DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08 DECEMBER 2025 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application (371 of PCT/EP2018/066005, filed 15 June 2018) under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority (GB1709531.6, filed 15 June 2017) under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendments
Applicant’s amendments filed 01 DECEMBER 2025 have been entered.
Claim 1 has been amended. Claims 1-10 and 12-22 are pending with Claims 16-22 withdrawn.
Regarding the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 101, Applicant’s amendments are persuasive; the as-amended claims have recited sufficient additional elements (i.e., an injection unit for preparing the buffer compositions) that amount to significantly more than the recited judicial exceptions. As such, the 35 U.S.C. 101 rejections of Claims 1-10 and 12-15 are withdrawn.
Regarding the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, Applicant’s amendments have been fully considered but are not sufficient to overcome the rejections.
Regarding the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 103 as being unpatentable over BLANK et al. (WO 2011/037530 A1), Applicant’s amendments to Claim 1 are persuasive; these rejections have been withdrawn. However, upon further consideration and search, new grounds of rejection have been made for Claims 1-10 and 12-15 under 35 U.S.C. 103 as being unpatentable over BLANK et al. (WO 2011/037530 A1) in view of POHL et al. (US 2017/0160244 A1).
Response to Arguments
Applicant’s arguments filed 01 DECEMBER 2025 have been fully considered.
Regarding the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 101, Applicant’s arguments are persuasive (pg. 8-9); as noted above, the added additional elements pertaining to the injection unit amount to significantly more than the recited judicial exceptions.
Regarding the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, Applicant’s arguments (pg. 9) have been fully considered but are not persuasive. Applicant argues that Claim 1 as amended adequately defines the objective function (pg. 9, §III, par. 1).
The Examiner respectively disagrees. While the amendments have corrected a few of the noted insufficiencies of the first objective function, it is noted that there remains errors that render Claim 1 indefinite. Specifically, there is no recitation as to what a functional evaluation of “1” or “0” entails; there are no definitions for “pH desiredmin”, “pH desiredmax”, “Conductivity desiredmin”, and “Conductivity desiredmax”, and most significantly, the input variable “C” is nowhere to be found in the formula. As such, the recited formula is improperly defined and renders Claim 1 indefinite.
Regarding the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 103 as being unpatentable over BLANK et al. (WO 2011/037530 A1), Applicant’s arguments (pg. 9, §IV, par. 1-4) have been fully considered but are not persuasive. Applicant argues that BLANK “does not disclose or suggest a method for performing chromatography, the method including, inter alia, obtaining a first objective function being dependent on a pH value and a conductivity value, and selected a subset of buffer compositions which have corresponding pH values and conductivity values that optimize the first objective function” (par. 2).
The Examiner respectfully disagrees.
As noted in the following prior art rejection, BLANK does in fact teach or suggest each of the recited steps of “obtaining a first objective function being dependent on a pH value and a conductivity value, and selected a subset of buffer compositions which have corresponding pH values and conductivity values that optimize the first objective function”. It is noted that the recited first objective function, although improperly claimed, seems relatively simple in that the function simply indicates whether a measured pH value and a measured conductivity value is within a desired range of each value. There is no further requirement by the claim that these values be dependent on any other variable. BLANK sufficiently discloses methods and provides examples as to how one of ordinary skill would be capable of utilizing the disclosed device to measure pH and conductivity in an eluent and to determine which buffer best suits their needs (i.e., “optimization”).
However, as indicated earlier, Applicant’s amendments to Claim 1 pertaining to the recitation of an “injection unit” is not explicitly taught by BLANK; as such, the rejections of Claims 1-10 and 12-15 under 35 U.S.C. 103 as being unpatentable over BLANK et al. (WO 2011/037530 A1) have been withdrawn. However, upon further search and consideration, new grounds of rejection have been made for Claims 1-10 and 12-15 under 35 U.S.C. 103 as being unpatentable over BLANK et al. (WO 2011/037530 A1) in view of POHL et al. (US 2017/0160244 A1).
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.
Claims 1-10 and 12-15 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.
