The present application is being examined under the pre-AIA first to invent provisions.
Claim 1 is canceled. Claims 2-20 are pending and under consideration.
Priority: This application is a CON of 16908401, filed June 22, 2020, now U.S. patent 12110312, which is a CON of 15493523, filed April 21, 2017, now U.S. Patent 10711034, which is a CON of 14645138, filed March 11, 2015, now U.S. Patent 9657056, which is a CON of 14195481, filed March 3, 2014, now U.S. Patent 9650412, which claims benefit of provisional applications 61/856390, filed July 19, 2013 and 61/775060, filed March 8, 2013.
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 2-20 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 2 is drawn to a process for manufacturing a recombinant therapeutic protein drug substance. Claim 2 then recites that the cells secrete the recombinant therapeutic protein. The language should be consistent throughout the claims for the recombinant therapeutic protein drug substance. Further clarification and/or correction is requested.
Similarly, claims 18-20 recite recombinant therapeutic protein instead of the recombinant therapeutic protein drug substance that is first recited in instant claim 2. Further clarification and/or correction is requested.
Claims 3-17 are included in this rejection because they are dependent on the above claim(s) and fail to cure its defects.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 2-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ransohoff et al. (US 20130260419; IDS 10.10.24) in view of Godawat et al. (2012 Biotechnol J 7: 1496-1508; IDS 10.10.24).
Ransohoff et al. disclose until recently, the majority of biopharmaceutical and biological products have been manufactured and purified at very modest scale, by inefficient batch processing techniques (paragraph 0004). Ransohoff et al. disclose the development of a continuous processing technology for the purification of biopharmaceuticals and biological products for increasing manufacturing productivity and efficiency (paragraph 0009), using continuous unit operations (paragraphs 100-101). Ransohoff et al. disclose unit operations in a manufacturing process of a biological product can benefit from continuous multicolumn or multistage operation; this has been demonstrated for the capture chromatography step by conversion from a batch operation to a continuous counter-current simulated moving bed (SMB) chromatography (paragraph 0100). In a batch operation, clarified conditioned media from a bioreactor is applied to a capture chromatography column, followed by wash, elution, cleaning (regeneration), and equilibration steps, with each step being completed before the next step is begun. In a continuous counter-current SMB multicolumn system, multiple columns are employed and then multiple steps are run simultaneously on different columns; utilizing a continuous flow, multicolumn system permits the capacity of the columns to be reduced, thus allowing a large bioreactor volume to be processed using small diameter columns (instead of scaling up column size to accommodate feed of a bioreactor by batch capture chromatography). See the operation of a SMB multicolumn system as illustrated in Fig. 10A-10E (paragraph 0100).
One of the initial unit operations in any biological product manufacturing process will be a capture step; the capture unit operation is commonly an affinity chromatography process, but depending on the target biological product it can also advantageously utilize any other suitable separation technique, such as hydrophobic interaction chromatography (HIC), affinity chromatography, ion exchange chromatography, and the like (paragraph 0121).
Ransohoff et al. disclose an exemplary manufacturing process for a biopharmaceutical process (Fig. 2A) where each block of the diagram represents a unit of operation, showing a cascade of connected unit operations that are running continuously and simultaneously, so that ideally no shutdown or interruption of the process occurs, and no unit operation needs to be delayed to wait for a previous operation to be completed (paragraph 0106). It is disclosed the first block represents a bioreactor in which a cell culture is produced, for example, by growing transformed host cells that express and secrete the biopharmaceutical (in this instance an antibody) into the cell culture medium, where the secreted biopharmaceutical product is clarified before transferring to the next unit of operation, where the next block represents a capture chromatography step (paragraph 0107). It is disclosed that the upstream processes involving creation of the biological product is conducted in a bioreactor and may be a continuous process, including perfusion cell culture (paragraph 0090). Ransohoff et al. disclose the throughput of the capture chromatography is transferred or fed continuously to at least one additional unit of operation, which include, depending on the biopharmaceutical product, include hydrophobic interaction chromatography, cation exchange chromatography, affinity chromatography, size exclusion chromatography, micro- or nano-filtration, and combinations thereof, where filtration would filter viruses, membrane adsorption operations, such as ion-exchange, remove product-specific impurities including virus adsorption, reasonably performed in any order (at least paragraphs 0089, 0100-0101, 0106-0107, 0121-0122, p. 16 claim 3(e)). Ransohoff et al. disclose a single unit operation may be designed to accomplish multiple objectives in the same operation (paragraph 0089).
