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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 07/20/2026 has been entered. Claims 1, 4-16, 20, 28-31, 39-42, and 46-53 are pending and have been examined on the merits.
Claim Interpretation
Claims 1, 13, and 20 have been amended to remove CO2 sparging as an active step, and now only recite CO2 sparging as a means by which the required CO2 pressure is obtained during the culturing step. That is, the limitation regarding the partial CO2 pressure during culture is now defined using product-by-process language. Product-by-process limitations are considered only in so far as the process of production affects the final product. Therefore, if the product (in this case, the required partial CO2 conditions) as claimed is the same or obvious over a product (condition) of the prior art (i.e., is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113.
Regarding claim 1: Claim 1 is directed to a method of producing antibody products comprising steps of seeding media with mammalian cells that produce antibodies; and culturing the cells under partial pressure of CO2 (pCO2) conditions that all the mammalian cells to produce antibody products with less acidic variants than would be obtained without the pCO2 conditions, wherein the pCO2 conditions are 120 mmHg to 140 mmHg of Co2 in the media. “[W]herein the pCO2 conditions are attained by CO2 sparging from at least day 5.5 through harvesting” is a product-by-process limitation that does not constitute an active step. Any method of achieving 120 mmHg to 140 mmHg CO2 will satisfy the pCO2 conditions required. Additionally, the limitation “wherein the proportion of acidic variants decreases as pCO2 conditions increase” is drawn to a trend and does not limit the active steps of the claimed method. Thus, the process of production involves seeding media with mammalian cells that produce antibodies and culturing the cells with 120 mmHg to 140 mmHg of CO2 in the media [i.e. the active steps of the method of claim 1]. The final product of claim 1 comprises antibody products with less acidic variants that would be obtained without culturing at 120 mmHg to 140 mmHg of CO2.
Regarding claim 13: Claim 13 is directed to a method of producing antibody products comprising steps of seeding media with mammalian cells that produce antibodies; and culturing the cells under partial pressure of CO2 (pCO2) conditions that all the mammalian cells to produce antibody products with less acidic variants than would be obtained without the pCO2 conditions, wherein the main peak form of antibodies produced by the cells comprises between 38% to 65% of total antibodies, the acidic variant of the antibodies comprises 20% to 47% of total antibodies and the basic variant of the antibodies comprises up to 36% of total antibodies. “[W]herein the pCO2 conditions are attained by CO2 sparging from at least day 5.5 through harvesting” is a product-by-process limitation that does not constitute an active step. Additionally, the limitation “wherein the proportion of acidic variants decreases as pCO2 conditions increase” is drawn to a trend and does not limit the active steps of the claimed method. Thus, the process of production involves seeding media with mammalian cells that produce antibodies and culturing the cells the cells under pCO2 conditions to produce antibody products with less acidic variants than would be produced by the cells without the pCO2 conditions [i.e. the active steps of the method of claim 13], this is understood to require the final product of claim 13 to comprise antibody products wherein the main peak form of antibodies produced by the cells comprises between 38% to 65% of total antibodies, the acidic variant of the antibodies comprises 20% to 47% of total antibodies and the basic variant of the antibodies comprises up to 36% of total antibodies.
