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 .
This action is responsive to the claimd filed on Oct. 17, 2024. Claims 1-69 are pending and examined below.
Priority
The application claims priority to provisional applications 63/544767, filed Oct. 18, 2023 and 63/708,147, filed Oct. 16, 2024; as such the earliest possible priority date is Oct. 18, 2023.
Information Disclosure Statement
The information disclosure statement filed Feb. 19, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
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 41-43 depend from claim 39 and recite the limitation "said acetic acid” or “said glycine.” There is insufficient antecedent basis for this limitation in the claim, as claim 39 does not recite acetic acid or glycine.
For the purpose of examination, claims 41-43 are interpreted as depending from claim 40.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 6, 17-24, 26-33, 36, 38-40, 43-46, 48-52, and 56-59 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hermans et al. (Monoclonal Antibodies: Methods and Protocols, 2014).
The claims are directed to methods for enriching a desired protein from a cell culture through contacting the cell culture sample to a centrifugal column including an affinity resin that binds to the desired protein, thereby immobilizing the sample; washing the immobilized sample, and eluting the desired protein from the sample.
With respect to independent claim 1, Hermans et al. teach purification of antibodies and antibody fragments using affinity resins (title). Specifically, Hermans et al. teach “…affinity chromatography has evolved into a well-established technology for the purification of antibodies…” (Abstract). Hermans et al. indicate that affinity chromatograpy (AC) is a liquid chromatography that make employs a reversible biological interaction for separation of specific targets in a sample: “…the binding agent, or affinity ligand, that selectively interacts with the desired target is immobilized onto a solid support in order to create an affinity matrix that can be used in a column format.” (pg. 297, “1 Introduction”). Hermans et al. further teach that AC includes the steps of binding of the target under conditions that support specific binding (“contacting cell culture sample to a centrifugal column including an affinity resin that binds to the desired protein, thereby immobilizing the sample”); washing out the contaminant in the non-bound fraction; and elution. (pg. 297, “1 Introduction”; pg. 306, Fig. 2).
With respect to claim 2, Hermans et al. teach the protein of interest is an antibody. (Abstract).
With respect to claims 3 and 6, Hermans et al. teach using AC to enrich monoclonal antibodies from mammalian based expression systems. (pg. 303, ll. 1-3).
With respect to claim 17-22, Hermans et al. teach the use of binding buffer (which would inherently be added to the cell culture as part of the contacting step) of phosphate buffered saline (PBS) at a pH of 7.2-7.4. (pg. 300, 1st full para.). PBS contains disodium hydrogen phosphate (“sodium phosphate”) (claims 18 and 20) and sodium chloride (claims 19 and 21).
With respect to claim 23, Hermans et al. teach adding a binding buffer (pg. 300, 1st full para.) and a total volume (cell culture + added binding buffer of 100 µl – 700 µl. (pg. 306, “3.3 Spin Column Format Purification, 4.”)
With respect to claim 24, Hermans et al. teach loading 100 µL of antibody-containing sample. (pg. 306, “3.3 Spin Column Format Purification, 4.”)
With respect to claim 26, Hermans et al. teach Protein A resin. (pg. 298, 1st para.).
With respect to claim 27, Hermans et al. teach the washing step includes adding washing buffer to the column and centrifuging, producing a washed flowthrough. (pg. 306, Fig. 2; pg. 307, steps 5 and 6).
With respect to claims 28-33, Hermans et al. teach the washing buffer is phosphate buffered saline (PBS) at a pH of 7.2-7.4. (pg. 306, Fig. 2; pg. 307, steps 5 and 6). PBS contains disodium hydrogen phosphate (“sodium phosphate”) (claims 28 and 30) and sodium chloride (claims 29 and 31). Hermans et al. teach the resin is washed two to four times. (pg. 307, step 6) (claims 32 and 33).
With respect to claims 36 and 38, Hermans et al. teach using 500 µl (“about 600 µl”) and centrifuging for one minute. (pg. 306, step 2, Fig. 2; pg. 307, step 6).
