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 .
Applicants filed a Preliminary Amendment of January 12, 2023, in which they canceled claims 9, 12, 15, 17-25, 29, and 34-37. Claims 1-8, 10-11, 13-14, 16, 26-28, and 30-33 are under examination.
Information Disclosure Statement
The Information Disclosure Statement filed July 21, 2023 has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
The phrase “high density,” when used in the context of culturing cells refers to a cell line or variant thereof, that is able to grow to densities of greater than about 1 x 106 cells/ml while maintaining cell viability in excess of about 80% (paragraphs [0056]-[0057]).
Claim Objections
Claims 6 and 26-27 are objected to because of the following informalities:
At claim 6, line 2, "(LiAc)” should be inserted after “acetate.”
Applicant is advised that should claim 26 be found allowable, claim 27 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 3, 6-8, 10-11, 13-14, 16, and 31 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 pre-AIA the applicant regards as the invention.
At claim 3, lines 2-5 it is not clear what is meant by "a derivative” of the 293 cells, 293F cells, PER-C6 cells, CHO cells, CapT cells, COS cells, COS-7 cells, or Sp2/0 cells. How like any of these cells must cells be in order to be considered a derivative of the cells? Are there any characteristics of the cells that must be present in a population of cells in order to be considered derivatives of the cells?
Claim 6 recites the limitation "said expression composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Is this the same composition as the expression enhancer composition of claim 1, or is this a different expression composition?
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “sugars”, and the claim also recites “including galactose” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 7 , 10, 13, and 16 depend from claim 6, and are therefore included in this rejection.
Claim 7 recites the limitation "the expression composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Is this the same composition as the expression enhancer composition of claim 1, or is this a different expression composition?
Claim 8 depends from claim 7, and is therefore included in this rejection.
Claim 10 recites the limitation "the expression composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Is this the same composition as the expression enhancer composition of claim 1, or is this a different expression composition?
Claim 11 depends from claim 10, and is therefore included in this rejection.
Claim 13 recites the limitation "the expression composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Is this the same composition as the expression enhancer composition of claim 1, or is this a different expression composition?
Claim 14 depends from claim 13, and is therefore included in this rejection.
Claim 16 recites the limitation "the expression composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Is this the same composition as the expression enhancer composition of claim 1, or is this a different expression composition?
Claim 31 recites the limitation "said expressed protein" in line 1. There is insufficient antecedent basis for this limitation in the claim. Is this the same protein as the recombinant protein of claim 1?
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 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.
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)(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.
(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 1-8, 26-28, and 30-31 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hildinger et al. (U.S. Patent Application Publication No. 2009/0023186, published January 22, 2009, and cited in the Information Disclosure Statement filed July 21, 2023). It is noted that the ‘186 publication was both published prior to the effective filing date of the instant application (102(a)(1)) and has a prior filing date to the instant application (102(a)(2)). Thus, this rejection is made under both 35 U.S.C. 102(a)(1) and 102(a)(2).
Regarding claim 1, Hildinger discloses culturing cells for the production of diagnostic and therapeutic proteins (abstract). Hildinger discloses a two-stage cell growth method, where the cells can be grown to maximum cell density in a suspension culture, transferred to a production medium, at which time the valproic acid can be added (paragraph [0025]). Hildinger discloses that the gene expression can be transient, which a gene expression vector encoding the protein of interest is transfected into the cells, where the cells are grown in a growth medium, transferred to a transfection medium, and then transferred into a production medium, where only the production medium comprises the valproic acid (paragraphs [0029] and [0065]). Hildinger discloses that plasmid DNA encoding a protein of interest (a light chain and/or a heavy chain of an IgG antibody) (paragraph [0087]).
Regarding claim 2, Hildinger discloses that the cell density at the time of valproic acid addition is at least 1 x 106 cells to at least 4 x 106 cells, which is considered high density (paragraph [0020]).
