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 .
Response to Amendment
Applicant’s remarks and claim amendments received 08/13/2026 have been acknowledged. Claims 1 and 9 have been amended. The claim amendments overcome the rejection under 35 USC 112(b) previously set forth in the Non-Final Rejection of 06/04/2026 and the terminal disclaimer filed overcomes the double patenting rejection.
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.
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 1-5, 7-11, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over De La Cruz (US20030087372A1), hereinafter De La Cruz in view of Lee et al (US20030096402A1), hereinafter Lee, and Winter (US20060051347A1).
De La Cruz discloses methods of culturing mammalian cells in a fed-batch cell culture for the production of a polypeptide of interest, wherein the polypeptide of interest is a monoclonal antibody such as the anti-IgE antibody E25; and the mammalian cells are CHO cells (Abstract, Para. 0008-0014 and Para. 0027-0028). Fed-batch cell culture refers to batch culture in which animal cells (e.g. mammalian cells) and culture medium are supplied to the culturing vessel initially, and additional culture nutrients are fed to the culture during the culturing process (Para. 0050). The cell culture medium refers to a nutrient solution used for growing mammalian cells and comprises at least one component from the following categories:
1) an energy source, usually in the form of a carbohydrate such as glucose;
2) all essential amino acids, and preferably, and most commonly, the basic set of twenty amino acids plus cysteine;
3) vitamins and/or other organic compounds required at low concentrations;
4) free fatty acids; and
5) trace elements, where trace elements are defined as inorganic compounds or naturally occurring elements that are typically required at very low concentrations, usually in the micromolar range (Para. 0082-0087). For example, the culture medium can contain folic acid (vitamin B9), pyridoxal (vitamin B6), riboflavin (vitamin B2), and cyanocbalamin (vitamin B12) (see Table 1, Para. 0146 of Examples). The mammalian cell culture process includes growth and production phases. The growth phase corresponds to the period exponential growth when cells are rapidly dividing, typically lasting about 1-4 days (Para. 0106). During this phase, the cells are contacted with the basal cell culture medium and transformed with expression or cloning vectors encoding the polypeptide of interest (e.g. an antibody) (Para. 0106 and Para. 0114-0117). Following the growth phase, the cells are cultured in a production phase to express the desired polypeptide (Para. 0119-0120). Cell growth has generally plateaued and protein production begins in the production phase (Para. 0120). The cell culture medium is supplemented with glucose and other components during this period in batch additions (Para. 0120-0121). For example, one or more batch feeds comprising nutrient mixtures can be added during the early and mid-production culturing phases to maintain cell viability and productivity. These batch feeds can comprise components at higher concentrations than that of the initial basal medium. Alternatively, the batch feeds can comprise fewer components or components at lower concentrations (Para. 0127 and Para. 0139). As such, the cell culture components (e.g. glucose, B vitamins, etc.) can be varied between the basal medium and feed medium. Temperature in the growth phase is generally maintained within a range of 35° C. and 39° C. The temperature in the production phase is preferably maintained at the same temperature as the growth phase (i.e. 35℃ to 39℃). The polypeptide of interest (e.g. a monoclonal antibody) is finally recovered from the culture medium as a secreted polypeptide or in host cell lysates: the culture medium/lysates is first centrifuged to remove particulate cell debris and thereafter the polypeptide is purified of contaminant soluble proteins/polypeptides via purification methods known in the art such as, but not limited to, gel filtration (Para. 0140-0142).
De La Cruz does not specifically teach a cell culture medium comprising all of the components present at the concentrations recited in the instant claims. Further, concentrating/enriching the purified E25 antibody to at least a 100 mg/mL antibody solution is also not taught.