As noted, Ransohoff et al. disclose that the upstream processes involving creation of the biological product is conducted in a bioreactor and may be a continuous process, including perfusion cell culture (paragraph 0090). Ransohoff et al. disclose that the cell culture in the bioreactor expresses or secretes the recombinant protein product into the cell culture medium, where the conditioned medium containing the recombinant protein product is clarified to remove cells and cell debris (at least paragraphs 0019-0020, 0107). Ransohoff et al. do not explicitly teach monitoring cell density in the cell culture.
Godawat et al. disclose integrated and continuous processing of recombinant proteins offers advantages over batch or semi-batch processing traditionally used in the biotechnology industry (p. 1496). Godawat et al. disclose a multicolumn periodic counter-current chromatography (PCC) system as a continuous purification step that is integrated with a perfusion cell culture process (p. 1496). Godawat et al. disclose cell lines producing a recombinant protein of interest were grown in perfusion bioreactors in a defined media; maintaining a constant cell density in the reactor and monitoring the cell density (p. 1497). Godawat et al. disclose an ATF™ (alternating tangential flow) system containing a polyethersulfone tangential flow membrane was used to retain the cells in the bioreactor; the clarified harvest (permeate) was either collected into a harvest bag or pumped to the PCC system (p. 1497).
It would have been obvious to one of ordinary skill in the art at the time of the invention to combine the references and arrive at the claimed process for manufacturing a recombinant therapeutic protein drug substance, the process comprising (a) culturing cells in a perfusion bioreactor comprising a liquid culture medium under conditions that allow the cells to secrete a recombinant therapeutic protein drug substance into the liquid culture medium, wherein the density of the cells are monitored and at least 90% of the liquid culture medium volume free of cells are continuously or periodically removed from the perfusion bioreactor and are fed into a MCCS; (b) capturing the recombinant therapeutic protein drug substance from the liquid culture medium with the MCCS; and (c) purifying and polishing the recombinant therapeutic protein drug substance by performing one or more of a hydrophobic interaction chromatography, cation exchange chromatography, affinity chromatography, size exclusion chromatography, micro- or nano-filtration, and combinations thereof, to yield the recombinant therapeutic protein drug substance, where the process is integrated and continuous (instant claims 2, 15). The motivation to do so is given by the prior art. Ransohoff et al. disclose a method for producing a recombinant therapeutic protein, comprising continuous culture of cells producing or secreting the recombinant therapeutic protein in a perfusion bioreactor, where the conditioned medium containing the recombinant protein is clarified to remove cells and cell debris. Ransohoff et al. disclose the advantages of converting a chromatography step, including the capture chromatography step, from a batch operation to a continuous counter-current simulated bed chromatography. In a continuous counter-current SMB multicolumn system, multiple columns are employed and then multiple steps are run simultaneously on different columns; utilizing a continuous flow, multicolumn system permits the capacity of the columns to be reduced, thus allowing a large bioreactor volume to be processed using small diameter columns (instead of scaling up column size to accommodate feed of a bioreactor by batch capture chromatography). Ransohoff et al. further disclose the throughput of the capture chromatography is transferred or fed continuously to at least one additional unit of operation, which include, depending on the biopharmaceutical product, include virus inactivation (at least Fig. 2A). Ransohoff et al. disclose a single unit operation may be designed to accomplish multiple objectives in the same operation (paragraph 0089). Godawat et al. also disclose integrated and continuous processing of recombinant proteins offers advantages over batch or semi-batch processing traditionally used in the biotechnology industry (p. 1496). Godawat et al. disclose a multicolumn PCC system as a continuous purification step is integrated with a perfusion cell culture process, where cell lines producing a recombinant protein of interest are grown in perfusion bioreactors in a defined media, maintained at a constant cell density in the reactor and monitored (p. 1496-1497). Godawat et al. disclose an ATF™ system containing a polyethersulfone tangential flow membrane is used to retain the cells in the bioreactor, where the clarified harvest (permeate) is then collected into a harvest bag or pumped to the PCC system (p. 1497). Therefore, it would have been obvious to modify the teachings of Ransohoff et al. by at least incorporating the steps of monitoring cell density to maintain cell density at a steady state and continuously flowing the cell culture into a cell retention system as suggested by Godawat et al. to arrive at the claimed process steps, because doing so allows more efficient manufacturing of the recombinant therapeutic protein drug substance. One of ordinary skill would have a reasonable motivation of success because Ransohoff et al. and Godawat et al. disclose continuous processing methods for biological products can be applied to the purification of any biological product and is more efficient than batch processing techniques, where continuous processing comprises a MCCS comprising a capturing operation and then further purification by another MCCS (Ransohoff et al.).