Regarding claim 3, Hildinger discloses that the cells may be HEK 293E cells and that valproic acid can be added at between 0.002 mmol/l and 200 mmol/l (paragraphs [0018] and [0031]).
Regarding claim 4, Hildinger discloses that the HEK 293E cells are suspension-adapted for growth under high density conditions, which is interpreted as being a derivative of 293F cells (paragraphs [0077] and [0083]).
Regarding claim 5, Hildinger discloses transfecting the cells in a volume of 0.5 mL, and incubating the cells for 4 hours with shaking, after which the valproic acid was added to a range of 1.3 mmol/l to 11.3 mmol/l, and 5 days post-transfection (paragraphs [0083]-[0090]).
Regarding claims 6-7, Hildinger discloses that adding valproic acid (an expression enhancer composition) to the cultured cells increase the overall batch yield and titer, and that valproic acid increases expression at a greater level than sodium butyrate (abstract).
Regarding claim 8, Hildinger discloses that valproic acid can be added at between 0.002 mmol/l and 200 mmol/l (paragraphs [0018] and [0031]).
Regarding claims 26-27, Hildinger discloses no additional replenishment, replacement or supplementation to the growth medium after transfection (paragraph [0088]).
Regarding claim 28, Hildinger discloses that the cell density at the time of valproic acid addition is at least 1 x 106 cells to at least 4 x 106 cells, which is considered high density (paragraph [0020]). Hildinger discloses that the medium is serum-free medium (paragraph [0083]). Hildinger discloses that cell viability is sustained at high cell density and results in high specific productivity for an extended period of time, which is interpreted as viability of at least 80% (paragraph [0079]).
Regarding claim 30, Hildinger discloses that the cells and protein can be harvested after transfection (paragraph [0036]).
Regarding claim 31, Hildinger discloses that the obtained protein may be purified (paragraph [0036]).
Hildinger discloses each and every limitation of claims 1-8, 26-28, and 30-31, and therefore anticipates claims 1-8, 26-28, and 30-31 under both 35 U.S.C. 102(a)(1) and 102(a)(2).
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.
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 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 6, 10-11, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hildinger et al. (U.S. Patent Application Publication No. 2009/0023186, published January 22, 2009, and cited in the Information Disclosure Statement filed July 21, 2023) in view of Chun et al. (25 Biotechnology Letters 315-319 (2003), and cited in the Information Disclosure Statement filed July 21, 2023).
Hildinger discloses culturing cells for the production of diagnostic and therapeutic proteins, as discussed above.
Hildinger fails to disclose or suggest that the expression enhancer can be sodium propionate or butyric acid.
Regarding claim 6, Chun discloses that both sodium priopionate and butyric acid can enhance the production of recombinant proteins, such as Factor VIII, in CHO cells in a protein-free medium (abstract).
Regarding claim 10, Chun discloses that sodium propionate can be the expression enhancer (abstract and page 315, column 2, second paragraph).
Regarding claim 11, Chun discloses that sodium propionate can be at a concentration of 1 mM or 4 mM (page 318, column 1, first paragraph and Figure 2).
Regarding claim 16, Chun discloses that sodium butyrate (butyric acid) can be the expression enhancer (abstract and page 317, column 2, first paragraph and Figure 2).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute the expression enhancers of Chun (sodium propionate and sodium butyrate) for the valproic acid of Hildinger because each of the three expression enhancers have been shown to increase the expression of recombinant proteins in cell culture. As such, one of ordinary skill in the art would be able to substitute one well-known expression enhancer for another well-known expression enhancer with a predictable and reasonable expectation of success.
Claims 6, 13-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hildinger et al. (U.S. Patent Application Publication No. 2009/0023186, published January 22, 2009, and cited in the Information Disclosure Statement filed July 21, 2023) in view of Nakashima et al. (U.S. Patent No. 5,378,612, issued January 3, 1995, and cited in the Information Disclosure Statement filed July 21, 2023).
Hildinger discloses culturing cells for the production of diagnostic and therapeutic proteins, as discussed above.
