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 .
DETAILED ACTION
The claims filed on April 11, 2024, have been acknowledged. Claims 1-10 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from KR10-2021-0134891 filed on October 21, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received April 30, 2024. While a certified copy of the foreign patent application KR10-2021-0134891 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Information Disclosure Statement
The information disclosure statements (IDS) filed on April 11, 2024, and December 10, 2025, have been considered.
Claim Rejections - 35 USC § 112
Claim 5-8 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling. The disclosure does not enable one of ordinary skill in the art to practice the invention without identifying the type of recombinant cells, the process steps, and culture media used for culturing the recombinant cells to generate the antibody populations of interest identified in claims 5-8, which is/are critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
The factors to be weighed to evaluate whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is undue are set forth in MPEP 2164.01(a).
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Although all the factors have been considered, the relevant factors will be addressed below.
Breadth of the claims: Claim 1 recites the following claim language, “A method for producing an antibody population, comprising: (a) a first temperature culture step of culturing recombinant cells expressing an antibody in a medium under conditions of pH 7.0 to 7.1 at a first culture temperature of 36 °C to 38 °C for four to six days; and (b) a second temperature culture step of culturing the cultured recombinant cells in a medium under conditions of pH 7.0 to 7.1 at a second culture temperature set to be 2 °C to 4 °C lower than the first culture temperature of the step (a), but higher than or equal to 34 °C for six to eight days.”
Claims 5-8 recite specific antibody populations produced using the method of claim 1.
Nature of the invention: The subject matter of the invention relates to a method of producing antibodies involving a temperature shift, specifically a reduction in temperature, between a first and second culture step to generate specific antibody populations as outlined in claims 5-8.
State of the prior art: The prior art teaches that the quality and structure of a specific recombinantly produced antibody is strictly dependent on the conditions under which they are prepared, including (among other factors) the clone of cells that produce them, the cell culture medium in which they are grown and the specific culture conditions. Moreover, the development and elaboration of production methods must be specifically adapted to the unique properties of each individual antibody, as such protocols cannot be universally applied to other antibodies, as identified by Eyster et al. (Biotechnol Progress 37: 1-13. 2021; referenced in IDS), Li et al. (Biotechnology and Bioengineering 109: 1173-1186. 2012; referenced in IDS), and Sissolak et al. (Journal of Industrial Microbiology & Biotechnology 46:1167–1178. 2019).
Eyster identifies that the N-glycosylation profile of monoclonal antibody (mAb) therapeutics can have a profound effect on function, safety, and efficacy. For example, increased galactosylation on IgG1 mAbs can impart anti-inflammatory properties, result in higher binding strength to FcγRIIIa whether afucosylated or not, and potentially increase antibody-dependent cell-mediated cytotoxicity. However, unlike gene
expression or protein translation, glycosylation is not controlled via biological template, but rather a series of enzymes localized across two organelles—the endoplasmic reticulum and Golgi apparatus—leading to a heterogeneous population of mAbs with varying ratios of sialylation/galactosylation. In the context of cell culture processes for the production of mAbs, it is known that bioreactor process parameters such as temperature, dissolved oxygen (DO) concentration, medium formulation, and ammonium concentration can have an impact on mAb N-glycosylation.8 However, the specific impact of any one parameter is heavily dependent on the host cell line and product.
Process development scientists have several tools at their disposal for modulating mAb glycosylation. One method for rapid modulation of glycosylation is control of nutrient feeds to the bioreactor. Feeds can alter cell metabolism and therefore specific process outcomes such as waste accumulation; an example of one such feed is lactic acid. While it is traditionally thought of as a metabolic waste product in mammalian bioprocesses, and many processes have an explicit goal of reducing its accumulation, feeding a low amount of lactic acid to a CHO bioprocess can lower accumulation of ammonium. Ammonium is a potent metabolic waste product known to negatively affect process outcomes such as cell growth, and correlates with changes to glycosylation to recombinant IgGs and erythropoietin. In addition, increasing ammonium has been noted to negatively impact IgG4 galactosylation. Thus, they examined whether using lactic acid feeding as a process lever for tuning ammonium, and in turn modulating galactosylation. They showed that Raman based feeding of lactic acid resulted in a significant impact on CHO metabolism, drastically lowering ammonium accumulation, and increasing galactosylation of a mAb product (page 1, column 1, paragraph 1-page 2, column 2, paragraph 1).