However, Lee discloses chemically defined culture media for the growth of immortalized cells in order to provide commercially useful amounts of the desired proteins expressed in such cell cultures (Abstract, Para. 0007, Para, 00013, and Claims), wherein the expressed protein is an IgG immunoglobulin of the IgG1, IgG2, IgG3, or IgG4 isotype (Claims 8-10). The immunoglobulin can also be rodent, human, humanized, chimeric, or a fragment thereof such as Fab, Fab’, F(ab’)2, or an scFv (Claims 11 and 12). Suitable immortalized cell lines include CHO cells (Para. 0017). The cell culture media includes at least one of specified buffers, salts, carbohydrates, vitamins, proteins, amino acids, lipids, trace elements, minerals, and the like as described therein. The vitamins can include folate/folic acid (vitamin B9), pyridoxal (vitamin B6), riboflavin (vitamin B2), and cyanocbalamin (vitamin B12) (Para. 0025). The protein or amino acid can include cystine (Para. 0026). The trace elements and minerals can include ferric citrate (Para. 0027). An exemplary formulation comprises – among other ingredients – ferric citrate present at 1-10 mg/L; cystine present at 0.05 – 0.2 g/L (50-200 mg/L); riboflavin (vitamin B2) present at 0.0002-0.0006 g/L (0.2-0.6 mg/L); pyridoxal (vitamin B6) present at 0.002-0.006 g/L (2-6 g/L); folate (vitamin B9) present at 0.002-0.006 g/L (2-6 mg/L); and cyanocbalamin (vitamin B12) present at 0.000005-0.000025 g/L (0.005 – 0.025 mg/L) (Para. 0028). Ferric citrate has a molecular weight of 244.94 g/mol (see PubChem release, OA. Appendix); thus 1-10 mg/L ferric citrate is equivalent to ~4 – 40 uM. A similar chemically defined media (CDM) possessed the capability to support cell growth at a higher density than other chemically defined media as shown in Example 1. Since the basal cell culture medium is used during the growth phase of cells as taught by De La Cruz, then the ferric-citrate containing CDM disclosed by Lee can be used as an initial/basal culture medium. In other words, iron can be present in the basal cell culture medium per instant claim 9.
Winter further discloses a method for preparing highly concentrated antibody products and pharmaceutical formulations via several ultrafiltration and diafiltration steps (Abstract and Summary). A preferred antibody composition of the disclosure includes recombinant humanized monoclonal anti-IgE antibodies (Para. 0066) such as rhuMAb E25 (or E25) as demonstrated in Example 1. Prior to ultrafiltration/diafiltration, the initial antibody product is obtained from a purification step involving, for example, centrifugation, filtration, chromatography, and the like (Para. 0046). Following ultrafiltration /diafiltration, the antibody product is at a concentration of 100 mg/mL or greater, preferably greater than 150 mg/mL, and is suitable for therapeutic administration to humans. The final preparation is also preferably substantially free from any protein aggregation (Para. 0071 and 0073).
It would have been obvious to one of ordinary skill in the art modify the fed-batch cell culture process disclosed by De La Cruz by using the chemically defined cell culture medium disclosed by Lee comprising ferric citrate, cystine; vitamin B2; vitamin B6; vitamin B9; and vitamin B12. One of ordinary skill in the art would have been motivated to do so since the chemically defined cell culture media disclosed by Lee are advantageous for the growth of immortalized cells (e.g. CHO cells) in order to provide commercially useful amounts of the desired proteins expressed in such cell cultures. Since the basal cell culture medium is used during the growth phase of cells as taught by De La Cruz, then the ferric-citrate containing CDM disclosed by Lee can be used as an initial/basal culture medium. In other words, iron is present in the basal medium per instant claim 9. Additionally, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of cystine, ferric citrate, and vitamins B2, B6, B9, and B12 present in the cell culture medium in order to improve the culturing process and production of the desired expressed protein (i.e. the E25 antibody) and arrive at the specific embodiments recited in the instant claims. Moreover, it would have been obvious to artisans to concentrate the purified antibody (e.g. E25 antibody) produced by the culturing process to at least 100 mg/L using ultrafiltration and diafiltration techniques taught by Winter in order to provide antibody products for pharmaceutical formulations and therapeutic human administration. It is noted that the wherein clauses stating that the resulting E25 antibody solution has a color reference standard value of BY4-BY7 according to the European Pharmacopoeia color standards (claim 1) and exhibits no more than 25% acidic charge variants are intended results of the claimed method and thus do not provide patentable distinctiveness over the prior art. The combined teachings of the prior art disclose the active process steps and culture media components in amounts that can be optimized to arrive at the ranges recited in the claims. As such, the cell culture method and media taught by the combined teachings of the prior art can yield an E25 antibody solution having a BY4-BY7 color value. Similarly, the phrase “the E25 antibody solution is used for preparing a pharmaceutical formulation” (claim 2) and the phrase “the pharmaceutical formulation is used for subcutaneous delivery” are statements of intended use that do not result in any structural difference between the claimed invention and the prior art and thus are not given patentable weight (MPEP 2111.02). Therefore, one of ordinary skill in the art would reasonably expect that a fed-batch culture process that uses the chemically defined media disclosed by Lee followed by downstream ultrafiltration/diafiltration of the antibody product as disclosed by Winter can effectively yield the E25 antibody preparation concentrated to at least 100 mg/L and having a B74-BY7 color value.
