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 .
Priority
Receipt is acknowledged of some of the certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 1/14/2022, 11/13/2023, 2/27/2024, and 8/8/2024 have been considered.
Status of the Application/Claims
Claims 1-10, filed 07/16/2025, are pending. Claims 1-10 are the subject of the present Official action.
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 1-10 is 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.
The term “high-density” in claim 1 is a relative term which renders the claim indefinite. The term “high-density” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The practice of the inoculation step of the cell culture method is rendered indefinite by the use of the term “high-density”. Dependent claims 2-10 are likewise rejected under 35 U.S.C. 112(b) because they do not correct the deficiencies of the claim upon which they depend.
Claims 2 and 10 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 claims 2 and 10, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Description of examples and preferences is properly set forth in the specification rather than in a single claim. A preferred embodiment may also be set forth in another independent claim or in a dependent claim. If stated in a single claim, preferences lead to confusion over the intended scope of the claim. See MPEP § 2173.05(c).
Claims 7-10 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 7 attempts to claim a use of a method for the culture of mammalian cells without setting forth any steps involved in the process. The claim is indefinite because it merely recites using the method for cell culture of claim 1 without any active, positive steps delimiting how this use is practiced. See MPEP 2173.05(p), section II. Claims 8-10 are additionally rejected under 35 U.S.C. 112(b) as they are dependent on Claim 7.
Claim Rejections - 35 USC § 102
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 and 6-10 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bruninghaus et al. (US 2015/0353896 A1; hereinafter Bruninghaus).
With regard to Claim 1, Bruninghaus teaches a high-density cell culture method for producing a recombinant protein, comprising (a) thawing a frozen cell bank and disposing a plurality of recombinant mammalian cells into a first culture medium comprised within a vessel, such as a flask or bag, to provide a first cell culture; (b) batch culturing the first cell culture to a cell density range of about 1.0x106 cells/mL to about 5.0x106 cells/ mL; (c) disposing a volume of the first cell culture of step (b) into a second culture medium comprised within a perfusion bioreactor, such as the last-stage cell amplification tank of the instant case, to provide a second cell culture with an initial cell density in a range of about 0.25×106 cells/mL to about 0.5×106 cells/mL; (d) perfusion culturing the second cell culture to a cell density range of between about 5×106 cells/mL to about 120×106 cells/mL; and (e) disposing a volume of the second cell culture of step (d) into a third culture medium comprised within a production bioreactor, such as the culture fermentation tank of the instant case, to provide a production cell culture with an initial cell density in a range of about 0.25×106 cells/ mL to about 8×106 cells/mL. See Figures 1-2 and Claims 1-2 of Bruninghaus. Bruninghaus also teaches harvesting the recombinant protein from the production cell culture. See Claim 34 and page 2, paragraph 0012 of Bruninghaus.
With regard to Claim 2, Bruninghaus teaches that the perfusion bioreactor can also be equipped with a mechanical device that is capable of removing a volume of the second liquid culture medium from the bioreactor and a filter within the mechanical device that removes the cells from the second liquid culture medium during the process of transfer of the second liquid culture medium out of the bioreactor, such as an alternating tangential flow (ATF) or a tangential flow filtration (TFF) system. Bruninghaus teaches that the bioreactor can also be equipped with one or more pumps, and one or more reservoirs to hold the removed second culture medium and the new culture medium to be perfused into the perfusion bioreactor. See, for example, page 14, paragraph 0086 of Bruninghaus. Bruninghaus also teaches that after perfusion culturing the second cell culture, the cell density range is between about 5×106 cells/mL to about 120×106 cells/mL. This range comprises a cell density of more than 107 cells/mL. See Claim 1 of Bruninghaus. Bruninghaus also teaches that after perfusion culturing the second cell culture, the cell density range is between about 15x106 cells/mL and about 140x106 cells/mL. See page 15 paragraph 0088 of Bruninghaus.
With regard to Claim 3, as stated above Bruninghaus teaches that the high-density perfusion culturing of the second cell culture in step (d) is to provide a cell density range between about 5×106 cells/mL to about 120×106 cells/mL; in step (e) of Bruninghaus, cells are inoculated into a third cell culture medium comprised within a production bioreactor to provide a production cell culture with an initial cell density in a range of about 0.25×106 cells/ mL to about 8×106 cells/mL. See Claim 1 of Bruninghaus. Bruninghaus also teaches that the N-1 perfusion bioreactors of Bruninghaus were able to reach 100×106 viable cells/mL, and could inoculate a 500-L bioreactor at 10×106 viable cells/mL, further reducing the growth phase duration. See page 29 paragraph 0171 of Bruninghaus. Additionally, Bruninghaus teaches that the production cell culture within the production bioreactor can have an initial cell density in a range of between about 9.0x106 cells/mL and about 10x106 cells/mL. See page 17 paragraph 0095 of Bruninghaus. The range comprises an initial cell density in the production bioreactor of more than 107 cells/mL, because about 107 cells/mL comprises more than 107 cells/mL.
