns and valves (Rathore, pages 3-4, see entire paragraph [0032]).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of Rose capable of a cyclic purification method comprising an affinity chromatography column with the method of controlling fraction collection by continuously recalibrating fraction collector timing as taught by Gilby, based on trigger points determined in the first cycle because of the teaching of Gilby that the method optimizes the timing of a fraction collector and minimizes the loss of target sample components.
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of controlling fraction collection as taught by Gilby in the system of Rose, because both Rose and Gilby teach collecting fractions and analyzing them and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection would not interfere with the cyclical purification system of Rose.
It would have further been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification system as taught by Rose in view of Gilby with the control unit of Rathore, capable of controlling the flow rate of all pumps and the positions of all valves in the chromatography system in real time based on data from flow cells, because of the teaching of Rathore that the system is able to handle extreme deviations when the concentration drops below the normal operating range by dynamically adjusting the times of the various steps of the method. One having ordinary skill in the art would have been motivated to do so because of the teaching of Rathore that this simultaneously assures both targeted resin utilization and consistent elution times and that resin costs are minimized and predictability is granted to elution time and quality, which is essential for the control of processes further downstream.
One having ordinary skill in the art would further have a reasonable expectation of success in having modified the system of Rose and Gilby with the control unit of Rathore, because Rose and Gilby teach column chromatography for the purification of samples and Rathore similarly teaches column chromatography and further teaches that the system is easily adaptable to any continuous chromatography system.
Regarding claim 8, Rose and the prior art above teaches a chromatography system substantially as claimed.
Rose teaches that at least one fraction of the eluate following the one or more first fraction(s) are re-loaded to the same chromatography matrix and this can be repeated several times and product is exhausted (Rose, column 5, lines 58-60 and Figure 2).
Rose does not teach that the elution captured in the first cycle is used for calibration purposes for the following cycle nor does Rose teach a control unit configured to determine the timing of the elution.
Gilby teaches a setup process by which the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely (use first cycle for calibration purposes), the setup process comprising detecting the signal exceeding a predetermined threshold on the waste detector chromatogram indicating the point on the peak where the fraction collector stopped collecting and comparing the trace to a reference chromatogram obtained by the waste stream detector after allowing a peak to pass uncollected by the fraction collector (Gilby, column 7, lines 45-57). Gilby further teaches making a second injection with the fraction collector delay time set based on the tsetup, i.e. the timing detected during the setup process (determine timing of elution for the following cycle), and further teaches that setting the fraction collector delay time to tsetup causes the fraction collector to start collecting before the peak reaches is, diverting mobile phase into the collection vial plus the leading portion of the peak (Gilby, column 8, lines 5-12). The fraction collector timing is adjusted to effect optimum fraction collection (applying timing Gilby, column 4, lines 15-23). Gilby further teaches that the method optimizes the timing of a fraction collector to minimize the loss of target sample components and allows for continuous recalibration of the fraction collector timing (Gilby, column 5, lines 48-54). Gilby further teaches that the method also eliminates fraction collector timing errors introduced by reliance on a calibrant that may be different from flow characteristics of a component at a later time in the eluent stream (Gilby, column 6, lines 17-21).
Rathore teaches a system comprising flow cells for analyzing spectra of the feed material to measure concentration of bio molecules in the feed material and at the outlet of one or more of the columns to determine breakthrough of the feed material and communicating to the chromatography system and the secondary control system. The system further comprises a secondary control system in communication with the flow cells and the first control system for transferring spectroscopy data to the first control system for electronically or pneumatically actuating supply of the feed material from the reservoir to one of the column and the first control system continuously processing the data from the flow cells or the secondary control system to change valve configuration, pump actuation, flow rate of feed material or a fluid to carry out steps selected from the group consisting of loading, second-pass loading to increase resin utilization and reduce idle time (Rathore, page 2, see entire paragraph [0012]). Rathore further teaches that the software layer of the first control system is able to control the flow rate of all pumps and the positions of all valves in the chromatography system in real time and that the pumps are used to supply the harvest and buffers and that outlet ports lead to the elution vessel, second-pass column and waste vessel. Rathore further teaches that that the timings and valve combinations for each step is programmed into the first control system with the option of dynamic time adjustment in the case of extreme deviations. Rathore further teaches that every 3 seconds, upon receiving concentration data from the flow cells via second control system, the control algorithm decides whether or not to change the flowrate of the loading pump (Rathore, page 5, paragraph [0044], lines 6-22). Put another way the control unit of Rathore receives data from the flow cells in real time and as such is capable of evaluating and adjusting timing of the valve combinations depending on the concentration data in the outlet flow. As such the control unit in the system of Rathore is capable of determining the timing of the elution during the elution phase for the following cycle. Rathore further teaches that the system is able to handle extreme deviations when the concentration drops below the normal operating range by dynamically adjusting the times of the various steps of the method (Rathore, page 3, paragraph [0031], lines 9-12). Rathore further teaches the system is unique in its ability to simultaneously assure both targeted resin utilization and consistent elution times and that resin costs are minimized and predictability is granted to elution time and quality, which is essential for the control of processes further downstream. Rathore further teaches that the system is easily adaptable to any continuous chromatography system with multiple columns and valves (Rathore, pages 3-4, see entire paragraph [0032]).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification method of Rose with the method of Gilby of using one cycle to calibrate timing of the next cycle because of the teaching of Gilby that this optimizes timing of a fraction collector and minimizes loss of target sample components. One having ordinary skill in the art would be motivated to do so because of the teaching of Gilby that the method eliminates timing errors by reliance on a calibrant that may be different from flow characteristics of a component at a later time in the eluent stream.