Li identifies that ammonia production is known to impact terminal sialylation of glycoproteins produced in CHO cells. As a result, controlling the production of ammonia is desirable. With culture metabolism and physiology being impacted due to lactate feeding, it was important to examine the impact, if any, on product quality attributes. Table IVA shows the product quality comparison from the sodium lactate feeding study using cell line A. Here, the charge variant profiles (categorized by acidic, main, and basic peak percentages) and the glycan distribution profiles were compared between the control culture and the sodium lactate-fed culture. Overall, both the charge variant and the glycan profiles were similar between the two cultures, with the control culture having slightly lower % G0 than the lactate-fed culture. Table IVB shows product quality attribute comparisons from the high titer, high density lactic acid feeding studies using cell line B. Time course at day 12, 14, 16, and 18 of the charge variant and glycosylation patterns were compared between the control culture and the lactic acid-fed culture. Overall, the control culture showed slightly higher acidic variant and lower main peak comparing to the lactic acid-fed culture. The glycosylation profiles showed some noticeable differences between the two cultures. The lactate fed culture had 4–6% higher % G0, while its % Man5 were 5–7% lower. The % G0-F and % G1/G1’ were slightly higher by 1–2%. Among the observed differences, the higher % Man5 in control culture can probably be attributed to the higher osmolality of the control culture, as higher osmolality has been reported to have impact on Man5 level. Of note, Mab A and Mab B have minimal sialylation, and thus are not suitable molecules to evaluate the potential impact of the ammonium profile differences on sialylation. Nonetheless, the ability to control ammonium at a low level throughout the entire culture duration would make it a very favorable condition for molecules where sialylation needs to be tightly controlled (page 1174, column 1, paragraph 1, page 1183, column 2, paragraph 2-page 1185, column 2, paragraph 2).
Sissolak identifies that post-translational modifications affect the micro-heterogeneity of the product and thereby influence important quality attributes, such as stability, solubility, pharmacodynamics and pharmacokinetics. The analysis of the surface charge distribution of monoclonal antibodies provides aggregated information about these modifications. They were able to provide insights into charge variant formation during a fed-batch process of a Chinese hamster ovary cell culture, in turn producing a monoclonal antibody under varying temperatures and glucose feed
strategies. Glucose concentration impacted the total emergence of acidic variants, whereas the variation of basic species was mainly dependent on process temperature. The recombinant cell line, the culture media and the process settings affect these quality attributes. During process development, it is important to ensure a reproducible, distinct and preferably homogenous pattern of the product. For the establishment of biosimilars, it is important to match the characteristics of the originator product. One additional important measure of mAb heterogeneity is the distribution of surface charge variants. Due to numerous modifications, the net surface charge of mAbs can be altered. Charge species with a lower isoelectric point (pI) than the main fraction of the product are defined as acidic variants and generated by sialylation, deamidation of asparagine and glutamine, glycation and other mechanisms. Glycation, for instance, is a non-enzymatic reaction where a reducing sugar molecule, most commonly glucose, is covalently bound to a reactive amino group. Basic variants are defined as species with a higher pI than the main fraction and generated by incomplete C-terminal lysine clipping of the heavy chains, as well as by fragmentation and aggregation. Several studies indicate that mAb variants can lead to varying biological responses. For instance, it was shown that the basic variants exhibited an increased
binding to the FC and the neonatal receptor, indicating an increased half-life. Another study reported that only a few specific variants of the tested mAb had a statistical
relevant impact on the cell proliferation assay. Hence, to know and understand the mechanism behind the charge heterogeneity is of particular importance. Monitoring and controlling of product quality are required for the whole production chain. The successful
application of process analytical technology (PAT) and quality by control (QbC) to bioprocesses requires reliable and unbiased product quality data over the time course
of a fermentation process.