With respect to claims 39, 40, 43-45, Hermans et al. teach an elution step including adding 400 µl elution buffer (glycine, 100mM (0.1 M), pH 3). (pg. 307, step 7).
With respect to claims 46 and 48, Hermans et al. teach one elution step “and for optimal recovery, additional steps may be required.”) and centrifuging for one minute. (pg. 306 Fig. 2; pg. 307, step 7).
With respect to claims 49-52, Hermans et al. teach the elution step includes adding a neutralizing buffer, specifically Tris-HCl, pH 8 (“Tris base”). (pg. 307, step 7). Herman et al. teach that the neutralizing buffer is 1/10 of the elution buffer, so 40 µl (claim 52).
With respect to claim 56, Hermans et al. inherently teaches the claimed duration. (pg. 306 Fig. 2, pgs. 306-307).
With respect to claims 57-59, Hermans et al. teach characterizing the size variations of the protein sample, including elution fraction, using SDS-PAGE (“electrophroresis”) (pg. 303, “2.4 Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE)).
Claim(s) 1, 6,7, 60 and 61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grom et al. (J Chromatog B, 2018).
With respect to independent claim 1, Grom et al. teach that monoclonal antibodies (mAbs) are one of the most important products of the biopharmaceutical industry, as they are used in treatments of cancer, autoimmune diseases, organ rejection response, infection and like hypercholemia. (pg. 44, “Introduction”). Grom et al. further teach that affinity chromatography enables purification of mAbs rom culture fluid to the required quality, and that most affinity chromatography operate as a cycle of loading, washing, elution and regeneration of the resin. (pg. 44, “Introduction”). Specifically for high-selectivity, Protein A affinity chromatography, the cell harvest with mAb is loaded to the affinity chromatography column, where the antibody (“protein of interest”) binds to protein A and is immobilized; the column is washed to remove unbound impurities and then the mAb is eluted. (para. bridging pgs. 44-45).
With respect to claims 6-7, Grom et al. teach that CHO cell culture containing mAbs was first centrifuged and separated to produce a cell-free culture fluid. (pg. 46, 1st col., 2nd full para.).
With respect to claims 60 and 61, Grom et al. teach characterization of mAb aggregates (“a high molecular weight species of said enriched protein of interest”) using size exclusion chromatography. (pg. 46, “2.5.2 Size exclusion chromatography”).
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.
Claim(s) 1, 6-10, 25, 34, 35 41, 42 and 53-55 are rejected under 35 U.S.C. 103(a)(1) as being obvious over Dumetz et al. (U.S. Patent App. No. 2021/0054023 A1) and further in view of Slingerland et al (J Chromatography, 1990).
With respect to claims 1 and 7-10, Dumetz et al. teaches purification of recombinant antibody from a host cell protein, including applying a cell culture product to the chromatography solid support, washing and eluting the recombinant antibody; specifically, Dumetz et al. teach clarified, CHO culture broth containing the recombinant antibody was cultured for 16 days and then applied to a Protein A affinity chromatographic column, washed and eluted. (Abstract, pg. 13-15, Example 1).
With respect to claims 25, 53-55, Dumetz et al. teach assessing yield loss and mitigation strategies, teaching the claimed % yield of protein, amount and concentration of recombinant antibody, and load ratios, which inherently teaches the claimed amount to protein at the contacting step. (pg. 15, Ex. 2).
With respect to claims 34 and 35, Dumetz et al. teach optimization of the wash and elution process, and further teach that sodium phosphate, sodium chloride and sodium acetate are all components in the wash and elution buffers. (para. [0033], [0076], [0077], [0128}
rendering obvious the claimed steps of using sodium phosphate and sodium chloride in a first wash and then using sodium acetate
With respect to claims 41 and 42, Dumetz et al. teach using 28.2 mM of acetic acid for elution (pg. 13, Example 1, Table 2), rendering obvious “about 40 mM” (claim 41) and “about 20 mM” (claims 41), as Dumentz et al. also teaches optimization and with 28.2 mM of acetic acid taught for elution, this would be routine optimization of result-effective variable. See MPEP 2144.05
Dumentz et al. do not teach that the affinity chromatography is centrifugal affinity chromatography.
