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 .
Status of the Claims
Claims 1-5, 7, 9-10, 15, 19, 21-24, and 27-30 are pending (claim set as filed on 10/19/2023).
Priority
This application is a 371 of PCT/US2021/054915 filed on 10/14/2021, which has a provisional application no. 63/092,327 filed on 10/15/2020.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 07/17/2023, 05/06/2025, and 08/04/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the Examiner.
Drawings
The drawings filed on 04/13/2023 have been accepted.
Abstract Objection
The abstract of the disclosure is objected to because it does not comply with the proper language and format (see MPEP 608.01(b)). Appropriate correction is required.
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as “means” and “said” should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns”, “The disclosure defined by this invention”, or “The disclosure describes”, etc.
Claim Rejections - 35 USC §102, Anticipation
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.
Claims 1, 3-5, 9-10, and 27-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bransby (US 2019/0337979 A1 - cited by the ISA and in the IDS filed on 07/17/2023).
Bransby’s general disclosure relates to methods, devices and systems for filtration of biological fluids, including filtration of bioreactor fluids; separating such cell debris from products of interest, including expressed target proteins, such as monoclonal antibodies, among others (see abstract & ¶ [0001], [0006]).
Regarding claim 1, Bransby teaches “filtration methods that comprise: (a) passing a first fluid that comprises cells, cell debris and a targeted product produced by the cells through a first filter such that the first fluid is separated by the first filter into a first retentate comprising the cells and a first permeate comprising the targeted product and a first portion of the cell debris that passes through the first filter; (b) combining resin beads having affinity for the targeted product with the first permeate such that a second fluid is formed that comprises the resin beads with bound target product and the first portion of the cell debris; and (c) passing the second fluid through a second filter such that the second fluid is separated by the second filter into a second retentate comprising the resin beads with the bound target product and second permeate comprising a second portion of the cell debris that passes through the second filter” (see ¶ [0007], [0030], [0054]-[0056], & Figure 6). Bransby teaches “the use of 1.0 μm up to 5.0 μm thick wall hollow fiber tangential flow filters employed in systems of this type have been shown to consistently pass nearly 100% of monoclonal-antibody-sized proteins for harvest from cell culture. However, a certain amount of cell debris also passes through such filters along with the protein. Therefore, a polishing filter is typically used to further separate the cell debris from the protein” (see ¶ [0002]-[0005]).
Regarding claims 3-5 pertaining to the filters, Bransby teaches the first filter has a mean pore size ranging from 1 μm to 8 μm, typically ranging from 1-2 μm (see ¶ [0015]-[0020], [0038]-[0039], & Figures 1-5 for the filters).
Regarding claims 9-10 pertaining to the filtration flow, Bransby teaches a first tangential flow filter and the second filter is a second tangential flow filter (see ¶ [0018], [0039]).
Regarding claims 27-28 pertaining to the biomolecule, Bransby teaches the targeted product is a protein, a monoclonal antibody or a polyclonal antibody (see ¶ [0013]).
Claim Rejections - 35 USC §103, Obviousness
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 non-obviousness.
Claims 1-5, 7, 9-10, 15, 19, 21-24, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (WO 2020/088180 A1) in view of Nakai (US 2019/0322975 A1) - both references cited by the ISA and in the IDS filed on 07/17/2023.
Zhou’s general disclosure relates to method and system for culturing cells and harvesting biologics (see abstract & ¶ [0002]).
Zhou teaches “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 at different rates and wherein the cell culture is passed through a separation system to continuously harvest the biological substance … The process of the present disclosure provides a considerable advantage in terms of PVCD (peak viable cell density) and Qp (Cell specific productivity). As a result, the present process can result in an improved productivity of the desired biological substance” (see ¶ [0007]-[0009], and claims). Zhou teaches the cells may be cultured for various durations of days (see Example 1).
Regarding claim 2 pertaining to the eukaryotic cell, Zhou teaches the cells may be animal cells, in particular mammalian cells (see ¶ [0058]).