With regard to Claim 4, Bruninghaus teaches that the volume of the second culture medium within the perfusion tank can be between 2.0 L and 800 L. See page 12 paragraph 0085 of Bruninghaus. Bruninghaus also teaches that the volume of the second cell culture disposed into the third culture medium, which is the cell culture solution inoculated from the perfusion bioreactor into the production bioreactor, can be between 2.0 L and 800 L, and the appropriate volume of second cell culture to dispose into the third culture medium to arrive at an initial cell density in the range of about 0.25×106 cells/mL to about 107 cells/mL for the production cell culture can be determined from the cell density of the second cell culture and the volume of third culture medium in the production bioreactor. See page 18 paragraph 0095 of Bruninghaus. The volume ranges taught by Bruninghaus include inoculating a cell culture solution with a volume less than or equal to half the volume in the perfusion bioreactor into the production bioreactor. Additionally, Bruninghaus teaches that the production cell culture within the production bioreactor can have an initial cell density in a range of between about 9.0x106 cells/mL and about 10x106 cells/mL. See page 17 paragraph 0095 of Bruninghaus. The range comprises an initial cell density in the production bioreactor of more than 107 cells/mL, because about 107 cells/mL comprises more than 107 cells/mL. Bruninghaus also teaches that the perfusion bioreactor can also be equipped with one or more pumps, and one or more reservoirs to hold the removed second culture medium and the new culture medium to be perfused into the perfusion bioreactor. See, for example, page 14, paragraph 0086 of Bruninghaus. Bruninghaus also teaches that the term “perfusion culturing” is a term of art and refers to cell culture in a vessel that includes the periodic or continuous removal of liquid culture medium present in the vessel and at the same time or shortly thereafter adding substantially the same volume of a replacement liquid culture medium to the vessel. See page 4 paragraph 0045 of Bruninghaus. Bruninghaus also teaches inoculation of cells from the perfusion bioreactor into multiple production bioreactors. See page 28 paragraph 0163 of Bruninghaus. Therefore, Bruninghaus teaches that the perfusion bioreactor is supplemented with the same volume of fresh medium culture for future inoculation into multiple production bioreactors.
With regard to Claim 6, Bruninghaus teaches that the perfusion bioreactor in step (c) has an internal volume range of about 7.5 L to about 1,000L. See page 2, paragraph 0010 of Bruninghaus.
With regard to Claims 7-9, Bruninghaus teaches the use of the cell culture method for the culture of mammalian cells such as CHO or CHO-K1 cells. See page 19 paragraph 0098 of Bruninghaus.
With regard to Claim 10, Bruninghaus teaches that a nucleic acid encoding a recombinant protein can be introduced into the mammalian cells. See page 19 paragraph 0099 of Bruninghaus. Bruninghaus teaches that the recombinant protein harvested from the mammalian cells can be a therapeutic recombinant protein such as an antibody including rituximab which is a bispecific antibody. See page 20 paragraph 0106 of Bruninghaus.
Claim Rejections - 35 USC § 103
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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Bruninghaus (US 2015/0353896 A1), as applied to Claims 1-4 and 6-10 above, and in further view of Tolstrup et al., (WO2009129814A1; hereinafter Tolstrup).
With regard to Claim 5, Bruninghaus does not teach thawing a frozen cell bank and performing amplification culture in a vessel such as a flask or bag in two batches and two perfusion tanks.
Tolstrup teaches methods for manufacturing drug products comprising at least two distinct members of a polyclonal protein, such as a polyclonal antibody, where each distinct member is expressed by a separate population of cells and involves at least an initial separate culturing step of cells expressing the distinct members of the polyclonal protein. See, for example, page 2 lines 15-33 of Tolstrup. Tolstrup also teaches that the term “polyclonal antibody” as used in Tolstrup can also be thought of as a mixture of two or more monoclonal antibodies. See page 6 lines 14-15 of Tolstrup. Tolstrup teaches that the protein production in mammalian cells such as CHO cells may employ a semi-continuous process of cell culturing including the steps from thawing the cells; initial expansion steps in vessels such as shaker flasks, plastic bags, etc.; and subsequent transfer to other bioreactors or fermenters. See, for example, the abstract, page 2 lines 15-33, and page 4 lines 1-18. Tolstrup teaches that the combination of the separate cell cultures can be prior to or during the production stage. The separate manufacturing is performed in parallel and can be continued such that the distinct protein members are kept separate to the point where the drug substance has been purified to the extent required, and then the drug substances are combined to form the final drug product, which comprises at least two distinct members of a polyclonal protein, such as two or more different antibodies targeting the same antigen. See, for example, claim 16 and page 8 lines 5-23 of Tolstrup. Therefore, Tolstrup teaches that cell culture steps from thawing the cell bank and performing amplification culture can be performed on the cell culture in two batches and transferred to separate perfusion bioreactors.
It would have been prima facie obvious to one of ordinary skill in the art to modify the high-density cell culture method of Bruninghaus to include separate culturing and perfusion of the cell populations, in view of Tolstrup, to harvest different monoclonal antibodies from separate cell populations. One of ordinary skill in the art would have been motivated to make such a modification with a reasonable expectation of success to enable parallel production of different monoclonal antibodies to be manufactured into a pharmaceutical composition.
Conclusion
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/H.P./Examiner, Art Unit 1631
/JAMES JOSEPH GRABER/Examiner, Art Unit 1631