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 .
Response to Amendments
Applicant's amendments filed 8/18/2025 to claims 62, 96 and 97 have been entered. Claims 62-63, 68-75, 90-92, 96-97, and 112 remain pending, of which claims 62-63, 68-75, 90-92, and 112 are being considered on their merits. Claims 96-97 remain withdrawn from consideration. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Election/Restrictions
Applicant’s election of Group I: claims 62-63, 68-75, 90-92, and 112, drawn to methods of culturing cells to produce a polypeptide, in the reply filed on 5/2/2025 stands.
Claim Interpretation
Claim 62 recites active steps of culturing a cell under specific conditions and purifying a polypeptide from said cell to a specific level of concentration. The claim follows these active steps with the recitation of “wherein the polypeptide has a color reference standard value selected from…”. This phrase does not insert any additional active steps into the method, but rather states an inherent property of the antibody following the active steps. Since this independent claim does not recite any additional active steps to alter the color of the polypeptide, but rather limits to the color being the result the claimed method, no additional steps are read into the claim. For this reason, a reference that teaches the active steps of the method reads on the limitations of the inherent properties of the polypeptide.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 62-63, 68-75, and 90-91 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lee et al (U.S. PGPUB 2003/0096402) in view of Qi et al (2009, Journal of Pharmaceutical Sciences, 98, 3117–3130), Lam et al (2006, U.S. Patent 6,991,790) and Jing et al (2012, Process Biochemistry, 47(1): 69-75).
Regarding claims 62, 68, 70-71, and 90-91, Lee teaches methods using a chemically defined media for growth of mammalian cells for production of commercially useful amounts of expressed proteins, and specifically production of IgG1 antibodies and antibody fragments that are therapeutic proteins, wherein antibody of choice may be a single chain Fv fragment (scFv), and wherein the cells are contacted with the media both during their growth and production phases (see abstract, paragraph [0019], Example 1 and claims 8-10).
Regarding claim 62, Lee teaches the defined cell culture medium may comprise 50 to 200 mg/L cystine, 1-10 mg/L (4-40 micromolar) ferric citrate, and 20-80 micrograms/L (0.05-0.22 micromolar) hydrocortisone (see paragraph [0028]).
Regarding claim 63, Lee teaches the defined cell culture medium may comprise 0.4 mg/L riboflavin (vitamin B2), 4 mg/L pyridoxal (vitamin B6 or pyridoxine), 4 mg/L folic acid (vitamin B9), and 0.013 mg/L cyanocobalamin (vitamin B12 or cobalamin) (see Table A2 in paragraph [0045] and paragraph [0037]).
Regarding claim 69, Lee teaches serum is commonly used in mammalian cell culture to promote cell growth and protein production (see paragraph [0003]); including serum reads on “chemically undefined”.
Regarding claims 70-71, Lee teaches culturing cells grew and expressed proteins when cultured in the medium (see Figures 1-3). Lee teaches that cell lines that can be used in this method include CHO cell lines (see paragraph [0017]).
Regarding claims 72-73, Lee teaches the defined cell culture medium may comprise 300-500 mg/L cysteine (see paragraph [0028]); this reads on “adding cysteine” in claim 72, and overlaps with the claimed range of 80 mg/L to 1500 mg/L in claim 73.
Lee does not specifically teach culturing a cell in a media comprising all of the claimed components, including about 400 – 1200 mg/L cystine, or concentrating the antibody to a specific level (claim 62). Lee does not teach including undefined additives (claim 69). Lee is silent as to the color of a polypeptide produced using the media (claim 62). Lee does not teach the amount of cysteine in claims 74-75.
Regarding claim 62, Qi teaches assaying a monoclonal antibody, and that they observed yellowish discoloration correlates with a loss in bioactivity (see abstract). Regarding claim 62, Qi teaches that the antibodies were concentrated to a level of 100 mg/mL (see page 3119).
Regarding claim 62, like Lee, Lam is also directed to pharmaceutical antibody formulations including antibody fragments wherein the of choice fragment is a single chain Fv fragment (scFv), and Lam teaches the antibody formulations are formulated to be preferably essentially pure and desirable essentially homogenous. Lam continues to define essentially pure antibody to mean a composition comprising at least about 90% by weight of the antibody, based on total weight of the composition, preferably at least about 95% by weight, and essentially homogeneous antibody to mean a composition comprising at least about 99% by weight of antibody, based on total weight of the composition; this teaching reads on at least 100 mg/mL. (See abstract and col. 9 lines 37-45).