Regarding claims 3, 5, and 29-30 pertaining to the filter characteristics, Zhou teaches “the biological substance produced is continuously harvested by the separation system with a hollow fiber filter. In at least one embodiment, the pore size or molecular weight cut-off of the hollow fiber filter is chosen such that the hollow fiber filter does not retain the biological substance of interest but retains the cells. Therefore, the biological substance produced by the cells are harvested and the cells are retained in the culture. In some embodiments, the pore size of the hollow fiber filter is about 0.08 μm to about 0.5 μm, preferably about 0.1 μm to about 0.5 μm, more preferably about 0.2 μm or about 0.45 μm” (see ¶ [0013]). Any filter may be used as the separation system, as long as the pore size or molecular weight cut-off (MWCO) is chosen such that the cells but not the biological substance of interest is retained (see ¶ [0086]). Zhou teaches using delta V controller to control temperature at 36.5°C, at a pH range of about between 7.2 and 6.8 and at DO at 40% air saturation and a hollow fiber filtration whose pore was 50 KD to retain both the cell and the biological product in the culture broth (see ¶ [0105]).
Regarding claim 9 pertaining to the filtration flow, Zhou teaches the separation system with a hollow fiber filter is an Alternating tangential flow (ATF) or Tangential flow filtration (TFF) device (see ¶ [0014], [0088]-[0089]). Zhou teaches process parameters with various flow rates (mL/min) or productivity (g/L/h) (see, e.g., Tables 1-4).
Regarding claims 19 and 29-30’s limitations pertaining to the bioreactor conditions, Zhou teaches the bioreactor maintains a favorable environment for the cells by providing the suitable culture conditions such as mixing, temperature, pH, oxygen concentration etc. (see ¶ [0056]). Cell culture conditions suitable for the methods of the present disclosure are those that are typically employed and known for perfusion culturing of cells or any combination of those methods, with attention paid to pH, dissolved oxygen (O2), and carbon dioxide (CO2), agitation and aeration, and temperature (see ¶ [0077]-[0079]). Zhou teaches using delta V controller to control temperature at 36.5°C, at a pH range of about between 7.2 and 6.8 and at DO at 40% air saturation and a hollow fiber filtration whose pore was 50 KD to retain both the cell and the biological product in the culture broth (see ¶ [0105]).
Regarding claims 21-22 pertaining to the harvesting step(d), Zhou teaches the process for producing a biological substance by perfusion culturing of a cell culture in a bioreactor allows for continuously harvest of the biological substance (see ¶ [0007], Figures) and a harvest time duration of from 7-17 days (see Tables 5-6).
Regarding claims 27-28 pertaining to the biomolecule, Zhou teaches the products are produced by cells include proteins or antibodies (see ¶ [0063]-[0067]).
However, Zhou does not teach: a second filter with the characteristics or limitations thereof as seen in claims 1(c), 4, 7, 10, 15, 29(c), and 30(c).
Nakai’s general disclosure relates to a cell culture apparatus and a cell culture method for separating specific components from a cell culture solution by membrane separation treatment (see abstract & ¶ [0002]-[0003]).
Nakai teaches “a cell culture apparatus according to the disclosed technology comprises a culture vessel that stores a cell suspension containing cells; a first filter part that has a first filter membrane that performs membrane separation treatment on the cell suspension extracted from the culture vessel; a first circulation flow path that allows components blocked by the first filter membrane to return to the culture vessel; a second filter part that has a second filter membrane that performs membrane separation treatment on components of the cell suspension permeated through the first filter membrane; a second circulation flow path that allows components permeated through the second filter membrane to return to the culture vessel; and a recovery flow path that recovers components blocked by the second filter membrane. In the cell culture apparatus according to the disclosed technology, an average hole diameter of the first filter membrane is 20 μm or smaller; and 0<B/A ≤ 0.5 is satisfied in a case where the average hole diameter of the first filter membrane is A, and an average hole diameter of the second filter membrane is B” (see ¶ [0011]-[0012], [0056], [0115]-[0118]).
Regarding claim 2 pertaining to the cells, Nakai teaches “cells used for antibody expression are not particularly limited. Examples thereof include animal cells; plant cells; eukaryotic cells such as yeast; prokaryotic cells such as Bacillus subtilis; E. coli; and the like. Animal cells such as CHO cells, BHK-21 cells, and SP2/0-Ag14 cells are preferable, and CHO cells are more preferable” (see ¶ [0039], [0053]).