Regarding claim 20: Claim 20 is directed to a method of producing antibody products comprising steps of seeding media with mammalian cells that produce antibodies, antibody derivatives or antibody fragments; and culturing the cells under partial pressure of CO2 (pCO2) conditions that all the mammalian cells to produce antibody products with less acidic variants than would be obtained without the pCO2 conditions, wherein the main peak form of antibodies, antibody derivatives, or antibody fragments produced by the cells comprises between 50% to 70% of total antibodies, antibody derivatives, or antibody fragments, the acidic variant of the antibodies, antibody derivatives, or antibody fragments, comprises 20% to 47% of total antibodies, antibody derivatives, or antibody fragments, and the basic variant of the antibodies, antibody derivatives, or antibody fragments, comprises up to 15% of total antibodies, antibody derivatives, or antibody fragments. “[W]herein the pCO2 conditions are attained by CO2 sparging from at least day 5.5 through harvesting” is a product-by-process limitation that does not constitute an active step. Additionally, the limitation “wherein the proportion of acidic variants decreases as pCO2 conditions increase” is drawn to a trend and does not limit the active steps of the claimed method. Thus, the process of production involves seeding media with mammalian cells that produce antibodies, antibody derivatives, or antibody fragments and culturing the cells under pCO2 conditions to produce antibodies, antibody derivatives, or antibody fragments with less acidic variants than would be produced by the cells without the pCO2 conditions [i.e. the active steps of the method of claim 20], this is understood to require the final product of claim 20 to comprise antibodies, antibody derivatives, or antibody fragments wherein the main peak form of antibodies, antibody derivatives, or antibody fragments produced by the cells comprises between 50% to 70% of total antibodies, antibody derivatives, or antibody fragments, the acidic variant of the antibodies, antibody derivatives, or antibody fragments comprises 20% to 47% of total antibodies, antibody derivatives, or antibody fragments, and the basic variant of the antibodies, antibody derivatives, or antibody fragments comprises up to 15% of total antibodies, antibody derivatives, or antibody fragments.
Claim Rejections - 35 USC § 102
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.
(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, 5, 8-9, and 11-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Irfan (New Castle University, 2017), cited in the 1/18/2023 IDS.
Irfan reports on the effect of pCO2 on mAb production in Chinese Hamster Ovary (CHO) cells (See abstract). Irfan discloses that CHO cells are a cell line commonly used as a mammalian production host for mAbs (See pg. 1 section 1.1 Introduction). CHO cells are able to produce antibodies with major glycoforms identical to glycoforms present in human antibodies (See pg. 5 section Glycosylation and Charge Variants (Product quality attributes)).
Irfan teaches that CO2 and carbonate base are used by most bioreactor processes to control the culture pH (See Pg. 13 Section culture pH) and the most prominent stirred bioreactor on the market controls pH through gas sparging (See pg. 9 section: Microbioreactors). In this study, Irfan reports a CHO-S cell line expressing a humanized IgG1 monoclonal antibody that binds Her2 (See pg. 28 section 2.2.1 Cell Line and Medium). The cells are inoculated to a working volume of 1.4L at a seeding density of 5x105 cells/mL (See pg. 29 section 2.2.2 Bioreactor Cell Culture Runs). The cells are cultured under various pCO2 conditions including baseline, 10, 60, 100, and 140 mmHg (See pg. 30 table 2.2) and harvested 312 hours (See pg. 29 section 2.2.2 Bioreactor Cell Culture Runs). The target mAb profile including mean target mAb, mean acidic variants and mean basic variants were quantified over time (See pg. 35-36, Fig. 2.4). Irfan discovers that increasing the pCO2 concentration has the desirable effect of reducing acidic variants. Charge variants in antibodies can have effects on stability, effect, and safety of mAbs (See pg. 5 Section Glycosylation and Charge Variants (Product quality attributes)).
Regarding claim 1: Irfan teaches culturing a CHO cell line and inoculating a working volume of 1.4L at a seeding density of 5x105 cells/mL which reads on seeding media with mammalian cells that produce antibodies.
Irfan teaches that culturing CHO cells with high CO2 condition (140 mmHg), for 312 hrs, results in a decrease in acidic charge variants compared to baseline (baseline: ~45% vs. 140 mmHg: ~37% see fig 2.4b). Therefore, culturing cells under 140 mmHg for 312 hrs reads on culturing the cells under pCO2 conditions that allow the mammalian cells to produce antibody products with less acidic acid variants than would be obtained without the pCO2.
Additionally, Irfan teaches culturing at 140mmHg pCO2 which reads on pCO2 conditions are 120 mmHg to 140 mmHg of CO2 in media.