Regarding claim 62, Lam notes that antibodies are proteins and Lam teaches proteins retain their physically stability in a pharmaceutical formulation if it shows no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity (see col. 1 lines 42-43 and col. 6 lines 6-9). Regarding claim 62, Lam teaches formulating antibodies for use in treatments and analyzing the antibody formulations to be clear and colorless prior to storage (see Example 1 and Table 4).
Like Lam, Jing also teaches that protein aggregates that commonly occur during bioprocessing is undesirable as it can affect purity, yield, and stability of the final product (see col. 1 on page 69). Jing further teaches aggregation becomes increasingly important for therapeutic proteins due to the potential for immunogenic response and pharmacokinetic issues (see col. 1 on page 69). Regarding claim 62, Jing teaches that supplementing CHO cell culture medium with high levels of cystine, specifically 1.28 mM to 3.84 mM (corresponding to 308 mg/L to 923 mg/L), is a satisfactory approach for reducing aggregation of proteins made by the CHO cells (see page 72 and Table 4). Regarding claim 62, Jing teaches that supplementation with the highest level of cystine, 3.84 mM (corresponding to 923 mg/L) drastically increased the amount of single chain antibody fragments (see page 72 and Table 4). Regarding claims 73-75, Jing teaches that further supplementing culture medium with different levels of cysteine, Jing exemplifies 1.65 mM to 4.95 mM (corresponding to 200 mg/L to 600 mg/L), is also an approach for reducing aggregation of proteins made by the cells, and that the amount of cysteine can be optimized as other components have this function, and that cystine in culture media can be converted to cysteine which also changes the amounts (see pages 70, 72 and 75, and Table 4); it is also noted that the term “about” renders the claimed amounts broad.
A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating any combination of Lee’s taught culture components into Lee’s cell culture media because Lee teaches that all of the taught substances can be useful in Lee's media. The skilled artisan would have been motivated to incorporate any combination of Lee’s taught culture components into Lee’s cell culture media because Lee specifically highlights each of these components as being useful in cell culture media.
A person of ordinary skill in the art would have had a reasonable expectation of success in concentrating the polypeptide produced because Qi teaches that antibodies can be concentrated to 100 mg/mL and Lam teaches that they can be concentrated up to 99% of the composition by weight. The skilled artisan would have been motivated to concentrate the antibody produced because Lee teaches the cells used can be used to produce polypeptides and Qi and Lam teach it is useful to use concentrated antibodies.
A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating Jing’s highest level of cystine into Lee’s cell culture media because Lee already teaches the use of cystine in the cell culture media, and Jing teaches that higher levels of cystine, and specifically 3.84 mM (corresponding to 923 mg/L) drastically increased the production amount of single chain antibody fragments, which is one of Lee’s preferred therapeutic antibody proteins. The skilled artisan would have been motivated to incorporate Jing’s higher level of cystine into Lee’s cell culture media because both Lee and Lam teach the usefulness of pharmaceutical antibody formulations single chain Fv fragment (scFv) antibodies, and Jing teaches higher concentrations of cystine results in a drastic increase in single chain antibodies made by the CHO cells, which is also one of Lee’s preferred cell lines.
A person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the amount of cysteine Lee’s cell culture media, including to levels of about 140 mg/L and about 1500 mg/L, because Lee already teaches the use of cysteine in the cell culture media, and Jing teaches that optimizing the levels of cysteine can be useful in media for protein production in cells. The skilled artisan would have been motivated to optimize the amount of cysteine Lee’s cell culture media, including to levels of about 140 mg/L and about 1500 mg/L, because both Lam and Jing each highlight the problems associated with aggregation during protein production and Jing teaches optimizing the concentrations of cysteine is a approach for reducing aggregation of proteins made by the CHO cells, and CHO cells are one of Lee’s preferred cell lines. Additionally, Jing teaches that cystine in culture media can be converted to cysteine which also changes the amounts, and that other media components function to reduce aggregation and result in higher single chain production, therefore it is obvious to adjust and optimize the levels.