Regarding claims 3 and 5 pertaining to the first filter, Nakai teaches “the first filter membrane may have an inlet-side opening which is formed on a first surface, and an outlet-side opening which is formed on a second surface opposite to the first surface and is communicated with the inlet-side opening; and the inlet-side opening and the outlet-side opening may be disposed at positions mutually offset in a direction parallel to a membrane surface” (see ¶ [0017]-[0020]). “An average hole diameter of the first filter membrane is preferably larger than 0 and 20 μm or smaller, is more preferably 0.05 μm to 10 μm, is even more preferably 0.1 μm to 9 μm” (see ¶ [0023]-[0024], [0062]-[0076], [0084] & Table 1).
Regarding claims 4 and 7 pertaining to the second filter, Nakai teaches “the second filter membrane may be an ultrafiltration membrane. In this case, a molecular weight cut-off of the second filter membrane is preferably more than 0 kDa and 100 kDa or less, and is more preferably 30 kDa to 70 kDa” (see ¶ [0022], [0063], [0077]-[0089], & Table 1).
Regarding claims 9-10 pertaining to the filtration flow, Nakai teaches a system of the membrane separation treatment by the filters membrane may be a tangential flow system (see ¶ [0014], [0034]-[0035]). In a case of forming alternately reciprocating flow, ATF system of Repligen can be suitably used (see ¶ [0059]).
Regarding claims 23-24 pertaining to the constant stir tank reactor, Nakai teaches “the pump is driven continuously or at a predetermined timing while the membrane separation treatment and the backwash treatment are being performed, and a fresh medium of an approximately the same amount as an amount of a medium sent to the recovery tank via the recovery flow path is supplied to the culture vessel via the medium supply flow path. Accordingly, an amount of a medium in the culture vessel is maintained substantially constant during the culture period” (see ¶ [0098]).
Regarding claims 27-28 pertaining to the biomolecule, Nakai teaches the objective is to
make it possible to improve antibody productivity while reducing an amount of medium used (see ¶ [0010]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ or use a second filter such as taught by Nakai in the method of Zhou for the recovery or harvest of biomolecules of interest. The ordinary artisan would have been motivated to do so is because Nakai teaches a second filter that performs membrane separation treatment on components of the cell suspension permeated through the first filter membrane to recover components blocked by the second filter membrane. In particular, Nakai suggests that “any filter may be used as the separation system, as long as the pore size or molecular weight cut-off (MWCO) is chosen such that the cells but not the biological substance of interest is retained” (see ¶ [0086]). In other words, the use of a dual or plurality of filters allows for improved purification of the desired biomolecules of interest and thereby, leads to better or efficient productivity of the bioreactor system to lower cost. The ordinary artisan would have had a reasonable expectation of success because both of the disclosures are drawn to cell cultivation systems and methods for producing a biological metabolite.
Furthermore, if not expressly taught by the references, based upon the overall objectives provided by Zhou and Nakai with respect maximizing efficiency or productivity of the cell culture processes that can lead to greater product yield (see, e.g., Zhou at ¶ [0006]), the adjustments of particular conventional working conditions (e.g., the bioreactor vessel conditions such as pH/temperature/agitation/rotary/gas levels, cell culture or harvest duration, filtration characteristics such as flow rates) are deemed a matter of judicious selection and routine optimization which is within the purview of the skill artisan. Therefore, the cited prior art disclosure(s) establishes the conditions of variable parameters such that one of ordinary skill in the art would recognize that these condition as result effective variables dependent upon the cell type employed and biomolecule of interest. As discussed above, for example, Zhou teaches the bioreactor maintains a favorable environment for the cells by providing the suitable culture conditions such as mixing, temperature, pH, oxygen concentration etc. (see Zhou at ¶ [0056]). Cell culture conditions suitable for the methods of the present disclosure are those that are typically employed and known for perfusion culturing of cells or any combination of those methods, with attention paid to pH, dissolved oxygen (O2), and carbon dioxide (CO2), agitation and aeration, and temperature (see Zhou at ¶ [0077]-[0079]). Zhou teaches using delta V controller to control temperature at 36.5°C, at a pH range of about between 7.2 and 6.8 and at DO at 40% air saturation and a hollow fiber filtration whose pore was 50 KD to retain both the cell and the biological product in the culture broth (see Zhou at ¶ [0105]). This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning these conditions, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variable which can be met as a matter of routine optimization (MPEP 2144.05 II).
Conclusion
No claims were allowed.
Correspondence Information
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653