Regarding claims 5, 8, and 9: Following the discussion of claim 1 above Irfan teaches a humanized IgG1 monoclonal antibody which reads on the antibodies are human monoclonal IgG antibodies.
Regarding claim 11: Following the discussion of claim 1 above, Irfan teaches culturing CHO cells and harvesting the cells at 312 hrs (13 days) which reads on the cells are cultured for 10-15 days.
Regarding claim 12: Following the discussion of claim 1 above, Irfan discloses using a Chinese hamster ovary (CHO) cell line which reads on the mammalian cells are CHO cells.
Regarding claim 13: Irfan teaches culturing a CHO cell line and inoculating a working volume of 1.4L at a seeding density of 5x105 cells/mL which reads on seeding media with mammalian cells that produce antibodies.
Irfan teaches that culturing cells under 140mmHg pCO2 results in ~63% main target antibody (See Fig2.4a), ~ 22% acidic charge variants (See Fig 2.4b), and ~ 15% basic charge variants (See Fig2.4c) which reads on culturing the cells under pCO2 conditions that that allow the mammalian cells to produce antibodies, wherein the main peak form of antibodies produced by cells comprises between 38% to 65% of total antibodies, the acidic variant of the antibodies comprises 20% to 47% of total antibodies and the basic variant of the antibodies comprises up to 36% of total antibodies.
Regarding claim 14: Following the discussion of claim 13 above, Irfan teaches a humanized IgG1 monoclonal antibody which reads on the antibodies are human monoclonal antibodies.
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.
Claims 1, 4-5, 8-9, 11-14, 20, 28-29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Irfan (New Castle University, 2017).
The Teachings of Irfan are set forth above.
Irfan anticipates claims 1, 5, 8-9, and 11-14.
Regarding claim 4: Following the discussion of claim 1 above, Irfan teaches that increasing pCO2 conditions causes a decrease in acidic charge variants (See fig 2.4b).
Irfan does not teach specific pCO2 conditions that result in 0.5% to 4% less acidic antibody variants compared to baseline.
Given that Irfan teaches fewer acidic charge variants can be produced by altering pCO2 conditions, routine optimization of pCO2 conditions needed to reach desired levels of acidic charge variants would have been prima facie obvious to one of ordinary skill in 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. See MPEP2144.05(II).
Regarding claim 20: Irfan teaches culturing a CHO cell line and inoculating a working volume of 1.4L at a seeding density of 5x105 cells/mL which reads on seeding media with mammalian cells that produce antibodies, antibody derivatives, or antibody fragments.
Irfan further teaches that culturing CHO cells under 140mmHg pCO2 for ~140 hrs results in ~63% main target antibody (See Fig2.4a), ~ 22% acidic charge variants (See Fig 2.4b), and ~ 15% basic charge variants (See Fig2.4c) which reads on culturing the cells under pCO2 conditions that that allow the mammalian cells to produce antibodies… wherein the main peak form of antibodies… produced by cells comprises between 50% to 70% of total antibodies, the acidic variant of the antibodies comprises 20% to 47% of total antibodies and the basic variant of the antibodies comprises up to 15% of total antibodies.
Regarding claims 28 and 29: Following the discussion of claim 20 above, Irfan teaches using CHO cells to produce humanized IgG1 monoclonal HER2 antibodies which reads on the mammalian cells produce human monoclonal IgG1 antibodies.
Regarding claim 31: Following the discussion of claim 20 above, Irfan discloses using pCO2 conditions of 60 mmHg, 100 mmHg and 140 mmHg which reads on pCO2 conditions are between 30 mmHg and 210 mmHg.
Claims 1, 4-6, 8-9, 11-15, 20, 28-29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Irfan (New Castle University, 2017) in view of Papadopoulos et al (US9987500B2).
The teachings of Irfan are set forth above.
Irfan anticipates claims 1, 5, 8-9, and 11-14 and renders claims 1, 4-5, 8-9, 11-14, 20, 28-29, and 31 obvious.
