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 .
Claim Objections -Necessitated by Amendment
Claims 20, 21, are objected to under 37 CFR 1.75 as being a substantial duplicate of claim 12,13. When claims are so similar that they cover the same subject matter, it is appropriate to object to the duplicate after allowing one claim, per MPEP § 608.01(m). Claim 20 and claim 12 claim the same method with the same limitation of using a CHO cell. Claim 21 and claim 13 depend from the aforementioned claims and add the same limitation that the CHO cell must be dhfr-.
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.
Claim Rejections - 35 USC § 112 – Necessitated by Amendment
Claim 1 is rejected under 35 U.S.C. 112(b) as indefinite because the recitation “wherein the mammalian cell has been directly adapted to grow in a first cell culture media having 0.03 mg/L or less IGF-1 and single cell cloned” fails to inform, with reasonable certainty, those skilled in the art of the scope of the claim. In particular, it is unclear what objective criteria establish that the mammalian cell is “single cell cloned,” whether this language refers to the currently cultured production cells or only to an ancestral derivation event in development of the cell line, and what boundaries distinguish a “single cell cloned” cell from a non-single-cell-cloned cell for purposes of the claimed method. The claim therefore does not particularly point out and distinctly claim the subject matter regarded as the invention. See MPEP § 2173 et seq.
Response to Arguments
In regard to applicant’s response/remarks (filed 2/19/2026) to the rejection of claim 1 and claim 5 under 112(b), the examiner has found the amendment to Claim 1 (wherein the cell comprises the heterologous nucleic acid), and the specification information cited by applicant, (defining comparable and heterologous) sufficient. The previous 112(b) rejections of Claim 1 and claim 5 are hereby withdrawn.
Claim Rejections - 35 USC § 102 – Maintained
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 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.
Claim(s) 1-4, 7-10 and 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2008/033517A2, published on 3/20/2008.
WO2008/033517A2 discloses, “a method for producing a protein comprising culturing mammalian cells comprising a nucleic acid encoding the protein in the culture medium of the invention; and transferring the culture of into a cell culture production medium, such that the protein is produced” (“summary of the invention” paragraph 19). In an exemplary embodiment, “anti-IL-18 antibody expressing CHO cell line was cultivated in a growth medium 2xP (SR371), and later produced antibody in a production medium 3xP (SR372)” (page 64). Table 4 (page 63) defines the composition of the growth (SR371) and production (SR372) media. The exemplary formulations include 8mg/kg recombinant human insulin (rHu insulin) in SR371 and 12mg/kg rHu insulin in SR372 media, and do not include IGF1 (table 4, page 63). The source further discloses that, “…the resulting expressed protein can be recovered...Fractionation processes can include but are not limited to one or more steps of filtration, centrifugations…” (page 51). This anticipates claim 1, as the reference discloses growing cells that express a protein of interest (anti-IL18 expressing CHO cells) in a media containing 0.03mg/ml or less IGF1, and then changing the media to a production media that contains 0.05mg/L or less IGF1 (rH insulin is included in place of IGF1 in both medias in the exemplary embodiment), and then recovering the protein of interest. Methods to recover the expressed protein are outlined (centrifugation).
Claim 2 defines the second culture media as having less than 0.03mg/L, claim 3 defines the second culture media as having no IGF1, and claim 4 defines the first cell culture media as having no IGF1. These are all anticipated by WO2008/033517A2 in the exemplary embodiment for the production of anti-IL18 antibody. Specifically, both the growth (SR371) and production (SR372) media compositions contain rHu insulin and no IGF1 (table 4, page 63).
Claim 7 defines the titer of recombinant protein produced using methods of claim 1 must be at least 50mg/L at day 10. This claim is anticipated by WO2008033517A2 in the aforementioned exemplary embodiment. Specifically, “The anti-IL-18 antibody expressing CHO cell line was cultivated in growth medium…and later produced antibody in a production medium…for a final titer of approximately 1g/L” (page64). Table 34 (page 95) shows the anti-IL18 antibody titer over time under all conditions tested, and it is noted that titer is above 50mg/L for every condition at day 10.
Claim 8 defines the expressed protein is an antigen binding protein, and claim 9 defines the antigen binding protein of claim 8 is selected from the group consisting of monoclonal antibodies, bi-specific T cell engagers, immunoglobulins, Fc fusion proteins and peptibodies. Both claims are anticipated by WO2008/033517A2 in the aforementioned exemplary embodiment. Specifically, “The anti-IL-18 antibody expressing CHO cell line was cultivated in growth medium…and later produced (monoclonal) antibody in a production medium…for a final titer of approximately 1g/L” (page64).