Regarding Claim 1, the recited mathematical formula of a “first objective function” is improperly defined. Although improperly formatted (i.e., there is no indication what conditions allow the function to evaluate to “1” or to “0”, and improper “if” clauses are recited), it appears that the function takes two arguments, “P” and “C” defined to represent pH and conductivity. Based on context, it seems the objective function evaluates to either a “1” or “0” based on certain conditions. However, it is unclear how such results are interpreted, i.e., there is no context as to what a value of “1” or a value of “0” provides for the overall method. The claim recites that the “first objective function” is optimized but does not define what is considered “optimized” by the Applicant. Even further, the additional variables (i.e., “pH desiredmin”, “pH desiredmax”, “Conductivity desiredmin”, “Conductivity desiredmax”) are not defined and therefore, lack antecedent bases. Even further, no “C” is actually recited in the first objective function.
Therefore, Claim 1 is considered indefinite for failing to particularly point out or distinctly claim the subject matter of the invention. Claims 2-10 and 12-15 are also rejected due to their dependence on Claim 1.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-10 and 12-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over BLANK et al. (WO 2011/037530 A1) in view of POHL et al. (US 2017/0160244 A1).
Regarding Claim 1, BLANK discloses a method and system for providing a liquid flow having pre-defined characteristics; said liquid flow is prepared by combining liquid flows from two or more component stock solutions (i.e., a set of buffer compositions… selected as a subset from a total set of buffer compositions within a design range) having known concentrations or other characteristics (i.e., obtaining design of experiment, DoE, data; pg. 11, line 32-pg. 12, line 7), in known or calculated ratios to produce said liquid flow with desired characteristics. Such characteristics are predicted based on calculations using known stock solution properties and are mixed according to predetermined recipes that can be adjusted if necessary (i.e., corresponding unique recipes; pg. 5, lines 16-26). BLANK further discloses the desired characteristics are pH and ionic strength/conductivity (i.e., wherein the… data is indicative of at least a pH value and a conductivity value; pg. 5, lines 28-34; pH: pg. 6, lines 1-30; conductivity: pg. 6, line 32-pg. 7, line 11). The described blending method and system is part of a larger chromatography system (i.e., a chromatography apparatus; pg. 4, lines 28-29; Claim 18) and the produced liquid flow is used as a buffer for the chromatography system (pg. 11, lines 26-27). BLANK further discloses the use of in-line sensors for sensing the desired characteristics, e.g., pH sensors and conductivity sensors (i.e., wherein pH is detected using a pH sensor, the conductivity value is detected using a conductivity sensor; pg. 8, lines 1-6).
A programmed control system (i.e., a controller) determines the relative proportions of each stock solution to be mixed together to obtain the desired liquid mixture/buffer by using a recipe (i.e., running a first set of experiments by… providing buffer compositions mixed according to each unique recipe indicated by the DoE data as the only input to the chromatography apparatus; pg. 12, lines 18-20). New stock solutions are prepared and used if measurements indicate stock solutions need to be adjusted or replaced (pg. 13, lines 25-27). Prepared/mixed solutions are then directed to an outflow whereby sensors monitor the produced buffer flow (i.e., obtaining results of experiment, RoE, data as output from the chromatography apparatus) to determine if the characteristics deviate from desired characteristics and whether the produced buffer flow would need to be remixed (pg. 14, line 33-pg. 15, line 2). The control system automatically calculates the appropriate mixing ratios to obtain a buffer having the desired characteristics using a predetermined equation or calculation recipe (i.e., obtaining a first objective function, the first objective function being dependent on a pH value and a conductivity value; pg. 14, lines 16-18). BLANK further discloses multiple blending systems in the chromatography apparatus for preparing multiple liquid mixtures (i.e., consecutively providing buffer compositions mixed according to each unique recipe; pg. 15, lines 4-9). BLANK discloses the preparation of as-determined buffers for performing chromatography (i.e., performing chromatography using at least one buffer composition mixed according to the one or more determined buffer composition recipes; pg. 4, lines 28-29; pg. 7, lines 13-16).
