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 .
All of the amended claims submitted on 12/20/2022, claims 1-19, are under examination on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 12/20/2022 is in compliance with 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: VVD stands for "vessel volumes/day" or "vessel volumes per day" and not "container volume/day", as indicate by the specification on p. 3.
Appropriate correction is required.
Claim Objections
Claims 1, 6-7, and 16 are objected to because of the following informalities: the claims recite “VVD”, which is an acronym that stands for "vessel volumes/day" or "vessel volumes per day". However, the acronym “VVD” needs to be "spelled out" since it is not as recognizable in the art as an acronym like DNA, which is broadly and unequivocally understood by one of ordinary skill in the art. Accordingly, the acronym VVD should be expanded to its full form (e.g., “vessel volumes/day” or “vessel volumes per day”). Appropriate correction is required.
Claims 1, 6, and 16 is objected to because of the following informalities: “and” should be added to the end of line 5 (claims 1 and 16) or line 6 (claim 6) after the semicolon. Appropriate correction is required.
Claims 2 and 8 are objected to because of the following informalities: “and” should be inserted on line 2 before “the continuous perfusion device”. Appropriate correction is required.
Claims 5, 11, and 19 are objected to because of the following informalities: “the host cell” on line 1 should be changed to “293 cell”. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: “or” should be inserted in line 2 after “AcdC68,” and before AdC3. Appropriate correction is required.
Claim 15 is objected to because of the following informalities: there is a typographical error on line 3, “followings” should read “following”; line 3 should have “and/or” inserted after “E protein,” and before “N protein.”; and “comprises a gene of a structural protein of SARS-CoV-2” on lines 1-2 should instead read “comprises a gene encoding a SARS-CoV-2 structural protein”. Appropriate correction is required.
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 6-19 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.
Claims 16-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: inoculating an adenovirus. The preamble of claim 16 indicates that the method is for preparing an adenovirus vector vaccine. However, the claim lacks an active step involving an adenovirus. It is not clear if and where an adenovirus is involved in the method, and whether an adenovirus vector vaccine can be prepared without the presence of an adenovirus. The method’s active steps appear to merely involve culturing cells. Claims 17-19 do not cure the deficiencies of claim 16 and are thus also indefinite and rejected.
Regarding claim 6, it recites “the following steps: (1) inoculating host cells for cell culture; (2) starting perfusion at a perfusion rate of 1-3 VVD after a cell density reaches 1x106-5x106 cells/mL; (3) adjusting the perfusion rate to 2-4 VVD after the cell density grows to 5x106-10x106 cells/mL; and (4) inoculating virus for culture.” The metes and bounds of the claim are unclear because it is not apparent if step (4) is re-inoculation or the first inoculation of host cells once step (3) is completed. Claims 7-15 depend from claim 6 but do not resolve this lack of clarity.
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.
Claims 1-11 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Nikolay, et al. (Perfusion Control for High Cell Density Cultivation and Viral Vaccine Production. Animal Cell Biotechnology - Methods in Molecular Biology, vol 2095. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0191-4_9, pp. 141-168; published 12/20/2019; hereinafter referred to as “Nikolay”) in view of Luo, et al. (CN110964688A, published 4/7/2020, machine translation due to original document being in Chinese language; hereinafter referred to as “Luo”).
The claimed invention encompasses a method for culturing an adenovirus host cell or for preparing an adenovirus vector vaccine, comprising the following steps: (1) inoculating host cells for culture; (2) starting perfusion at a perfusion rate of 1-3 VVD after a cell density reaches 1x106-5x106 cells/mL; and (3) adjusting the perfusion rate to 2-4 VVD after the cell density grows to 5x106-10x106 cells/mL (claims 1 and 16). In a specific embodiment, the perfusion is performed by using a continuous perfusion device; and the continuous perfusion device uses an alternating tangential flow filtration, wherein a filtration pore size of a hollow fiber column is 0.1-0.8 µm (claim 2). In another embodiment, a concentration of glutamine is maintained at 2 mM or more in the cell culture (claims 3 and 17). In specific embodiments, the host cell is a 293 cell (claims 4 and 18), or more specifically an HEK293 cell or an HEK293.CS cell (claims 5 and 19).