Regarding claims 6 and 15: Following the discussion of claims 1,5, 13, and 14 above, Irfan teaches using CHO cells to produce humanized IgG1 monoclonal HER2 antibodies. The antibodies are produced under increasing pCO2 conditions leading to a decrease in acidic variants. This is a desirable effect because charge variants can have an effect on an antibody’s stability, effect, and safety.
Irfan does not teach antibodies capable of binding to PD-1 factor.
Papadopoulos, et al. discloses antibodies and antigen binding fragments that bind PD-1. The antibodies are further described as recombinant monoclonal antibodies or antigen binding fragments that bind specifically to PD-1 and may bind human PD-1 (See col. 2 ln 55-58). The antibodies can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen binding portion and may be modified to affect functionality (See Col. 2 lns 48-51). PD-1 antibodies are useful in treating diseases or disorders such as cancer, viral infections, and autoimmune diseases (See Col. 2, lns 45-47). The PD-1 antibodies can be produced by any known method (See col. 21 lns 20-22) including using mammalian cells, such as CHO cells, to express an immunogen (See col. 21 lns 39-42).
Irfan and Papadopoulos, et al. both teach using CHO cells to produce human monoclonal IgG antibodies and that using CHO cells for antibody production is a known method in the field. Papadopoulos, et al. further teaches that CHO cells can specifically produce PD-1 antibodies. Therefore, it would have been prima facie obvious to modify the method of Irfan to produce the PD-1 antibody of Papadopoulos, et al. because the PD-1 antibody of Papadopoulos, et al. is useful in treating diseases such as cancer, viral infections, and autoimmune disorders. One would have a reasonable expectation of success that producing the PD-1 antibodies of Papadopoulos, et al. via the method of Irfan et al, specifically at a pCO2 level of 140 mmHg would similarly yield the lowered level of acidic variants as demonstrated by Irfan et al. Furthermore, would have a reasonable expectation of successfully producing the PD-1 antibodies via the method of Irfan et al because Papadopoulos, et al. teaches PD-1 antibodies can be produced using CHO cells.
Claims 1, 4-5, 7-14, 16, 20, 28-31, and 39-42 are rejected under 35 U.S.C. 103 as being unpatentable over Irfan (New Castle University, 2017) in view of Xu (Biotechnol. Prog., 2017) and Martin et al (US20090074793A1).
The teachings of Irfan are set forth above.
Irfan anticipates claims 1, 5, 8-9, and 11-14 and renders claims 1, 4-5, 8-9, 11-14, 20, 28-29, and 31 obvious.
Regarding claims 7, 16, 39-42: Following the discussion of claims 1, 5, 13-14, and 20 above, Irfan teaches using CHO cells to produce humanized IgG1 monoclonal HER2 antibodies. The antibodies are produced under increasing pCO2 conditions, including 140 mmHg, leading to a decrease in acidic variants. The increase in pCO2 results in ~63% main target antibody, ~ 22% acidic charge variants, and ~ 15% basic charge variants (See Fig2.4). This is a desirable effect because charge variants can have an effect on an antibody’s stability, effect, and safety.
Irfan does not teach antibodies capable of binding IL-4 receptors or dupilumab antibodies.
Martin, et al. teaches an antibody or antigen binding fragment that specifically binds human Interleukin-4 receptor which reads on the antibodies are capable of binding IL-4 receptors (See Pg. 84 claims 1-3). The human antibodies are characterized by binding to hIL-4R with high affinity and by the ability to neutralize hIL-4 activity. In specific embodiments, the human antibodies are capable of blocking hIL-13/hIL-13R1 complex binding to hIL-4R, and thus inhibit signaling by hIL-13 (See ¶0083). The antibodies of Martin thus meet the description of dupilumab provided in the instant specifications. Martin further teaches, the antibodies can be full-length for example, an IgG1 or IgG4 antibody, may comprise only an antigen binding portion, and may be modified to effect functionality and can be produced using CHO cell lines (See pg. 1, ¶0006 and pg. 7, ¶0064). The Il-4R antibodies can be used to treat diseases or disorders which are improved, inhibited or ameliorated by reducing IL-4 activity such as arthritis, herpetiformis, chronic idiopathic urticaria, scleroderma, hypertrophic scarring, Whipple’s Disease, etc. (See pg. 7, ¶0060).