Slingerland et al. teach that gravity affinity chromatography works as well as centrifugal based methods, however, the time to process the sample is reduced by employing centrifugal methods. (para. bridging pg. 209-210).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the general protocol taught by Dumentz et al. to incorporate performing centrifugal affinity chromatography because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Making this modification would have led to predictable results with a reasonable expectation of success because Slingerland et al. teach that using centrifugal power provides an increased speed, thereby decreasing the processing costs. (pg. 210, last para.) As such, one of ordinary skill in the art would have used centrifugal affinity chromatography in the process taught by Dumentz et al.
Claim(s) 11-16, 57, 68 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Dumetz et al. (U.S. Patent App. No. 2021/0054023 A1) and Slingerland et al (J Chromatography, 1990), as applied to claims 1, 6-10, 25, and 53-55 above and further in view of Burg et al. (U.S. Patent App. No. 2012/0177640).
Dumetz et al. generally teaches optimization of antibody yield, but does not teach the specifically claimed steps found in claims 11-16.
With respect to claims 11-16, Burg et al. teach repeating the steps of obtaining a sample from the medium and determining a ratio of antibody to an antibody variant. (claim 7). Burg et al. further teach that a harvesting time can be chosen based on the time point when the composition or quality of the antibody is as desired. In order to determine this timepoint, Burg et al. teach that samples can be taken and compared, thereby determining when the most favorable timepoint for selecting the antibody will be – to obtain the desired ratio of antibody to antibody variants. (paras. [0144]-[0145].
With respect to claims 57, 68 and 69, Dumetz et al. teach characterizing a product quality attribute (for example, glycosylation) and using this information to determine if the cell culture should be continued, discontinued or modified. (claims 68-69) (paras. [0144]-[0149]).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the process taught by Dumetz et al. to include repeating steps, sampling the cell culture, comparing samples to one another and determining optimized parameters for desired antibody production (as taught by Burg et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating these modifications would have led to predictable results with a reasonable expectation of success because both references are concerned with antibody enrichment using affinity chromatography.
Claim(s) 37 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Hermans et al. (Monoclonal Antibodies: Methods and Protocols, 2014),
as applied to claims 1-3, 6, 17-24, 26-33, 36, 38-40, 43-46, 48-52, and 56-59 above, and further in view of Slingerland et al (J Chromatography, 1990).
Hermans et al. does not teach using a very low RCF for centrifugation, such as 100 RCF.
Slingerland et al. teach that gravity affinity chromatography works as well as centrifugal based methods, however, the time to process the sample is reduced by employing centrifugal methods. (para. bridging pg. 209-210). Slingerland et al. further teach that “the type of matrix and the applied centrifugal speed can be very important.” (pg. 210, last para.)
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the general protocol taught by Hermans et al. to incorporate a low RCF, such as 100 RCF during the wash and elution process because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Making this modification would have led to predictable results with a reasonable expectation of success because Slingerland et al. teach that centrifugal speed is a result-effective variable – increasing the speed may speed the process up, and slowing it down may be necessary so that the fluid in the affinity matrix does not get removed from internal pores, as if this happens, it can be difficult to rewet the matrix, thereby driving up the cost of the process. (pg. 210, last para.) As such, one of ordinary skill in the art would have struck the balance between speed and preserving the matrix with the centrifugal speed based on the specifics of protein being enriched and would have chosen 100 RCF in the case where an affinity matrix is easily dried out, causing rewetting issues.
Claim(s) 1 and 4 are rejected under 35 U.S.C. 103(a)(1) as being obvious over Li et al. (U.S. Patent App. No. 2021/0380638 A1) and further in view of Slingerland et al (J Chromatography, 1990).