Another embodiment of the claimed invention encompasses a method for producing an adenovirus, comprising the following steps: (1) inoculating host cells for cell culture; (2) starting perfusion at a perfusion rate of 1-3 VVD after a cell density reaches 1x106-5x106 cells/mL; (3) adjusting the perfusion rate to 2-4 VVD after the cell density grows to 5x106-10x106 cells/mL; and (4) inoculating virus for culture (claim 6). In a specific embodiment, in step (4), the culture is a perfusion culture at a perfusion rate of 1-3 VVD (claim 7). In a specific embodiment, the perfusion is performed by using a continuous perfusion device; and the continuous perfusion device uses an alternating tangential flow filtration, wherein a filtration pore size of a hollow fiber column is 0.1-0.8 µm (claim 8). In another embodiment, a concentration of glutamine is maintained at 2 mM or more in the cell culture (claim 9). In specific embodiments, the host cell is a 293 cell (claim 10), or more specifically an HEK293 cell or an HEK293.CS cell (claim 11).
The Prior Art
Nikolay teaches the design and optimization of perfusion processes for very high cell densities require careful selection of strategies for optimal perfusion rate control, and discusses various options, such as reactor volume exchange regimes and perfusion rate control based on process variables such as cell concentration and metabolite or by-product concentration, to guarantee high cell-specific virus yields (Abstract). Nikolay further discloses that a typical process for cell culture-derived virus production comprises two phases in which cells are first propagated in a cultivation vessel and then infected with the virus, and that in order to intensify a virus production process with suspension cells, both phases can be optimized, the host cells can be cultivated to higher cell concentrations before infection and process parameters at time point of infection can be changed for improved virus replication (p. 142, para. 1). Nikolay also discloses that to obtain high cell densities, perfusion bioreactor systems are required to replace spent medium with fresh medium while suspension cells are retained, and several options for perfusion rate control have been established to supply cells continuously with sufficient amounts of substrates and to remove waste products (p. 142, para. 2).
Nikolay teaches that reactor volume exchange regimes describe the perfusion flow rate in terms of the total working volume, and perfusion rates can be set to a fixed flow rate or increased step-wise with progressing cultivation time, but not necessarily coupled to the actual cell concentration (pp. 142-143, bridging para.). Alternatively, cell-specific perfusion rate control can be determined by measuring the viable cell concentration, which results in a constant cell-specific perfusion rate (p. 144, para. 2). Nikolay’s Figure 1 summarizes the perfusion rate control strategies, where RV/d (reactor volume exchange rate, akin to perfusion rate), is in blue (p. 143, Fig. 1). Nikolay also discloses that when cells are infected at certain cell concentrations, a decrease in cell-specific virus yields can be observed for many viruses such as adenovirus, and that limitation in yields can be overcome by replacing spent cell growth medium by fresh medium at the time of infection and expanding the bioreactor working volume during the infection phase (pp. 164-165, bridging para.). Nikolay further discloses cultivation of cells with 2 mM L-glutamine (p. 146, last para.; and Nikolay in general), that the perfusion bioreactor may have a vertically positioned hollow fiber membrane (p. 151), and that an alternating tangential filtration unit using a 0.2 µm pore size membrane may be utilized (p. 148).
However, Nikolay does not specifically teach starting perfusion at a perfusion rate of 1-3 VVD after a cell density reaches 1x106-5x106 cells/mL or adjusting the perfusion rate to 2-4 VVD after the cell density grows to 5x106-10x106 cells/mL, or where the host cell is a 293 cell, or specifically an HEK293 cell.
Luo teaches cell culture methods of perfusion culture of animal cells, including HEK293 cells (Abstract; p. 3; claim 6). Luo’s methods comprise inoculating the animal cells into a bioreactor for 2-3 days, perfusion culture for 30-35 days, and adjusting the perfusion rate to 1.2 to 2 RV/day (Abstract). Luo further discloses use of bioreactors with a hollow fiber column with a pore diameter of 0.22 µm connected by a silicon pipe, using alternating tangential flow (p. 6).
