The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group I, claims 1-3, 5, 8, 10, 12, 16, 18, 20, 23-28, 30, 32, 34, in the reply filed on November 10, 2025 is acknowledged.
Claims 4, 6-7, 11, 13-15, 17, 19, 21-22, 29, 31, 33, 37-38, 40-41, 44-45, 47, 49 are canceled. Claims 35-36, 39, 42-43, 46, 48, 50 have been withdraw from further consideration by the examiner because they are drawn to non-elected inventions.
Claims 1-3, 5, 8, 10, 12, 16, 18, 20, 23-28, 30, 32, 34 are under consideration.
Priority: This application is a 371 of PCT/US2021/070985, filed July 27, 2021, which claims benefit of provisional application 63/057800, filed July 28, 2020.
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.
Claims 1-3, 5, 8, 10, 12, 16, 18, 20, 23-28, 30, 32, 34 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (WO 2020088180) in view of Becker et al. (WO 2014067898). Zhou et al. disclose a process for producing a biological substance by perfusion culturing of a cell culture in a bioreactor, wherein a basal medium and a feed medium are fed to the cell culture and wherein the cell culture is passed through a separation system to continuously harvest the biological substance, where during the culture process the cells are retained in the bioreactor without bleeding (at least paragraphs 0007-0009), where the biological substance are recombinant proteins (at least paragraph 0063, also Fig. 1). Zhou et al. disclose the biological substance is harvested by the separation system with a hollow fiber filter having a pore size or molecular weight cut-off that does not retain the biological substance of interest but retains the cells, where the separation system with the hollow fiber is an alternating tangential flow (ATF) or tangential flow filtration (TFF) device (at least paragraphs 0013-0015, 0085-0086). Zhou et al. disclose that by circulating the cell culture comprising the biological substance, cells, and cell culture medium over the a separation system, the cells are retained in the reactor and the biological substance of interest is harvested (at least paragraph 0087). Zhou et al. disclose the circulation of the cell culture over a filter may be a flow substantially parallel to the filter surface, also known as tangential flow, for example unidirectional tangential flow (TFF) or cross-flow, where a preferred example of cross-flow is alternating tangential flow (ATF) as with ATF it was found that filter clogging does not occur (quickly) even at very high cell densities (at least paragraph 0088). Zhou et al. disclose that the biological substance produced can be further captured from the harvest material in down-stream processing including several purification steps in varying combinations and order, where non-limiting examples include separations steps (i.e. chromatography), steps for concentration (i.e. ultrafiltration or diafiltration), steps to exchange buffers and/or steps to remove or inactivate viruses (at least paragraph 0091). Therefore, Zhou et al. can be deemed to disclose harvesting a polypeptide of interest into another vessel from the bioreactor in contact with the ATF retaining the cells. Zhou et al. differ from the claimed method by not explicitly teaching a second ATF filter.
Becker et al. disclose methods for separating a molecule of interest from a solution containing the molecule using dual stage tangential-flow ultrafiltration (TFF) (at least abstract, p. 1). Becker et al. disclose the methods utilizing TFF unit operations supplement, improve or replace traditional processes for purification of proteins of interest for a feed stream may represent significant saving in both direct and indirect costs (at least abstract, p. 1, 5-7). Becker et al. disclose that the TFF unit operations are particularly suited to process cell culture solutions prior to downstream, e.g. chromatographic, purification and isolation processes that are used to bring the product stream to final formulation and/or purity (at least p. 6-7). Becker et al. disclose that the methods are also suited for the separation of a protein of interest from a feed stream that is a cell culture solution (at least p. 7-8). Becker et al. disclose the TFF unit operations include a first TFF unit operation having a cut-off such that the protein of interest is recovered in the retentate of the first TFF unit operation and a second TFF unit operation having a cut-off such that the protein of interest is recovered in the permeate of the second TFF unit operation (at least p. 9-10, see also Figures 1-4). Becker et al. disclose vessels with the TFF unit operations (at least Figures 1-4). Becker et al. disclose that the terms “first” and “second” in connection with the specific at least two TFF unit operations are understood to be merely designators of the individual TFF unit operations are not intended to imply any process or chronological order within the dual stage TFF method itself (at least p. 15). Becker et al. disclose the TFF unit operations relate to crossflow or tangential flow filtration (TFF) (p. 54).