Hildinger fails to disclose or suggest that the expression enhancer can be sodium propionate or butyric acid.
Regarding claim 6, Nakashima discloses that both lithium acetate and butyric acid can enhance the production of recombinant proteins, such as Factor VIII, in CHO cells in a protein-free medium (column 2, line 42 to column 3, line 13 and column 5, lines 40-49).
Regarding claim 13, Nakashima discloses that lithium acetate can be the expression enhancer (column 5, lines 40-49 and Table 4).
Regarding claim 11, Nakashima discloses that lithium acetate can be at a concentration of 10 mM (page 318, column 1, first paragraph and Figure 2).
Regarding claim 16, Nakashima discloses that sodium butyrate (butyric acid) can be the expression enhancer (column 2, line 42 to column 3, line 13 and column 5, lines 40-49).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute the expression enhancers of Nakashima (butyric acid and lithium acetate) for the valproic acid of Hildinger because each of the three expression enhancers have been shown to increase the expression of recombinant proteins in cell culture. As such, one of ordinary skill in the art would be able to substitute one well-known expression enhancer for another well-known expression enhancer with a predictable and reasonable expectation of success.
Claims 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Hildinger et al. (U.S. Patent Application Publication No. 2009/0023186, published January 22, 2009, and cited in the Information Disclosure Statement filed July 21, 2023) in view of Backliwal et al. (36(15) Nucleic Acids Research e96 1-7 (2008), and cited in the Information Disclosure Statement filed July 21, 2023).
Hildinger discloses culturing cells for the production of diagnostic and therapeutic proteins, as discussed above.
Hildinger fails to disclose or suggest that the cells can express an expression enhancing protein.
Regarding claims 32-33, Backliwal discloses that HEK 293E cells can be used to produce recombinant antibodies using transient transfection under serum-free conditions (abstract). Backliwal discloses that the cell densities are high cell densities at 4 million cells/ml (abstract). Backliwal discloses that addition of valproic acid provides for enhanced protein production (abstract). Backliwal further discloses that cell cycle regulators p18 and p21 can be added to the vector, which also enhances protein production (abstract, page 1, column 2, second full paragraph, and page 2, column 1, first paragraph).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Backliwal’s expression enhancer proteins in the methods disclosed by Hildinger, such as p18 and/or p21 because these proteins could be added to the plasmids of Hildinger because the plasmids are all known expression plasmids and one of ordinary skill in the art would have a predictable and reasonable expectation of success in doing so. It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to include Backliwal’s expression enhancing protein sequences in the plasmid disclosed and suggested by Hildinger because this will provide for expression of a protein that enhances the expression of the desired recombinant and therapeutic proteins produced by the method disclosed by Hildinger. The motivation to do so would be the enhancement of recombinant protein production, which is desirable in a protein production method where the proteins can be used for diagnostics and/or therapeutics.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-8, 10-11, 13-14, 16, 26-28, and 30-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 24-26 of U.S. Patent No. 10,066,000.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘000 patent and the instant application claim methods of producing a recombinant protein using expression enhancers.
Regarding claims 1 and 7, the ‘000 patent claims a method of producing a recombinant protein in 293 cells comprising obtaining a suspension culture of 293 cells in a high density culture medium having a cell density between about 2 x 106 to about 2 x 107 cells/ml; transfecting the cells with an expression vector containing a sequence capable of producing an expressed protein; incubating the transfected cells for a first period of time; contacting the transfected cells with a valproic acid expression enhancer; incubating the transfected cells in the presence of the valproic acid for a period of time such that the vector expresses the protein; harvesting the transfected cells after the second period of time; wherein the culture medium is not replaced, replenished, or supplemented after the transfection (claim 1).
Regarding claim 2, the ‘000 patent claims that the cells are adapted for high density growth conditions (claims 2-3).
Regarding claims 3-4, the ‘000 patent claims that the cells are 293F cells, which is interpreted as encompassing derivatives of 293F cells (claim 4).