It would have been obvious to one of ordinary skill in the art to modify the cell perfusion and viral vaccination production methods of Nikolay to incorporate use of perfusion rates and HEK293 cells disclosed by Luo. Although Nikolay does not specifically teach starting perfusion at a perfusion rate of 1-3 VVD after a cell density reaches 1x106-5x106 cells/mL or adjusting the perfusion rate to 2-4 VVD after the cell density grows to 5x106-10x106, it would have been obvious to one of ordinary skill in the art through routine optimization, since Nikolay discloses that perfusion rate can be adjusted depending on the cell density or time. See MPEP §2144.05. One of ordinary skill in the art would have been motivated to obtain a high cell density for virus propagation. There would be a reasonable expectation of success because Nikolay discloses that perfusion processes should be optimized, and Luo discloses that HEK293 cells may be grown in a continuous perfusion process and provides sample perfusion rates and particular cell densities. Therefore, claims 1-11 and 16-19 were prima facie obvious before the priority date of the instant invention.
Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Nikolay and Luo as applied to claims 1-11 and 16-19 above, and further in view of Cortin (Biotechnol Prog. 2004 May-Jun;20(3):858-63. doi: 10.1021/bp034237l. PMID: 15176892; hereinafter referred to as “Cortin”).
In specific embodiments of the claimed invention, the adenovirus is a human adenovirus or a chimpanzee adenovirus (claim 12), or is selected from: AdHu5, AdHu4, AdHu7, AdHu11, AdHu26, AdHu55, AdC68, or AdC3 (claim 13). In another embodiment, the adenovirus is a recombinant adenovirus comprising a coding exogenous gene (claim 14).
The Prior Art
The teachings of Nikolay and Luo are described above. However, they do not disclose a human adenovirus, AdHu5, the adenovirus being recombinant and comprising an exogenous coding gene.
Cortin discloses high-titer adenovirus vector production in 293S cell perfusion culture (Title), wherein a adenovirus production is performed in a perfusion system (Abstract). Cortin further discloses that gene therapy is a promising approach to treat diseases, where viral vectors are used for the transfer of therapeutic genes (p. 858, col. 1, para. 1). Cortin also discloses that recombinant adenovirus vectors are used in such gene therapy protocols, and perfusion culture is a means to improve the yield of the viral vector production (p. 858). Additionally, Cortin specifically discloses a serotype 5 adenovirus containing a GFP expression cassette (p. 859, col. 1, para 3).
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Nikolay and Luo to use propagate the serotype 5 adenovirus disclosed by Cortin. One of ordinary skill in the art would have been motivated to obtain a propagate adenovirus. There would be a reasonable expectation of success because Nikolay’s method was successful in propagating other viruses, Nikolay contemplates adenovirus specifically, and Cortin discloses that high-titer adenovirus vectors may be produced by cell perfusion culture. Therefore, claims 12-14 were prima facie obvious before the priority date of the instant invention.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Nikolay, Luo, and Cortin (supra) as applied to claims 12-14 above, and further in view of Wu, et al. (Nat Commun. 2020 Aug 14;11(1):4081. doi: 10.1038/s41467-020-17972-1. PMID: 32796842; hereinafter referred to as “Wu”).
In another embodiment of the claimed invention, the adenovirus comprises a gene of a structural protein of SARS-CoV-2, the structural protein is selected from: one or more of the following: S protein, M protein, E protein, and N protein (claim 15).
The Prior Art
The teachings of Nikolay, Luo, and Cortin are described above. However, they do not disclose an adenovirus comprising a gene encoding a structural protein of SARS-CoV-2, such as S protein.
Wu discloses a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV), which protected mice completely against mouse-adapted SARS-CoV-2 infection after a single vaccination (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the methods disclosed by Nikolay, Luo, and Cortin to propagate an adenovirus vector encoding a SARS-CoV-2 spike protein. One of ordinary skill in the art would have been motivated to propagate the adenoviral vector for later use as a vaccine against SARS-CoV-2, as disclosed in Wu. There would be a reasonable expectation of success because Cortin describes propagation of adenovirus vectors by perfusion culture and Wu discloses adenoviral vectors encoding SARS-CoV-2 spike protein. Therefore, claim 15 was prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is allowed.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671