While BLANK is deficient in explicitly disclosing selecting a second subset from the total set of buffer compositions which [has] corresponding pH values and conductivity values [that] optimize the first objective function (or the subsequent step of determining the one or more buffer composition recipes utilizing said second subset), such a step would be obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention. BLANK discloses the overall process is an “iterative procedure” (pg. 11, line 1) and further discloses the use of sensors for monitoring the produced buffer flow for the desired characteristics such that the feedback from the sensors will allow for the control system to adjust the mixing recipes (pg. 11, lines 19-24). Thus, even though BLANK did not explicitly disclose selecting a second subset as claimed, one of ordinary skill in the art would find such a step to be obvious to practice especially if the initial selected recipe and produced buffer flow did not satisfy the desired buffer flow characteristics.
Furthermore, while BLANK is deficient in explicitly disclosing the claimed first objective function, as noted in the above 35 USC 112(b) rejection, the first objective function is improperly defined. The resultant values of “1” and “0” are devoid of any contextual use. Even further, it is unclear how the function can be evaluated due to a number of additional undefined variables and the lack of evaluation of an input “C”. It is interpreted that Applicant intended such a claimed first objective function to inform a user whether a certain combination of a pH value and of a conductivity value would be acceptable or not (i.e., a “1” or “0”, respectively) within respective desired ranges to prepare a buffer for a chromatographic separation. Such a function would be obvious to one of ordinary skill in the art; as noted by BLANK, the above disclosed control system automatically calculates the appropriate mixing ratios to obtain a buffer having the desired characteristics (having a certain pH value and a certain conductivity value; pg. 9, lines 1-5) using a predetermined equation or calculation recipe (pg. 14, lines 16-18). Disclosure of “appropriate mixing ratios” implies that any “first objective function” would evaluate to a positive result indicating the preparation of a proper buffer for chromatography.
BLANK is deficient in disclosing the buffer compositions are delivered via an injection unit to a plurality of reservoirs via respective inlets connected to the injection unit.
POHL discloses a chromatography system 100 configured to provide different mobile phases (abstract). The system includes four mobile phase reservoirs (i.e., buffer compositions; 102A-D), an eluent proportioning valve assembly 106 (i.e., an injection unit), a tubing assembly 108, a pump 110, a pressure transducer 112, a multi-lumen mixing device 114 (i.e., a reservoir [with] a respective inlet connected to the injection unit), an injection valve 116, a chromatography column 118, and a detector 120 (p0039; FIG. 1). In operation, buffer/eluent is drawn by the eluent proportioning valve assembly 106 and delivered to the multi-lumen mixing device 114 for flow through injection valve 116 of the chromatography column 118 (p0040). Such a mixing device advantageously provides for the careful control of buffer/eluent delivered to a chromatography column to achieve reproducible and predictable results (p0003). While POHL is deficient in disclosing a plurality of reservoirs with their respective inlets, such a limitation is directed toward a multiplicity/duplication of parts. The mere duplication of the essential working parts of a device involves only routine skill in the art (St. Regis Paper Co. v. Bemis Co., 193 USPQ 8). Therefore, prior to the effective filing date of the claimed invention, one of ordinary skill in the art would have found it obvious to provide an injection unit to a plurality of reservoirs via respective inlets connected to the injection unit as suggested by POHL in the method for performing chromatography obvious over BLANK.
Regarding Claims 2 and 3, modified BLANK makes obvious the method of Claim 1. Applicant has broadly claimed “a pH objective function and a conductivity objective function” (Claim 2) and “a pH predictive function” and “a conductivity predictive function” (Claim 3); because Applicant has not indicated any specific details about such functions, the Examiner will by broadest reasonable interpretation consider these functions to be related to optimization functions obvious to one of ordinary skill in the art. Because BLANK further discloses controlling pH values and conductivity values based on the individual values/concentrations of the used stock solutions and the desired characteristics of the produced buffer flow (pH: pg. 6, lines 1-30; conductivity: pg. 6, line 32-pg. 7, line 11), BLANK is considered to describe the general conditions of the claim. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation absent unexpected results or evidence indicating such optimum or workable ranges are critical (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); MPEP§2144.05).
Regarding Claim 4, modified BLANK makes obvious the method of Claim 1. BLANK further discloses predetermined recipes used for mixing the stock solutions (pg. 5, lines 20-26), up to four stock solutions (pg. 7, lines 18-20).