Li et al. teach protein A affinity chromatography using specific conditions to optimize its effectiveness for antibody removal. (Abstract) Li et al. teach contacting a cell culture sample with an affinity column and binding of the antibody under conditions that support specific binding; washing out the contaminant in the non-bound fraction; and elution. (paras. [0012], [0016], [0024], [0055]).
Li et al. do not teach that the affinity chromatography is centrifugal affinity chromatography.
Slingerland et al. teach that gravity affinity chromatography works as well as centrifugal based methods, however, the time to process the sample is reduced by employing centrifugal methods. (para. bridging pg. 209-210).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the general protocol taught by Li et al. to incorporate performing centrifugal affinity chromatography because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Making this modification would have led to predictable results with a reasonable expectation of success because Slingerland et al. teach that using centrifugal power provides an increased speed, thereby decreasing the processing costs. (pg. 210, last para.) As such, one of ordinary skill in the art would have used centrifugal affinity chromatography in the process taught by Li et al.
With respect to claim 4, Li et al. teach that their optimized process is appropriate for enrichment of dupilumab. (para. [0044]).
Claim(s) 1, 5 and 66 are rejected under 35 U.S.C. 103(a)(1) as being obvious over Karur (U.S. Patent App. No. 2020/0283472 A1) and further in view of Slingerland et al (J Chromatography, 1990).
Karur teaches purification of Fc fusion proteins using a series of steps, one of which is capture of a Fc fusion protein from a clarified cell culture broth and using Protein A chromatography, where the resin binds to the Fc fusion protein and non-desired proteins are removed in the flowthrough or subsequent washes and elution. (abstract, paras. [0030], [0031], Ex. 1, paras. [0052] –[0058]).
Karur do not teach that the affinity chromatography is centrifugal affinity chromatography.
Slingerland et al. teach that gravity affinity chromatography works as well as centrifugal based methods, however, the time to process the sample is reduced by employing centrifugal methods. (para. bridging pg. 209-210).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the general protocol taught by Karur et al. to incorporate performing centrifugal affinity chromatography because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Making this modification would have led to predictable results with a reasonable expectation of success because Slingerland et al. teach that using centrifugal power provides an increased speed, thereby decreasing the processing costs. (pg. 210, last para.) As such, one of ordinary skill in the art would have used centrifugal affinity chromatography in the process taught by Karur.
With respect to claim 5, Karur teach that their process is appropriate for enrichment of aflibercept. (para. [0003], claim 2).
With respect to claim 66, Karur teach that the active form of Fc fusion proteins require the correct glycan profile in a final product, therefore, the process requires characterization of the glycan profile. (paras. [0004], [0012], [0013]).
Claim(s) 1 and 62-67 are rejected under 35 U.S.C. 103(a)(1) as being obvious over Kalo et al. (U.S. Patent App. No. 2020/0362003 A1) and further in view of Slingerland et al (J Chromatography, 1990).
Kalo teaches purification of IL-22 Fc fusion protein using a series of steps, one of which is capture of a Fc fusion protein from a clarified cell culture broth using affinity chromatography, where the resin binds to the Fc fusion protein and non-desired proteins are removed in the flowthrough or subsequent washes and elution. (Fig. 18, para. [0049])
Kalo et al. do not teach that the affinity chromatography is centrifugal affinity chromatography.
Slingerland et al. teach that gravity affinity chromatography works as well as centrifugal based methods, however, the time to process the sample is reduced by employing centrifugal methods. (para. bridging pg. 209-210).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the general protocol taught by Kalo et al. to incorporate performing centrifugal affinity chromatography because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Making this modification would have led to predictable results with a reasonable expectation of success because Slingerland et al. teach that using centrifugal power provides an increased speed, thereby decreasing the processing costs. (pg. 210, last para.) As such, one of ordinary skill in the art would have used centrifugal affinity chromatography in the process taught by Kalo et al.
With respect to claim 62-67, Kalo et al. teach further purification of the IL-22 Fc fusion protein using CE-SDS; characterizing a charge variant using iCIEF; and characterizing a glycan using HILIC analysis (entire doc., especially pg. 59, Table 1)
Conclusion
No claims are allowed.
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/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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