A person of ordinary skill in the art would have had a reasonable expectation of success in measuring the color of the antibody produced in the method of Lee in view of Jing because Lam and Qi teach that the colorless of antibody preparations can be assayed. The skilled artisan would have been motivated measure the color of the antibody produced in the method of Lee in view of Jing because Qi teaches and that yellowish discoloration correlates with a loss in bioactivity in antibodies, and Lam teaches proteins retain their physically stability in a pharmaceutical formulation if it shows no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity. Furthermore, Lam exemplifies measuring the color. Furthermore, for the reasons stated above in the Claim Interpretation section, the recitation of the appearance of the isolated antibody is a passive result of the active step of isolating the antibody. As the cited references teach the active steps of the method, they render obvious the passive resulting appearance.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claim 112 remains rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lee et al (U.S. PGPUB 2003/0096402) in view of Qi et al (2009, Journal of Pharmaceutical Sciences, 98, 3117–3130), Lam et al (2006, U.S. Patent 6,991,790) and Jing et al (2012, Process Biochemistry, 47(1): 69-75) as applied to claims 62-63, 68-75, and 90-91 above, and further in view of European Pharmacopoeia (2008, Council of Europe, Edition 7, pages 21-22).
The teachings of Lee in view of Qi, Lam and Jing are discussed and relied upon above.
Lee does not teach determining the color of the purified polypeptide (claim 112).
Regarding claim 112, European Pharmacopoeia teaches the clarity and degree of opalescence and coloration (COC) of a sample can be assayed and determined by comparing to established color standards.
A person of ordinary skill in the art would have had a reasonable expectation of success in determining the color of the polypeptide produced in the method of Lee in view of Qi, Lam and Jing using European Pharmacopoeia’s established method because European Pharmacopoeia provides details on how to assay color by comparing to known established references. The skilled artisan would have been motivated measure the color of the polypeptide produced in the method of Lee in view of Qi, Lam and Jing using European Pharmacopoeia’s established method because Qi teaches and that yellowish discoloration correlates with a loss in bioactivity in antibodies, and therefore it is useful to determine the color.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claim 92 remains rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lee et al (U.S. PGPUB 2003/0096402) in view of Qi et al (2009, Journal of Pharmaceutical Sciences, 98, 3117–3130), Lam et al (2006, U.S. Patent 6,991,790) and Jing et al (2012, Process Biochemistry, 47(1): 69-75) as applied to claims 62-63, 68-75, and 90-91 above, and further in view of Gadgil et al (U.S. PGPUB 2011/0097318).
The teachings of Lee in view of Qi, Lam and Jing are discussed and relied upon above.
Lee does not teach that the antibody is anti-Beta-7.
Like Lee, Gadgil also teaches antibodies can be produced in CHO cells (see paragraph [0045]). Regarding claim 92, Gadgil teaches that useful antibodies include anti-Beta-7 (see paragraphs [0105] and [0157]).
A person of ordinary skill in the art would have had a reasonable expectation of success in producing a Beta-7 antibody using the method of Lee in view Qi, Lam and Jing because Lee teaches methods of producing antibodies, and Gadgil teaches antibodies specific to Beta-7 can be produced in cell culture. The skilled artisan would have been motivated to produce a Beta-7 antibody using the method of Lee in view of Qi, Lam and Jing because Gadgil teaches antibodies specific to Beta-7 are useful to produce.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 8/18/2025 have been fully considered but they are not persuasive.
Applicant highlights the amendment to the independent claim, and alleges that there is no motivation to use this newly claimed higher level of cystine in Lee’s cell culture medium. Applicant points to Table 4 in Jing, and alleges that there is no motivation to use Jing’s 3.84 mM cystine (corresponding to 923 mg/L) in Lee’s method of producing an antibody since Jing teaches 1.28 mM (corresponding to 308 mg/L) yielded better results of both titer and viable cell density. Applicant concludes that Jing teaches away from the use of 3.84 mM cystine (923 mg/L).
Applicant’s amendment to the independent claim narrowing the amount of cystine to about 400 mg/L to about 1200 mg/L necessitated new grounds for rejection as the rejection is now over the specific motivation to select the highest level of cystine in Jing, instead of Jing’s 1.28 mM (corresponding to 308 mg/L) in the prior rejection. Specifically, as stated in the above rejection, Jing teaches that highest levels of cystine (3.84 mM corresponding to 923 mg/L) drastically increased the production amount of single chain antibody fragments, which is one of Lee’s preferred therapeutic antibody proteins. Therefore, while applicant alleges that Jing only provides motivation to use 1.28 mM cystine (corresponding to 308 mg/L), this is not the case as Jing teaches significantly superior results of single chain antibody production with the higher levels of cystine (3.84 mM corresponding to 923 mg/L) as compared to both lower levels of cystine and to controls lacking cystine. For this reason, Jing does provide both teaching and motivation and this argument is not persuasive.
Conclusion
No claims are free of the art. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/S.A.M/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
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