Response to Arguments
Applicant's arguments filed 08/13/2026 have been fully considered but they are not persuasive.
With respect to the rejection under 35 USC 103, Applicant argues that the claimed media component concentrations unexpectedly reduce the color associated with the expressed protein, even when the expressed protein is highly concentrated. In particular, Applicant points to the Meier Declaration which states that the instant claims are directed to the surprising finding that: “culturing host cells in media comprising certain components at certain concentrations, e.g. from 400 mg/L to 1200 mg/L cystine, is advantageous for obtaining antibody-based drug products that conform to these color standards, despite such concentrations not being optimal for achieving the highest production levels.” Further, Applicant argues that increases in cystine cell culture concentration have a deleterious effect on protein production as well as viable cell density and is associated with the undesirable production of single chain species as noted by the prior art (Jing et al, cited by Applicant).
In addition to being associated with the undesirable production of single chain species, Applicant contends that increased cystine cell culture concentrations are demonstrated in Jing to be associated with other deleterious effects. For example, inclusion of cystine at either 2x (corresponding to 308 mg/L cystine) or 6x concentrations (corresponding to 923 mg/L) reduced the titer, peak viable cell density (VCD), and final VCD of the cell cultures. Titer for the 2x and 6x concentrations were reduced by 10.4% and 62.1%, respectively. Peak VCD for 2x and 6x concentrations were reduced from 100% in the control experiment to 89.0% and 42.9%, respectively. Final VCD for 2x and 6x concentrations were reduced from 100% in the control experiment to 87.8% and 45.9%, respectively. These results clearly indicate that increases in cystine concentration have a significant deleterious effect on protein production (titer) as well as VCD.
Thus, Applicant contends that in view of the Meier Declaration and the arguments presented above, it is clear that one of skill would not have been motivated to modify the teachings of Lee (or De La Cruz or Winter) to increase cystine concentrations to the levels currently claimed or have a reasonable expectation of success that doing so would improve the culturing process or production of the desired expressed protein.
In response to Applicant’s arguments, the Examiner notes that Applicant’s reliance on Jing et al does not support the conclusion that the claimed cell culture conditions, particularly the presence of 400 mg/L to 1200 mg/L cystine, unexpectedly reduce coloration of monoclonal antibody (mAb)-containing solutions, specifically solutions containing the anti-IgE antibody E25 (omalizumab). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). Here, however, Jing does not provide an appropriate basis for determining whether the claimed cell culture method reduces coloration of mAb-containing solutions because Jing does not assess coloration. Rather, Jing examines the effects of environmental factors (temperature, pH, and dissolved oxygen) and medium components (bivalent copper ion, cysteine, and cystine) on the aggregation of recombinant IgG fusion proteins expressed by CHO cells. Thus, not only does Jing assess different culture conditions and different proteins unrelated to the claimed anti-IgE antibody, but it also does not address whether the presence or concentration of cystine in CHO cell culture affects the coloration of mAb-containing solutions, let alone solutions containing omalizumab. Therefore, Jing does not provide a meaningful basis for determining whether cystine, or the claimed cell culture conditions as a whole, would have been expected to reduce coloration of an omalizumab-containing solution.
Further, Jing does not teach away from the use of cystine at high concentrations in CHO cell culture. Instead, Jing specifically identifies altering cystine concentration and culture temperatures shifts together as an effective and practical strategy for reducing protein aggregation, and reports that this could be done without negative effects on harvest titer and protein sialyation (Abstract). While Jing may have observed effects on the level of single-chain fragments under particular conditions, such observation does not amount to a teaching away from cystine generally or from the claimed cystine concentrations. In fact, Jing recognizes cystine concentration as a variable that can be optimized along with temperature shifts to improve protein quality while maintaining other process attributes.
Accordingly, in view of the above, Applicant’s arguments regarding unexpected results are not persuasive, and the rejections under 35 USC 103 are maintained.
Conclusion
No claims are allowable.
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.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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