Given that Irfan and Martin, et al. both teach using CHO cells to produce human monoclonal antibodies, it would have been prima facie obvious to modify the method of Irfan to produce the Il-4R antibody of Martin et al. because the Il-4R antibody of Martin, et al. is useful in treating diseases or disorders which are improved, inhibited or ameliorated by reducing IL-4 activity. One would have a reasonable expectation of success that producing the IL-4R antibodies of Martin, specifically the dupilumab antibodies, via the method of Irfan et al, specifically at a pCO2 level of 140 mmHg would similarly yield the lowered level of acidic variants as demonstrated by Irfan et al.
Regarding claims 10, and 30: Following the discussion of claims 1, 5, 8, 9, 20, and 28 above, Irfan teaches using CHO cells to produce human monoclonal IgG1 antibodies.
Irfan does not teach the antibodies are IgG4 antibodies.
Martin, et al. discloses human monoclonal Il-4R antibodies which can be full length IgG1 or IgG4 (reads on the antibodies are IgG4) antibodies and can be produced by CHO cells. Martin, et al. further discloses that during antibody production, mouse constant regions can be replaced with desired human constant regions (reads on antibody isotype) to generate… IgG4 or IgG1 antibodies and that constant regions selected may vary according to specific use (See pg. 6 ¶0048).
Irfan and Martin, et al. both teach using CHO cells to produce monoclonal IgG antibodies and that using CHO cells for antibody production is a known method in the field. Martin, et al. further teaches that CHO cells can specifically produce monoclonal Il-4R antibodies with an IgG4 isotype. It would have been prima facie obvious to modify the method of Irfan to produce the Il-4R antibody with an IgG4 isotype of Martin, et al because the Il-4R antibody of Martin, et al. is useful in treating diseases or disorders which are improved, inhibited or ameliorated by reducing IL-4 activity. One would have a reasonable expectation of success that producing the IL-4R antibodies of Martin via the method of Irfan et al, specifically at a pCO2 level of 140 mmHg would similarly yield the lowered level of acidic variants as demonstrated by Irfan et al. Furthermore, one would have a reasonable expectation of successfully producing the IgG4 antibodies via the method of Irfan et al because Martin teaches IL-4R IgG4 antibodies can be produced using CHO cells.
Claims 1, 4-5, 8-9, 11-14, 20, 28-29, 31, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Irfan (New Castle University, 2017) in view of Xu (Biotechnol. Prog., 2017) and Reusch et al (Glycobiology, 2015).
The teachings of Irfan are set forth above.
Irfan anticipates claims 1, 5, 8-9, and 11-14 and renders claims 1, 4-5, 8-9, 11-14, 20, 28-29, and 31 obvious.
Regarding claim 46: Irfan teaches culturing a CHO cell line and inoculating a working volume of 1.4L at a seeding density of 5x105 cells/mL which reads on seeding media with mammalian cells that produce antibodies.
Irfan teaches that culturing CHO cells with high CO2 condition of 140 mmHg (reads on increasing pCO2 conditions to above 120 mmHg in the media), for 312 hrs (reads about 10-15 days), results in a production of antibodies comprising ~37% acidic charge variants (reads on 20% to 47%) (see fig 2.4b).
Irfan does not explicitly state the timepoint during culture at which pCO2 conditions are attained. However, Irfan discloses harvesting samples post 144 hours from cultures with 140 mmHg pCO2 conditions therefore, Irfan discloses attaining pCO2 conditions by 144 hours (i.e. day 6) which reads on after day 5 (See pg. 32).
