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 .
Election/Restrictions
Applicant’s election without traverse of (i) BY4-BY7 as the color reference standard, (iii) a chemically defined media (claim 5), and (iv) cells contacted in the growth phase (claim 11) in the reply filed on 05/18/2026 is acknowledged. As explained in the Remarks of 05/18/2026, claim 8 has been amened to recite that “the concentration of the B2, B6, B9, and B12 vitamins added to the culture is varied between the basal medium and the feed medium”; thus a species election is not required for this claim.
Claims 6 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/18/2026.
Claims 1-5, 7-11, and 13-15 are examined on the merits in the present Office 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.
Claim 9 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.
Claim 9 recites the limitation "the iron" in line 1. There is insufficient antecedent basis for this limitation in the claim. While ferric citrate is a source of iron, it is not the same as raw elemental iron; rather, it is a complex of ferric ions and citrate. As a result, the metes and bounds of the desired patent prosecution desired cannot be determined.
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.
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 1-5, 9, 10, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 62-63, 68-75, 90-92, and 96-97 of copending Application No. 18491555 (reference application) in view of McKay et al (McKay, Sue, and Antoon JM van Oosterhout. "Anti-allergic drugs." Principles of Immunopharmacology. Basel: Birkhäuser Basel, 2005. 265-280), hereinafter McKay.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method for culturing cells to produce a polypeptide, comprising
culturing in a cell culture medium a cell encoding the polypeptide, wherein the cell culture medium comprises:
from about 400 mg/L to about 1200 mg/L cystine
from about 2 uM to about 80 uM ferric citrate; and
from about 0.05 uM to about 0.5 uM hydrocortisone
purifying the polypeptide expressed by the cell; and
concentrating the polypeptide to a concentration of at least 100 mg/mL;
wherein the polypeptide has a color reference standard value selected from the group consisting of B4-B9, BY4-BY7, Y4-Y7, GY4-GY7, and R4-R7 according to the European Pharmacopeia color standards, European Pharmacopoeia, 2008 7th edition, Page 22 (co-pending claim 62), wherein the polypeptide is an IgG1 antibody (co-pending claims 90-91). The cell culture medium further comprises vitamin B2, vitamin B6, vitamin B9, and vitamin B12 (co-pending claim 63). The cell culture medium is a chemically defined cell culture medium (co-pending claim 68). The cells are contacted with the cell culture medium during the growth phase (co-pending claim 70) or production phase (co-pending claim 71); thus the cell culture comprises both phases. If the cells of claim 62 are contacted to the cell culture medium during the growth phase and the cell culture medium of claim 62 comprises ferric citrate, then iron is present in the basal media.
The co-pending claims do not recite that the anti-IgG1 antibody is E25 nor that the cells are CHO cells. Further, specific concentrations of each of the B vitamins present is not recited.
However, McKay teaches that omalizumab (Xolair®, rhuMAb-E25, E25) is a humanized monoclonal IgG1 antibody produced in Chinese Hamster Ovary (CHO cells) and selectively binds to the Cε3 domain of free, thereby inhibiting binding to the FcεR1 on the surface of mast cells and basophils and preventing the release of inflammatory mediators involved in the allergic response (“Anti-IgE” section beginning on Page 275 and the “Biochemical and Pharmacological Effects” subsection). Xolair has been approved by the FDA for the treatment of moderate to severe allergic asthma and is administered by by subcutaneous injection.
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that the anti-IgG1 antibody is E25 (omalizumab) and the cell culture used is the CHO cell line. One of ordinary skill in the art would have been motivated to do so since the anti-IgE antibody E25 (omalizumab) is an anti-IgG1 antibody commercially produced in CHO cells, and the cell culture method of the co-pending claims can be used to produce IgG1 antibodies. Further, 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 polypeptide (i.e. the E25 antibody). Lastly, 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 the cell culture method and medium of the co-pending claim can be used to effectively yield an E25 antibody (IgG1 isotype) preparation concentrated to at least 100 mg/L and having a B74-BY7 color value.
Claims 7, 8, 11, and 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 62-63, 68-75, 90-92, and 96-97 of copending Application No. 18491555 (reference application) in view of McKay as applied to claims 1-5, 9, 10, and 15 above, and further in view of De La Cruz et al (US20030087372A1), hereinafter De La Cruz.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of McKay have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that culturing process is fed-batch culture wherein the B vitamins are varied between the basal medium and feed medium and the temperature during both phases is maintained within a range of 35 – 40 ℃.
However, 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) in order to maintain cell viability and productivity (Para. 0139). 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, vitamins (such as B vitamins), amino acids, trace elements, free fatty acids, 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).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that culturing process is a fed-batch culture, wherein the cell culture components (e.g. the B vitamins) are varied between the basal medium and feed medium and the temperature during both phases is maintained within a range of 35 – 40 ℃. One of ordinary skill in the art would have been motivated to do so in order to help maintain cell viability and productivity as taught by De La Cruz. Therefore, one of ordinary skill in the art would reasonably expect that the fed-batch cell culture process taught by De La Cruz can effectively produce the E25 antibody from cell culture.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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