As noted above, Zhou et al. disclose that ATF is a preferred example of cross-flow TFF (paragraphs 0088-0089).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the prior art and arrive at the claimed method comprising a method for producing a polypeptide, comprising: (a) culturing, in a culture medium in a first bioreactor, a host cell that expresses the polypeptide under conditions suitable for expression of the polypeptide, wherein the first bioreactor is in fluid connection with ATF microfilter such that the host cell, the culture medium, and the polypeptide from the first bioreactor contact the ATF microfilter; (b) transferring the polypeptide and a portion of the culture medium through the ATF microfilter into a second bioreactor that is in fluid connection with the ATF microfilter, wherein the ATF microfilter causes the host cell to be retained in the first bioreactor and allows the polypeptide and the portion of the culture medium to pass into the second bioreactor; (c) contacting the polypeptide and the portion of the culture medium in the second bioreactor with an ATF ultrafilter that is in fluid connection with the second bioreactor, wherein the ATF ultrafilter causes the polypeptide to be retained in the second bioreactor and allows culture medium to exit the second bioreactor; and (d) collecting the polypeptide from the second bioreactor (instant claim 1). One of ordinary skill would have reasonable motivation to incorporate the at least two TFF unit operations disclosed in Becker et al., wherein the TFF unit operations are ATF unit operations and at least one ATF unit operation retains a polypeptide of interest in a vessel (i.e. a second vessel/bioreactor), with the downstream processing steps for the polypeptide of interest harvested in the method comprising culturing a cell culture in a bioreactor in contact with an ATF unit that retains the cells of Zhou et al. noted above because the prior art disclose incorporating multiple TFF unit operations for separating a polypeptide of interest from a cell culture where a preferred example of TFF is ATF, to thereby arrive at the claimed method. One of ordinary skill would have a reasonable expectation of success because cell culture processes for producing a polypeptide of interest and cell retention by ATF and separating a polypeptide of interest by ATF are known in the prior art.
Regarding instant claim 2, Becker et al. disclose the dual stage TFF unit operations may be run in batch or continuous operations, or in a semi-continuous manner (at least p. 63). Therefore, it would be obvious that the polypeptide of interest collected in the vessel or bioreactor with a another ATF unit operation is in a non-continuous batch.
Regarding instant claim 3, Zhou et al. disclose in a typical perfusion process, cells are cultured over long periods of time (paragraph 0004). Zhou et al. disclose culturing and maintaining the cell culture for a period of time, including 19 days, and the amounts of polypeptide of interest produced (at least Fig. 2-34). “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05. Therefore, it would have been obvious to culture the cells in the bioreactor with the ATF retaining the cells for a period of about 2 weeks or 3 weeks and collect the polypeptide of interest from another bioreactor with an ATF retaining the polypeptide of interest in a batch each period by routine optimization.
Regarding instant claim 5, Zhou et al. disclose volumetric productivities of 10 g/L or more (at least p. 45) and Becker et al. disclose obtaining polypeptide of interest concentrations with the TFF unit operations including 15.23 g/L, 1.13 g/L, 12.0 g/L, and chromatography including 8.6 g/L (at least p. 80). Therefore, it would have been obvious to arrive at the recited concentrations for the collected polypeptide by routine optimization.
Regarding instant claim 8, Zhou et al. disclose a continuous process for culturing the cell culture and producing the polypeptide of interest (at least paragraphs 0007-0009, also Fig. 1) and Becker et al. disclose the dual stage TFF unit operations may be run in batch or continuous operations, or in a semi-continuous manner (at least p. 63). Therefore, it would be obvious that the process steps are in a continuous manner, the collection of the polypeptide is in a non-continuous manner, and the culturing in the bioreactor with the ATF occur simultaneously.
Regarding instant claim 10, as noted above, Zhou et al. disclose a continuous process for culturing the cell culture and producing the polypeptide of interest (at least paragraphs 0007-0009, also Fig. 1) and Becker et al. disclose the dual stage TFF unit operations may be run in batch or continuous operations, or in a semi-continuous manner (at least p. 63). Therefore, it would be obvious that the process steps are in a continuous manner to produce a desired level of the product of interest before it is collected.