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of calibrating timing of fraction collection as taught by Gilby to the purification method of Rose, because both Rose and Gilby teach collecting fractions and analyzing them and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection as taught by Gilby would not interfere with the cyclical purification method of Rose.
It would have further been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of Rose in view of Gilby with a control unit configured to determine the timing of the elution during the following cycle because of the teaching of Rathore that the system is unique in its ability to simultaneously assure both targeted resin utilization and consistent elution times and that resin costs are minimized and predictability is granted to elution time and quality, which is essential for the control of processes further downstream.
One having ordinary skill in the art would have a reasonable expectation of success in having modified the system of Rose and Gilby with the control unit of Rathore, because Rose and Gilby teach column chromatography for the purification of samples and Rathore similarly teaches a column chromatography system.
Regarding claim 9, Rose and the cited art above teach a chromatography system substantially as claimed.
Rose and the cited art above teach a cyclic chromatography system essentially as claimed.
Rose does not teach that the control unit is configured to collect elution captured in the first cycle.
Rathore teaches a system comprising flow cells for analyzing spectra of the feed material to measure concentration of bio molecules in the feed material and at the outlet of one or more of the columns to determine breakthrough of the feed material and communicating to the chromatography system and the secondary control system as discussed previously in detail above. Rathore further teaches that the system comprises chromatography columns having an inlet and an outlet, wherein the inlet is connected through one of a plurality of valves of the channels of the system to one of the control-system-operable pump and the outlet is connected through one of a plurality of valves to a plurality of outlet ports characterized by a first control system connected to the system for operating the plurality of the pumps and the valves of the apparatus. The system further comprises a first control system continuously processing the data from the flow cells or the secondary control system to change valve configuration, pump actuation, flow rate of feed material or a fluid to carry out steps selected from the group consisting of loading, second-pass loading to increase resin utilization and reduce idle time (Rathore, page 2, see entire paragraph [0012]). Rathore further teaches that the software layer of the first control system is able to control the flow rate of all pumps and the positions of all valves in the chromatography system in real time and that the outlet ports lead to the elution vessel. Rathore further teaches that every 3 seconds, upon receiving concentration data from the flow cells via second control system, the control algorithm decides whether or not to change the flowrate of the loading pump (Rathore, page 5, paragraph [0044], lines 6-22). Put another way the control unit of Rathore receives data from the flow cells in real time and as such is capable of evaluating and adjusting timing of the valve combinations depending on the concentration data in the outlet flow. As such the control unit in the system of Rathore is capable of determining the timing of the elution during the elution phase for the following cycle (Rathore, page 3, paragraph [0031], lines 9-12).
Even though Rathore does not explicitly teach collecting the elution captured in the first cycle, Rathore does teach that the control unit receives data from the flow cells in real time and further teaches valves connected to the various outlet ports that are actuated by the first control unit. As such the control unit of Rathore is capable to actuate the valve to collect the elution captured in the first cycle in the elution vessel.
It would have further been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of Rose in view of Gilby with a control unit configured to collect elution captured in the first cycle because of the teaching of Rathore that the system increases resin utilization and reduce idle time.
One of ordinary skill in the art would have a reasonable expectation of success because Rathore teaches success with a control unit in a column chromatography system and Rose and Gilby similarly teach a column chromatography system.