Regarding claim 5, the ‘000 patent claims that the culture is in the range of about 200 µL to about 5 L (claim 5).
Regarding claim 6, the ‘000 patent claims an addition expression enhancer can be sodium propionate, lithium acetate, DMSO, galactose, amino acid mixtures, butyric acid (claim 6).
Regarding claim 8, the ‘000 patent claims that the valproic acid is in the range of about 0.20 mM to about 25 mM (claims 7-8).
Regarding claim 10, the ‘000 patent claims that the expression composition further comprises sodium propionate (claim 9). Regarding claim 11, the ‘000 patent claims that the final concentration of sodium propionate in the culture is in the range of about 0.2 mM to about 100 mM (claims 10-11). Regarding claim 13, the ‘000 patent claims that the expression enhancer composition further comprises lithium acetate (LiAc) (claim 12). Regarding claim 14, the ‘000 patent claims that the final concentration of LiAc in the culture is in the range of about 0.25 to about 25 mM (claims 13-14).
Regarding claim 16, the ‘000 patent claims the expression enhancer composition further comprises butyric acid (claim 15).
Regarding claims 26-27, the ‘000 patent claims that the culture medium is not replaced, replenished, or supplemented after the transfection (claim 1). Regarding claim 28, the ‘000 patent claims that the high density culture medium is a serum-free/protein-free chemically defined culture medium capable of promoting the growth of transfected cells at cell densities in excess of 2.5×10.sup.6 cells/ml with cell viability remaining in excess of 80% (claim 23).
Regarding claim 30, the ‘000 patent claims harvesting the transfected cells after the second period of time (claim 1). Regarding claim 31, the ‘000 patent claims purifying said expressed protein (claim 24). Regarding claim 32, the ‘000 patent claims that the cells express one or more expression enhancing proteins (claim 25). Regarding claim 33, the ‘000 patent claims that the expression enhancing proteins are selected from the list consisting of AKT, P18, P21, Bcl-X.sub.L, and PKBa (claim 26).
Therefore, the claims are not deemed to be patentably distinct.
Claims 1-8, 10-11, 13-14, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,498,949.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘949 patent claims a transient expression system for the production of recombinant proteins and the instant application claims a method of producing a recombinant protein using expression enhancers.
Regarding claims 1,7, 10, the ‘949 patent claims a system for producing a recombinant protein in 293 cells comprising obtaining a suspension culture of 293 cells in a high density culture medium having a cell density between about 2 x 106 to about 2 x 107 cells/ml; transfecting the cells with an expression vector containing a sequence capable of producing an expressed protein; incubating the transfected cells for a first period of time; contacting the transfected cells with a valproic acid expression enhancer; incubating the transfected cells in the presence of the valproic acid or sodium propionate for a period of time such that the vector expresses the protein; harvesting the transfected cells after the second period of time; wherein the culture medium is not replaced, replenished, or supplemented after the transfection (claim 1).
Regarding claim 2, the ‘949 patent claims that the cells are adapted for high density growth conditions (claim 2).
Regarding claims 3-4, the ‘949 patent claims that the cells are 293 cells adapted for cell culture, which is interpreted as encompassing derivatives of 293F cells (claims 4 and 7).
Regarding claim 5, the ‘000 patent claims that the culture is in the range of about 200 µL to about 5 L (claim 5).
Regarding claim 6, the ‘949 patent claims an addition expression enhancer can be sodium propionate, lithium acetate, DMSO, galactose, or butyric acid (claim 3).
Regarding claim 8, the ‘949 patent claims that the valproic acid is in the range of about 0.20 mM to about 25 mM (claims 14-16).