Regarding instant claim 12, Becker et al. disclose that the at least two TFF unit operations include a first TFF unit operation where the protein of interest is recovered in the retentate of the first TFF unit operation and a second TFF unit operation where the protein of interest is recovered in the permeate of the second TFF unit operation (at least p. 9-10, see also Figures 1-4). Therefore, it would have been obvious to further remove another portion of the culture medium through an ATF unit operation before collecting the polypeptide of interest.
Regarding instant claim 16, Becker et al. disclose obtaining polypeptide of interest concentrations with the TFF unit operations including 15.23 g/L, 1.13 g/L, 12.0 g/L, and chromatography including 8.6 g/L (at least p. 80). Therefore, it would have been obvious to let the polypeptide of interest accumulate in a vessel with an ATF unit operation up to a specific level or concentration before collecting the polypeptide of interest.
Regarding instant claim 18, Zhou et al. disclose a basal medium and a feed medium are fed to the cell culture at different rates in the bioreactor with the ATF retaining the cells before downstream processing of the polypeptide of interest (at least paragraphs 0007-0009, 0010-0011, Fig. 1). Therefore, it would be obvious that additional culture medium is added to the bioreactor with the ATF retaining the cells before downstream processing of the polypeptide of interest in another vessel/bioreactor with an ATF that retains the polypeptide of interest and collection of the polypeptide of interest.
Regarding instant claim 20, Zhou et al. disclose producing a biological substance by perfusion culturing of a cell culture in the bioreactor with the ATF retaining the cells before downstream processing of the polypeptide of interest (at least paragraphs 0007-0009, 0010-0011, Fig. 1).
Regarding instant claims 23-24, Zhou et al. disclose the biological substance of interest is a recombinant protein, including a secreted polypeptide, including immunoglobulins and antibodies (at least paragraph 0063) and Becker et al. also disclose the polypeptide of interest is an antibody (at least p. 2, 80).
Regarding instant claims 25-26, Zhou et al. disclose further downstream processing, including chromatography steps (at least paragraph 0091) and Becker et al. disclose that the TFF unit operations are particularly suited to process cell culture solutions prior to downstream, e.g. chromatographic, purification and isolation processes that are used to bring the product stream to final formulation and/or purity (at least p. 6-7). Therefore, it would be obvious to further purify the polypeptide of interest collected by or from the vessel/bioreactor with an ATF that retains the polypeptide of interest with an additional downstream purification step, such as a chromatography purification step.
Regarding instant claim 27, Zhou et al. disclose additional downstream processing includes chromatography, including affinity chromatography (paragraph 0091), where art-known affinity chromatography is Protein A affinity chromatography (paragraph 0070). Becker et al. also disclose the TFF unit operations can be combined with downstream standard purification processes known in the art, such as affinity purification (p. 7), where the affinity chromatography is Protein A chromatography (p. 47). Therefore, it would be obvious to further purify the polypeptide of interest collected by or from the vessel/bioreactor with an ATF that retains the polypeptide of interest with an additional downstream purification step, such as a Protein A chromatography step.
Regarding instant claim 28, Zhou et al. disclose the ATF for retaining the cells has a pore size of about 0.8 µm to about 0.5 µm (at least paragraph 0013).
Regarding instant claim 30, Becker et al. disclose that the polypeptide of interest is about 10 kD to about 300 kD, including to about 100 kD (at least p. 18). Becker et al. disclose the TFF (or ATF) for retaining the polypeptide of interest has a cut-off of 30 kD to 50 kD (p. 19). Therefore, it would have been obvious to arrive at an ATF for retaining the polypeptide of interest having cut-off of about 30 kD to 50 kD by routine optimization.
Regarding instant claim 32, Zhao et al. disclose the cells in the cell culture are mammalian cells (at least paragraphs 0057-0058) and Becker et al. disclose the cells for producing the molecules of interest are mammalian cells (p. 51, 60).
Regarding instant claim 34, Zhao et al. disclose the cell culture medium is a defined culture medium (at least paragraph 0062).
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656