Regarding claim 10, Rose teaches loading feed to a chromatography matrix (step a), eluting the product, holding the second fraction in one or more containers and loading the second fraction to the chromatography matrix (step e) and further teaches that the chromatography matrix in steps a and e is the same chromatography matrix. As such Rose teaches a chromatography system using a single chromatography column (Rose, column 9, lines 21-48 and Figure 1).
Regarding claim 12, Rose and the prior art above teach a chromatography system substantially as claimed.
Rose teaches recording chromatograms during multiple cycles of fraction collection (register target product over time as elution curve; Rose, column 6, lines 54-56 and Figures 8-14).
Rose does not teach a control unit that is configured to determine the initiation of the elution phase from the elution curve.
Gilby teaches that the fraction collector can be timed to begin collection before a peak reaches it and to stop collecting before the peak has passed completely and that the optimum fraction collector delay time can be found by comparing the trace to a reference chromatogram obtained by the waste stream detector after allowing a peak to pass uncollected by the fraction collector (Gilby, column 7, lines 45-56). Gilby further teaches that this is a way the signature of the waste stream detector can be used to establish the fraction collector delay time (Gilby, column 7, lines 57-59).
Rathore teaches a system comprising flow cells for analyzing spectra of the feed material to measure concentration of bio molecules in the feed material and at the outlet of one or more of the columns to determine breakthrough of the feed material and communicating to the chromatography system and the secondary control system as discussed previously in detail above. Rathore further teaches that the software layer of the first control system is able to control the flow rate of all pumps and the positions of all valves in the chromatography system in real time and that the outlet ports lead to the elution vessel. Rathore further teaches that every 3 seconds, upon receiving concentration data from the flow cells via second control system, the control algorithm decides whether or not to change the flowrate of the loading pump (Rathore, page 5, paragraph [0044], lines 6-22). Rathore further teaches that the system is able to handle extreme deviations when the concentration drops below the normal operating range by dynamically adjusting the times of the various steps of the method (Rathore, page 3, paragraph [0031], lines 9-12). Rathore further teaches the system is unique in its ability to simultaneously assure both targeted resin utilization and consistent elution times and that resin costs are minimized and predictability is granted to elution time and quality, which is essential for the control of processes further downstream. Rathore further teaches that the system is easily adaptable to any continuous chromatography system with multiple columns and valves (Rathore, pages 3-4, see entire paragraph [0032]).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the cyclic purification method of Rose with the method of Gilby of comparing the chromatogram obtained from the waste stream detector to a reference chromatogram because this can be used to establish the fraction collector delay time.
One having ordinary skill in the art would have a reasonable expectation of success in applying the method of establishing the fraction collector delay time as taught by Gilby to the purification method of Rose, because Gilby teaches success establishing a fraction collector delay time for sample collection and both Rose and Gilby teach collecting fractions and analyzing them and as such the analysis of timing of the fractions and applying the results to adjust the timing of the next fraction collection as taught by Gilby would not interfere with the cyclical purification method of Rose.
It would have further been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of Rose in view of Gilby with the control unit of Rathore, capable of handling extreme deviations when the concentration drops below the normal operating range by dynamically adjusting the times of the various steps of the method because of the teaching of Rathore that the system is unique in its ability to simultaneously assure both targeted resin utilization and consistent elution times and that resin costs are minimized and predictability is granted to elution time and quality, which is essential for the control of processes further downstream.
One of ordinary skill in the art would have a reasonable expectation of success because Rathore teaches success with a control unit in a column chromatography system and Rose and Gilby similarly teach a column chromatography system.
Regarding claims 13 and 14, Rose and the cited art above as applied to claim 7 also applies to claims 13 and 14.
Rose and the prior art above teaches a method of controlling fraction collection of a target product in a chromatography system substantially as claimed.
Rose does not teach a computer program comprising instructions when executed cause the processor to carry out the method.
Rathore teaches that the timing and valve combinations for each step in the base method is programmed into the system using a scheduler module in Python with the option of dynamic time adjustment and that overall cycle time was also monitored by the Python software in order to conduct the normal operation of the system including all valves in the valve cassette open/close and pump on/off and flowrate operations for all buffers at the correct times. Put another way, Rathore teaches that the normal operation of the Python scheduler module is opening and closing the valves and pumps which also has the option of dynamically adjusting the timing of the operation. Rathore further teaches a computer-readable storage medium loaded with the Python software (computer-readable storage medium carrying a computer program; Rathore, page 4, paragraph [0033], lines 18-20).
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEFANIE J KIRWIN whose telephone number is (571)272-6574. The examiner can normally be reached Monday - Friday 7.30 - 4 pm.
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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