Claim 10 defines the mammalian cell culture process utilizes a fed-batch culture process, a perfusion culture process or a combination thereof. This claim is anticipated by WO2008/033517A2. “The invention also provides an improved fed batch method and related cell culture media for producing proteins in mammalian cell culture, eg. CHO cells. One aspect of the invention is a fed batch method of producing a protein comprising culturing mammalian cells comprising a nucleic acid encoding the protein in a cell culture comprising a cell culture production medium; and feeding the mammalian cells by adding a hydrolysate enrichment solution and a basal enrichment solution to the cell culture during a time period.” (page 10). The exemplary embodiment of “Adalimumab Fed Batch Process” outlined on page 70 details the fed-batch process. Specifically, under the “methods” section on page 73 it discloses, “To inoculate the reactor, a vial was thawed and expanded following the Humira seed train process description…Then reactor was topped off to 13L level with production media (SR-286)”. Refer to table 2 on page 60 for media formulations and note that all listed growth and production medias, including SR-286, use rH insulin and no IGF1.
Claim 12 defines the mammalian cell to be a CHO cell. This claim is anticipated by WO2008/033517A2. In the exemplary embodiment, “anti-IL-18 antibody expressing CHO cell line was cultivated in a growth medium 2xP (SR371), and later produced antibody in a production medium 3xP (Sr372).” (page 64).
Claim 13 defines that the CHO cell outlined in claim 12 is also deficient in dihydrofolate reductase or is a glutamine synthetase knock out cell. This claim is anticipated by WO2008/033517A2. “All antibodies, including anti-IL12, anti-IL18 and anti-EPO/R antibodies were fully human IgG1 antibodies expressed by transfected dhfr(-) CHO cell lines as described previously” (page 64).
Claim 14 defines that the recovered protein of interest is purified and formulated in a pharmaceutically acceptable formulation. This claim is anticipated by WO2008/033517A2. “The invention also optionally encompasses further formulating the proteins. By the term “formulating” is meant that the proteins can be buffer exchanged, sterilized, bulk-packaged and/or packaged for a final user. Such compositions can comprise an effective amount of the protein, in combination with other components such as physiologically acceptable diluent, carrier, or excipient.” (page 52).
Claim Rejections - 35 USC § 102 – Necessitated by Amendment
Claims 20-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2008/033517A2.
WO2008/033517A2 discloses a method of producing a monoclonal antibody (mAB) using a dhfr(-) CHO cell line comprising a heterologous nucleic acid encoding a protein (aka a mAB) of interest, wherein the CHO cell has been adapted to grow in a media containing 0.03mg/L or less of IGF-1, and expresses the protein of interest (mAB) in a second cell culture media containing 0.05mg/L or less IGF-1 and purifying the protein. WO2008/033517A2 discloses in an exemplary embodiment, “anti-IL-18 antibody expressing CHO cell line was cultivated in a growth medium 2xP (SR371), and later produced antibody in a production medium 3xP (SR372)” (page 64). Table 4 (page 63) defines the composition of the growth (SR371) and production (SR372) media. The exemplary formulations do not include IGF1 (table 4, page 63). The source further discloses that, “…the resulting expressed protein can be recovered...Fractionation processes can include but are not limited to one or more steps of filtration, centrifugations…” (page 51). Importantly, “All antibodies, including anti-IL12, anti-IL18 and anti-EPO/R antibodies were fully human IgG1 antibodies expressed by transfected dhfr(-) CHO cell lines as described previously” (page 64). Finally, “Such compositions can comprise an effective amount of the protein, in combination with other components such as physiologically acceptable diluent, carrier, or excipient.” (page 52). This anticipates claim 20 (method of producing protein of interest from a CHO cell adapted to a culture medium that is IGF1- media and used to produce protein in a second media that is IGF1-), claim 21 (the CHO cell is dhfr-), claim 22 (pharmaceutically acceptable formulation), and claim 23 and claim 24 (the protein produced is a mAB towards IL18).
Response to Arguments
Applicant’s arguments have been considered but are not persuasive. WO ’517 inherently teaches that the recombinant mammalian cells are adapted to grow in the recited first medium because the reference discloses actual cultivation of those cells in low-IGF/IGF-substituted growth medium. A cell that is successfully grown in that medium necessarily is adapted to grow in that medium. See MPEP § 2112.