Regarding Claims 5, 6, 8, and 9, modified BLANK makes obvious the method of Claim 4. Pre-defined stock solutions include (i) an acid, (ii) a base, (iii) a salt, and (iv) water (i.e., wherein the first fluid is an acid, the second fluid is a base… and the third fluid is water; a fourth fraction of a fourth fluid, wherein the fourth fluid is a salt solution; a fourth fraction of a fourth fluid, wherein the fourth fluid is another solution; pg. 12, lines 14-16). BLANK further discloses Na2HPO4 and NaH2PO4 acid/base solutions (i.e., the second fluid is a base of the acid; wherein the acid and the base are a conjugate pair; pg. 15, line 20). Further, BLANK discloses mixing recipes that call for certain mixing ratios of each stock solution, e.g., to control for certain salt concentrations in the produced buffer flow (i.e., the first fraction and the second fraction are constrained by a given buffer concentration; pg. 13, lines 18-23).
Regarding Claim 7, modified BLANK makes obvious the method of Claim 6. BLANK further discloses the addition of salts is an effective way to control the conductivity (i.e., wherein the fourth fluid is used to adjust the conductivity; pg. 7, lines 7-8). Further, BLANK discloses mixing recipes that call for certain mixing ratios of each stock solution, e.g., to control for certain salt concentrations in the produced buffer flow (i.e., the first fraction and the second fraction are constrained by a given buffer concentration; pg. 13, lines 18-23).
Regarding Claim 10, modified BLANK makes obvious the method of Claim 1. BLANK further discloses the method and system produces buffer flows for chromatography (pg. 4, lines 28-29; pg. 7, lines 13-16) useful for separating samples (pg. 15, lines 11-14; Claim 17), e.g., protein separations (pg. 1, line 22). As is well-known to one of ordinary skill in the art, chromatography separations balance between quality and yield, i.e., a better resolved sample would result in increased purity but comes at the cost of lower throughput/yield and vice versa. BLANK discloses that buffers having specific pH and conductivity determine the selectivity of separations and thereby determines the purity and yield of a wanted substance in a sample (pg. 1, lines 19-24).
While the prior art is deficient in explicitly disclosing running a second set of experiments and the claimed subsequent steps, such steps would be obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention. BLANK discloses the overall process is an “iterative procedure” (pg. 11, line 1) and further discloses the use of sensors for monitoring the produced buffer flow for the desired characteristics such that the feedback from the sensors will allow for the control system to adjust the mixing recipes (pg. 11, lines 19-24). Thus, even though the prior art did not explicitly disclose running a second subset as claimed, one of ordinary skill in the art would find such a step to be obvious to practice especially if the initial selected recipe and produced buffer flow did not satisfy the desired buffer flow characteristics to produce the desired sample separation results (e.g., yield and purity).
Regarding Claims 12-15, modified BLANK makes obvious the method of Claim 5. Because Applicant has not indicated any specific details about the claimed unique recipes, the Examiner will by broadest reasonable interpretation consider these recipes to be related to optimization of mixing ratios obvious to one of ordinary skill in the art. Because BLANK further discloses controlling pH values and conductivity values based on the individual values/concentrations of the used stock solutions and the desired characteristics of the produced buffer flow (pH: pg. 6, lines 1-30; conductivity: pg. 6, line 32-pg. 7, line 11), modified BLANK is considered to describe the general conditions of the claims. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation absent unexpected results or evidence indicating such optimum or workable ranges are critical (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); MPEP§2144.05).
Further, BLANK discloses varying the ratios of each stock solution mixed to produce the buffer flow (pg. 13, lines 29-34). While the claimed methods of keeping one fraction constant and varying the other fractions are not explicitly claimed, one of ordinary skill in the art would find such steps to be obvious because such steps are considered simple optimization procedures that have known results, e.g., increasing the amount of acid would correspondingly decrease the pH. The claimed parameter is recognized as a result-effective variable as taught by the prior art and can be optimized through routine experimentation (MPEP §2144.05 II B). Absent showings that such steps would result in a result wholly unexpected, e.g., raising an acid ratio resulting in an increased pH, the claimed method steps would have been obvious to one skilled in the art at the time of the invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RYAN B HUANG whose telephone number is (571)270-0327. The examiner can normally be reached 9 am-5 pm EST.
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/Ryan B Huang/Primary Examiner, Art Unit 1777
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