Regarding instant claim 3, Ransohoff et al. disclose simulated moving bed chromatography provides a way of continuous processing in a capture unit operation; the continuous purification is aided by integrated valve modules, such as the valve manifold, which can be programmed for automatic switching of column feeds (at least paragraph 0122).
Regarding instant claim 4, Ransohoff et al. disclose in a continuous counter-current SMB multicolumn system, multiple columns are employed and then multiple steps are run simultaneously on different columns; utilizing a continuous flow, multicolumn system permits the capacity of the columns to be reduced, thus allowing a large bioreactor volume to be processed using small diameter columns (instead of scaling up column size to accommodate feed of a bioreactor by batch capture chromatography). See the operation of a SMB multicolumn system as illustrated in Fig. 10A-10E (paragraph 0100).
Regarding instant claims 5-7, 16, Ransohoff et al. disclose the throughput of the capture chromatography is transferred or fed continuously to at least one additional unit of operation, which include, depending on the biopharmaceutical product, include hydrophobic interaction chromatography, cation exchange chromatography, affinity chromatography, size exclusion chromatography, micro- or nano-filtration, and combinations thereof, where filtration would filter viruses, membrane adsorption operations, such as ion-exchange, remove product-specific impurities including virus adsorption, reasonably performed in any order (at least paragraphs 0089, 0100-0101, 0106-0107, 0121-0122, p. 16 claim 3(e)), where an unit operation may be designed to accomplish multiple objectives in the same operation (paragraph 0089). Therefore, Ransohoff et al. reasonably disclose including an additional MCCS for purifying the recombinant therapeutic protein drug substance after a capturing operation from a first MCCS.
Regarding instant claim 8, Ransohoff et al. disclose simulated moving bed chromatography provides a way of continuous processing in a capture unit operation; the continuous purification is aided by integrated valve modules, such as the valve manifold, which can be programmed for automatic switching of column feeds (at least paragraph 0122). Therefore, it would be obvious that the additional MCCS noted above includes column switching.
Regarding instant claim 9, Ransohoff et al. disclose in a continuous counter-current SMB multicolumn system, multiple columns are employed and then multiple steps are run simultaneously on different columns; utilizing a continuous flow, multicolumn system permits the capacity of the columns to be reduced, thus allowing a large bioreactor volume to be processed using small diameter columns (instead of scaling up column size to accommodate feed of a bioreactor by batch capture chromatography). See the operation of a SMB multicolumn system as illustrated in Fig. 10A-10E (paragraph 0100). Therefore, it would be obvious that the additional MCCS noted above utilizes at least two chromatography columns.
Regarding instant claims 10-11, Godawat et al. disclose an ATF™ (alternating tangential flow) system containing a polyethersulfone tangential flow membrane was used to retain the cells in the bioreactor; the clarified harvest (permeate) was either collected into a harvest bag or pumped to the PCC system (p. 1497).
Regarding instant claims 12-14, Ransohoff et al. disclose the transformed CHO cells are grown in the perfusion bioreactor (at least paragraph 0107) and Godawat et al. also disclose the CHO cells producing mAb are grown in perfusion bioreactors (p. 1497). Therefore, it would be obvious that the transformed CHO cells are grown in suspension.
Regarding instant claim 17, Ransohoff et al. disclose obtaining a composition comprising a product of interest substantially free of undesired components, from the units of operation performed. Therefore, it would have been obvious to formulate a pharmaceutical composition comprising the recombinant therapeutic protein.
Regarding instant claims 18-20, Ransohoff et al. disclose the recombinant therapeutic protein drug substance is any target protein (at least paragraph 0090) and Godawat et al. disclose target proteins produced including an antibody and an enzyme (at least p. 1497).
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 2-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12110312 (‘312) in view of Ransohoff et al. (supra) and Godawat et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘312 patent claims are drawn to a process for manufacturing a recombinant therapeutic protein drug substance, the process comprising providing a liquid culture medium comprising a recombinant therapeutic protein that is substantially free of cells removed from a perfusion bioreactor, feeding the liquid culture medium into a MCCS (i.e. or PCCS), capturing the recombinant therapeutic protein by the MCCS, and purifying and polishing the recombinant therapeutic protein. The elements and/or features recited in the instant dependent claims are reasonably disclosed and/or suggested in the dependent claims of the ‘312 patent, which disclose the same variations or features of the MCCS or PCCS. If a feature of the MCCS recited in the instant claims is not explicitly recited in the claims of the ‘312 patent, it would have been obvious to incorporate the feature(s) in the ‘312 patent claims in view of the teachings of Ransohoff et al. and/or Godawat et al. noted above. Therefore, the process for manufacturing a therapeutic protein drug substance using a MCCS (i.e. or PCCS) of the instant claims and the ‘312 patent claims are not patentably distinct from each other.