As to the recitation that the mammalian cell was single cell cloned, claim 1 is directed to a production method and does not recite any present structural or functional property of the cell resulting from that prior cloning history. The “single cell cloned” language therefore merely describes the provenance of the starting cell line and does not meaningfully distinguish the claimed method over WO ’517 absent a claimed resulting difference in the cell itself. See MPEP § 2113. Accordingly, the rejection under 35 U.S.C. § 102(a)(1) is maintained.
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.
Claims 5-6 and claim 11 are rejected under 35 U.S.C 103 as being unpatentable over WO2008/033517A2.
The teachings of WO2008/033517A2 are described above (page 6, claim 1). WO2008/033517A2 does not specifically teach the limitations of claim 5 and claim 6. WO2008/033517A2 does teach the optimization of cell culture conditions. “The invention relates to improved cell culture media, including media for growing cells for protein expression and cell culture production media optimized for protein expression. The invention also includes optimized methods and media formulations for high protein expression in mammalian cell culture.” (page 1, “background of the invention”). In particular, the optimization of temperature (table 12 page 74), pH and time in culture (table 17 page 81), and media composition (table 21 page 82) for cell growth (turbidity).
Therefore, WO2008/033517A2 provides explicit teachings/motivations to optimize culture conditions to achieve desired growth characteristics, and illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of skill in the art prior to the effective filing date to optimize culture conditions (media composition, temperature, pH, time in culture, etc.) to achieve a desired growth rate and doubling time.
The same rationale applies to Claim 11, which defines inoculating a bioreactor of at least 100L with least 0.5 *10^6 to 3.0*10^6 cells/ml in a serum free medium containing 0.03mg/L or less IGF1.
The teachings of WO2008/033517A2 are described above (page 6, claim 1). While WO2008/033517A2 does not specifically teach the limitations of claim 11, it is disclosed that, “In the new process for anti-IL18 production, although the cells were still cultivated in medium SR371 during seed training, medium SR372 was used in the seed bioreactor one-step before the production stage” (page 66). According to table 4 (page 63), it is clear that the SR372 media formulation has been significantly changed from SR371, which results in significant effects on cell growth characteristics (as noted above) and cell viability density over time (table 35 page 96).
Thus, WO2008/033517A2 provides an explicit teaching/motivation to optimize culture parameters which determine growth kinetics, inoculation parameters, and total culture volumes through routine experimentation. Therefore, claim 11 represents a result-effective variable and it would have been obvious to one of ordinary skill in the art before the effective filing date to determine the workable ranges for inoculation cell concentrations and total culture volumes.
In the case of a result-effective variable, the discovery of an optimum value of the variable in a known process is ordinarily within the skill of the art. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, it would have been obvious to one of ordinary skill in the art to determine through routine experimentation the optimum or workable ranges of parameters such as doubling-time, growth rate, and cell seeding concentration since the variables would have been recognized as result-effective.
Response to Arguments
Applicant’s arguments have been considered and are not persuasive. Applicant argues, “This limitation is not merely about optimizing growth conditions: it requires a specific comparative outcome where cells adapted to low/no IGF-1 media maintain growth rates similar to non-adapted cells of the same lineage. WO '517 does not address this concept.” However, the examiner re-notes the previous citation of WO ‘571 stating, “The anti-IL-18 antibody expressing CHO cell line was cultivated in growth medium…and later produced (monoclonal) antibody in a production medium…for a final titer of approximately 1g/L” (page64). This disclosure indicates protein production rates (which are linked to growth rates) are similar to other K1-derived dhfr- mAB producing CHO-cells, as supported by Kim, DY et al 2006 (See fig 3). Applicant also argues, “Claim 6 requires a doubling time of less than 30 hours for cells that have been directly adapted to grow in media having 0.03 mg/L or less IGF-1. WO '517 provides no data on doubling times for cells grown in IGF-1-free conditions, nor does it suggest that directly adapted cells would achieve such doubling times.” The examiner points to the disclosure of WO ‘517 example 4.1 titled “Effect of sodium butyrate on growth and productivity of an IL-18-producing CHO cell line cultivated in growth medium” (paragraph 3 on page 93) and in particular Table 32. (page 94). Every condition listed in table 32 result in a cell population at least doubling from day 0 to day 3 in growth medium (note growth medium is SR-371).
The applicant argues “Claim 11 requires inoculating a bioreactor of at least 100 L with specific cell densities in serum-free media with 0.03 mg/L or less IGF-1. The Examiner's routine optimization rationale does not account for the fact that the claimed method requires cells that have been "directly adapted" to low/no IGF-1 conditions.” This objection has been addressed above (see response to arguments for 102(a)(1) above).
Accordingly, the rejections under 35 U.S.C. § 103 is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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