Irfan does not disclose using CO2 sparging to attain pCO2 conditions
Xu (Biotechnol. Prog., 2017) teaches a process for bioreactor scale-up in the production of monoclonal antibodies by CHO cells (See pg. 1147 section Cell line and inoculum expansion). In the disclosed experiments, bioreactor pH was controlled by CO2 sparging (see pg. 1147 section Bioreactor operations). Xu teaches that during process scale-up, lactate consumption increases resulting in pH changes (See pg. 1154 section CO2 removal efficiency). Since pH is largely controlled by lactate and pCO2, active CO2 sparging, which leads to a rapid pCO2 increase, is used to control the pH (See pg. 1152 section. Process scale-up using a combination of P/V and vvm as criterion and pg. 1154 section CO2 removal efficiency). Increasing pCO2 by active gas sparging reads on pCO2 conditions are attained by CO2 sparging.
Given that Irfan teaches using high pCO2 conditions to change antibody charge variants in antibody production by CHO cells and Xu teaches using CO2 sparging to increase pCO2 during antibody production by CHO cells, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the CO2 sparging method of Xu to increase pCO2 conditions of Irfan in order to regulate the culture pH which can be altered by lactate consumption. One would have a reasonable expectation of success because Xu teaches that CO2 sparging can be used to increase pCO2 in culture during antibody production. See MPEP 2143(I)(A).
Additionally, Irfan does not disclose the antibody products comprise 3-8% non-glycosylated heavy chain (NGHC) variants. However, Irfan teaches the efficacy of an antibody therapeutic is critically dependent on appropriate post-translational modifications (PTM), such as glycosylation (See pgs. 4-5, Sec. Glycosylation and Charge Variants (Product Quality Attributes)). Additionally, glycosylation attributes of glycoproteins can affect many of their properties, such as solubility, activity, circulatory half-life and immunotolerance (See pg. 5, Sec. Glycosylation and Charge Variants (Product Quality Attributes)). Temperature, dissolved oxygen (DO), carbon dioxide, nutrient and metabolite concentrations and culture osmolality have been shown to affect glycosylation (See pg. 6, Sec. Glycosylation and Charge Variants (Product Quality Attributes)). Thus, while optimizing process conditions to achieve high productivity, it is critical to monitor product quality changes at every stage of development, as a number of process factors affect the product quality attributes of mAbs (See pg. 6, Sec. Glycosylation and Charge Variants (Product Quality Attributes)).
Reusch et al teaches antibodies with high levels of NGHC have significantly reduced bioactivity and effector function (See pg. 1330, Sec. Nonglycosylated heavy chain).
Given that Reusch et al teaches antibodies with high levels of NGHC have significantly reduced bioactivity and effector function and Irfan teaches glycosylation is affected by temperature, dissolved oxygen, carbon dioxide, nutrient and metabolite concentrations and culture osmolality and Irfan further teaches optimizing conditions of the culture is critical to achieve high productivity, it would have been prima facie obvious to a person of ordinary skill in the art to optimize temperature, dissolved oxygen, carbon dioxide, nutrient and metabolite concentrations and/or culture osmolality in order to reduce NGHC antibody variants and arrive at the claimed concentration of 3-8% through routine optimization. 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. See MPEP2144.05(II).
Claims 1, 4-5, 7-14, 20, 28-31, 39-42 and 46-53 are rejected under 35 U.S.C. 103 as being unpatentable over Irfan (New Castle University, 2017) in view of Xu (Biotechnol. Prog., 2017), Reusch et al (Glycobiology, 2015) and Martin et al (US20090074793A1).
The teachings of Irfan, Xu, Reusch et al, and Martin et al are set forth above.
Irfan anticipates claims 1, 5, 8-9, and 11-14 and renders claims 1, 4-5, 8-9, 11-14, 20, 28-29, and 31 obvious.
Irfan, Xu, and Reusch et al render claims 1, 4-5, 8-9, 11-14, 20, 28-29, 31, and 46 obvious.