Claims 2-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10711034 (‘034) in view of Ransohoff et al. (supra) and Godawat et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘034 patent claims are drawn to a process for manufacturing a recombinant therapeutic protein, the process comprising providing a liquid culture medium comprising a recombinant therapeutic protein that is substantially free of cells removed from a perfusion bioreactor, feeding the liquid culture medium into a MCCS (i.e. or PCCS), capturing the recombinant therapeutic protein by the MCCS, and purifying and polishing the recombinant therapeutic protein. The elements and/or features recited in the instant dependent claims are reasonably disclosed and/or suggested in the dependent claims of the ‘034 patent, which disclose the same variations or features of the MCCS or PCCS. If a feature of the MCCS recited in the instant claims is not explicitly recited in the claims of the ‘034 patent, it would have been obvious to incorporate the feature(s) in the ‘034 patent claims in view of the teachings of Ransohoff et al. and/or Godawat et al. noted above. Therefore, the process for manufacturing a therapeutic protein drug substance using a MCCS (i.e. or PCCS) of the instant claims and the ‘034 patent claims are not patentably distinct from each other.
Claims 2-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 9657056 (‘056) in view of Ransohoff et al. (supra) and Godawat et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘056 patent claims are drawn to a process for manufacturing a recombinant therapeutic protein, the process comprising providing a liquid culture medium comprising a recombinant therapeutic protein that is substantially free of cells removed from a perfusion bioreactor, feeding the liquid culture medium into a MCCS (i.e. or PCCS), capturing the recombinant therapeutic protein by the MCCS, and purifying and polishing the recombinant therapeutic protein. The elements and/or features recited in the instant dependent claims are reasonably disclosed and/or suggested in the dependent claims of the ‘056 patent, which disclose the same variations or features of the MCCS or PCCS. If a feature of the MCCS recited in the instant claims is not explicitly recited in the claims of the ‘056 patent, it would have been obvious to incorporate the feature(s) in the ‘056 patent claims in view of the teachings of Ransohoff et al. and/or Godawat et al. noted above. Therefore, the process for manufacturing a therapeutic protein drug substance using a MCCS (i.e. or PCCS) of the instant claims and the ‘056 patent claims are not patentably distinct from each other.
Claims 2-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of U.S. Patent No. 9650413 (‘413) in view of Ransohoff et al. (supra) and Godawat et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘413 patent claims are drawn to a process for manufacturing a recombinant therapeutic protein, the process comprising providing a liquid culture medium comprising a recombinant therapeutic protein that is substantially free of cells removed from a perfusion bioreactor, feeding the liquid culture medium into a MCCS (i.e. or PCCS), capturing the recombinant therapeutic protein by the MCCS, and purifying and polishing the recombinant therapeutic protein. The elements and/or features recited in the instant dependent claims are reasonably disclosed and/or suggested in the dependent claims of the ‘413 patent, which disclose the same variations or features of the MCCS or PCCS. If a feature of the MCCS recited in the instant claims is not explicitly recited in the claims of the ‘413 patent, it would have been obvious to incorporate the feature(s) in the ‘413 patent claims in view of the teachings of Ransohoff et al. and/or Godawat et al. noted above. Therefore, the process for manufacturing a therapeutic protein drug substance using a MCCS (i.e. or PCCS) of the instant claims and the ‘413 patent claims are not patentably distinct from each other.
Claims 2-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 9650412 (‘412) in view of Ransohoff et al. (supra) and Godawat et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘412 patent claims are drawn to a process for manufacturing a recombinant therapeutic protein, the process comprising providing a liquid culture medium comprising a recombinant therapeutic protein that is substantially free of cells removed from a perfusion bioreactor, feeding the liquid culture medium into a MCCS (i.e. or PCCS), capturing the recombinant therapeutic protein by the MCCS, and purifying and polishing the recombinant therapeutic protein. The elements and/or features recited in the instant dependent claims are reasonably disclosed and/or suggested in the dependent claims of the ‘412 patent, which disclose the same variations or features of the MCCS or PCCS. If a feature of the MCCS recited in the instant claims is not explicitly recited in the claims of the ‘412 patent, it would have been obvious to incorporate the feature(s) in the ‘412 patent claims in view of the teachings of Ransohoff et al. and/or Godawat et al. noted above. Therefore, the process for manufacturing a therapeutic protein drug substance using a MCCS (i.e. or PCCS) of the instant claims and the ‘412 patent claims are not patentably distinct from each other.
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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