Regarding claim 10, the ‘949 patent claims that the expression composition further comprises sodium propionate (claim 1). Regarding claim 11, the ‘949 patent claims that the final concentration of sodium propionate in the culture is in the range of about 0.2 mM to about 100 mM (claims 11-13). Regarding claim 13, the ‘949 patent claims that the expression enhancer composition further comprises lithium acetate (LiAc) (claim 4). Regarding claim 14, the ‘949 patent claims that the final concentration of LiAc in the culture is in the range of about 0.25 to about 25 mM (claims 5-6). Regarding claims 28, the ‘949 patent claims that the high density culture medium is a serum-free/protein-free chemically defined culture medium capable of promoting the growth of transfected cells at cell densities in excess of 2.5×10.sup.6 cells/ml with cell viability remaining in excess of 80% (claims 8-10).
Therefore, the claims are not deemed to be patentably distinct.
Claims 1-8, 10-11, 26-28, and 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 13-15, 19-21, 23-27, and 35-37 of copending Application No. 19/157,224 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘224 application and the instant application claim methods of producing a recombinant protein using expression enhancers.
Regarding claims 1, 7, and 30, the ‘224 application claims a method of producing a recombinant protein in 293 cells comprising obtaining a suspension culture of 293 cells in a high density culture medium having a cell density between about 2 x 106 to about 2 x 107 cells/ml; transfecting the cells with an expression vector containing a sequence capable of producing an expressed protein; incubating the transfected cells for a first period of time; contacting the transfected cells with a valproic acid expression enhancer; incubating the transfected cells in the presence of the valproic acid for a period of time such that the vector expresses the protein; harvesting the transfected cells after the second period of time; wherein the culture medium is not replaced, replenished, or supplemented after the transfection (claims 1 and 4).
Regarding claim 2, the ‘224 application claims that the cells are adapted for high density growth conditions (claim 15).
Regarding claims 3-4, the ‘224 application claims that the cells are suspension adapted 293F cells, which is interpreted as encompassing derivatives of 293F cells (claim 13).
Regarding claim 5, the ‘224 application claims that the culture is in the range of about 200 µL to about 5 L (claim 29).
Regarding claim 6, the ‘224 application claims an addition expression enhancer can be sodium propionate, lithium acetate, DMSO, galactose, amino acid mixtures, butyric acid (claims 19-21).
Regarding claim 8, the ‘224 application claims that the valproic acid is in the range of about 0.20 mM to about 25 mM (claims 23-24).
Regarding claim 10, the ‘224 application claims that the expression composition further comprises sodium propionate (claim 25). Regarding claim 11, the ‘224 application claims that the final concentration of sodium propionate in the culture is in the range of about 0.2 mM to about 100 mM (claims 26-27).
Regarding claims 26-27, the ‘224 application claims that the culture medium is not replaced, replenished, or supplemented after the transfection (claim 14). Regarding claim 28, the ‘224 application claims that the high density culture medium is a serum-free/protein-free chemically defined culture medium capable of promoting the growth of transfected cells at cell densities in excess of 2.5×10.sup.6 cells/ml with cell viability remaining in excess of 80% (claim 35).
Regarding claim 30, the ‘224 application claims harvesting the transfected cells after the second period of time (claim 13). Regarding claim 31, the ‘224 application claims purifying said expressed protein (claim 36). Regarding claim 32, the ‘224 application claims that the cells express one or more expression enhancing proteins (claim 37).
Therefore, the claims are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Baldi et al. (801 Methods in Molecular Biology 13-26 (January 1, 2012), and cited in the Information Disclosure Statement filed July 21, 2023) disclose large scale transfection of mammalian cells to provide for production of recombinant proteins in HEK-293 cells (abstract). Baldi discloses that these cells are cultivated in serum-free suspension to yield 1 g/L in a 10-day process (abstract). Baldi discloses transfection of the cells at high density (i.e., the cells are adapted to grow to high density in suspension) of about 20 x 106 cells/mL (abstract). The cells are then diluted and valproic acid added, after which the resultant recombinant protein is affinity purified (abstract). Because Baldi discloses the same method of producing recombinant proteins as Hildinger, cited above, Baldi is deemed to be cumulative prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached on Monday - Thursday 8:00 AM - 6:30 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, NEIL HAMMELL can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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