Irfan, Xu, and Martin et al render 1, 4-5, 7-14, 16, 20, 28-31, and 39-42 obvious.
Regarding claims 47, 50, and 52: Following the discussion of claim 46 above, Irfan teaches using CHO cells to produce human monoclonal IgG1 antibodies by culturing the cells with 140 mmHg pCO2.
Irfan does not teach the antibodies are IgG4 antibodies.
Martin, et al. discloses human monoclonal Il-4R antibodies which can be full length IgG1 or IgG4 (reads on the antibodies are IgG4) antibodies and can be produced by CHO cells. Martin, et al. further discloses that during antibody production, mouse constant regions can be replaced with desired human constant regions (reads on antibody isotype) to generate… IgG4 or IgG1 antibodies and that constant regions selected may vary according to specific use (See pg. 6 ¶0048).
Irfan and Martin, et al. both teach using CHO cells to produce monoclonal IgG antibodies and that using CHO cells for antibody production is a known method in the field. Martin, et al. further teaches that CHO cells can specifically produce monoclonal Il-4R antibodies with an IgG4 isotype. It would have been prima facie obvious to modify the method of Irfan to produce the Il-4R antibody with an IgG4 isotype of Martin, et al because the Il-4R antibody of Martin, et al. is useful in treating diseases or disorders which are improved, inhibited or ameliorated by reducing IL-4 activity. One would have a reasonable expectation of success that producing the IL-4R antibodies of Martin via the method of Irfan et al, specifically at a pCO2 level of 140 mmHg would similarly yield the lowered level of acidic variants as demonstrated by Irfan et al. Furthermore, one would have a reasonable expectation of successfully producing the IgG4 antibodies via the method of Irfan et al because Martin teaches IL-4R IgG4 antibodies can be produced using CHO cells.
Regarding claims 48, 49, 51, and 53: Following the discussion of claim 46 above, Irfan teaches using CHO cells to produce human monoclonal IgG1 antibodies by culturing the cells with 140 mmHg pCO2.
Irfan does not teach antibodies capable of binding IL-4 receptors or dupilumab antibodies.
Martin, et al. teaches an antibody or antigen binding fragment that specifically binds human Interleukin-4 receptor which reads on the antibodies are capable of binding IL-4 receptors (See Pg. 84 claims 1-3). The human antibodies are characterized by binding to hIL-4R with high affinity and by the ability to neutralize hIL-4 activity. In specific embodiments, the human antibodies are capable of blocking hIL-13/hIL-13R1 complex binding to hIL-4R, and thus inhibit signaling by hIL-13 (See ¶0083). The antibodies of Martin thus meet the description of dupilumab provided in the instant specifications. Martin further teaches, the antibodies can be full-length for example, an IgG1 or IgG4 antibody, may comprise only an antigen binding portion, and may be modified to effect functionality and can be produced using CHO cell lines (See pg. 1, ¶0006 and pg. 7, ¶0064). The Il-4R antibodies can be used to treat diseases or disorders which are improved, inhibited or ameliorated by reducing IL-4 activity such as arthritis, herpetiformis, chronic idiopathic urticaria, scleroderma, hypertrophic scarring, Whipple’s Disease, etc. (See pg. 7, ¶0060).
Given that Irfan and Martin, et al. both teach using CHO cells to produce human monoclonal antibodies, it would have been prima facie obvious to modify the method of Irfan to produce the Il-4R antibody of Martin et al. because the Il-4R antibody of Martin, et al. is useful in treating diseases or disorders which are improved, inhibited or ameliorated by reducing IL-4 activity. One would have a reasonable expectation of success that producing the IL-4R antibodies of Martin, specifically the dupilumab antibodies, via the method of Irfan et al, specifically at a pCO2 level of 140 mmHg would similarly yield the lowered level of acidic variants as demonstrated by Irfan et al.
Conclusion
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/MARISOL ANN O'NEILL/ Examiner, Art Unit 1633
/ALLISON M FOX/ Primary Examiner, Art Unit 1633
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