The process temperatures had a significant impact on overall productivity, growth
rates and viability of the cells (see Fig. 2). Reduced process temperature can, moreover, be used for the proliferation control of cell culture processes. Even though glucose concentrations in the cultures varied from 2 to 15 g/L (Fig. 2d), depending on the feed and temperature, almost no impact on the monitored process
variables could be detected. To evaluate the impact of process variation on charge
distribution, several fed-batch samples from day 4, followed by samples after the temperature shift until the harvest criteria with a viability of 70%, were applied to the CEX column (n = 36). In turn, it became obvious that variation in the process parameters, glucose concentration and temperature affected the charge variant distributions to a great extent (see Fig. 3). Since the glucose concentration had no
apparent influence on cell metabolism, it was supposed to have affected the mAb charge distribution in an extracellular manner (see Fig. 3a, c, e, g). This is also evidenced by the fact that the K0 main proportion correlates linearly with the percentage of acidic species (Fig. 3a). The resulting basic species are in opposition to this observation due to the fact that they mostly derive from incomplete C-terminal
lysine processing, which is a known intracellular process (see Fig. 3b, d, f). Under these defined process conditions, the basic species were generally rare, which suggests that C-terminal lysine processing occurred almost completely. However, process temperature predominantly affected the basic variant formation. Evidently, lowering the temperature resulted in imperfect C-terminal lysine processing. The vast impact of glucose on the micro-heterogeneity of the mAb was evident. The highest main variant (K0) content was observed at 34 °C with Feed 1 (low glucose). At an
elevated glucose concentration, the amount of K0 was significantly reduced. For instance, the process at 31 °C with Feed 3 (high glucose) resulted in the highest charge heterogeneity. Acidic variants were the most abundant variants and ranged
from 60 to 90% of the total peak area. It was obvious that an increase in the acidic species was attended by a decrease in the main variant (see Fig. 3a). The process at 31 °C, however, exhibited a slight parallel shifted linear correlation, due to the increased amount of basic species. At 31 °C, the proportion of basic variants was, on average, 5% higher than in the case of the other processes, which resulted in a decreased offset value of around the same proportion. However, both correlations exhibited a similar slope (Fig. 3a). The acidic heterogeneity was mainly dependent on the feed
used; thus, an increase in glucose in the supernatant resulted in an enriched fraction of acidic variants (see Fig. 3c, e). It was lowest at 34 °C and 37 °C when a low glucose feed was applied. Acidic variant formation was mainly provoked by two parameters: the
increasing total amount of main variants and incremental glucose concentration in the supernatant (abstract , page 1167, column 1, paragraph 1-page 1168, column 1, paragraph 3, page 1172, column 1, paragraph 2-column 2, paragraph 2).
As such, the prior art shows that a careful consideration of the recombinant cell line, the culture media, the antibody being produced, and the process settings affect the unique properties of the produced antibodies.
Level of predictability in the art: The prior art has successfully reduced to practice careful consideration of the recombinant cell line, the culture media, the antibody being produced, and the process settings affect the unique properties of the produced antibodies. As such, this results in unpredictability about how someone can use this method to generate specific antibody populations as outlined in claims 5-8 without identifying the type of recombinant cells, the process steps, and the culture media used.
Amount of direction provided by the inventor and existence of working examples: The Applicant discloses that they produced an adalimumab antibody from Chinese hamster ovary cells (CHO) in an amount of 1.1 mL into 24 disposable culture vessels, each with a volume of 15 mL, and the culture solution was cultured for a total of 12 days in an Ambr®15 bioreactor of Sartorius under the culture conditions shown in Table 1: A temperature shift from 37°C to 35°C on the fifth day of culture or continuous 37°C culture; at pH 6.9, 7.0 or, 7.1; and with/without lactic acid supply. Specifically, 12 of the 24 culture vessels were assigned to a group in which the temperature was changed during culture (CS1-1 to CS1-12), and the other 12 culture vessels were assigned to a group in which the temperature was not changed (CS2-1 to CS2-12), and each group was further divided into three subgroups, which were respectively cultured under conditions of pH 6.9, pH 7.0, and pH 7.1. In addition, one culture vessel per subgroup under each pH condition was cultured by injecting 100 μl of 1 M l-lactic acid solution per 10 ml of working volume (WV) every day from the 7th to the 11th day of culture.
It was confirmed that the IgG titer of the culture medium was significantly affected by both culture temperature and pH conditions, and in particular, it was confirmed that the IgG titer was more affected by temperature than pH. In addition, within a certain range, the lower the temperature and the higher the pH, the higher the IgG titer. Accordingly, it was confirmed that conditions of a relatively high pH of 7.0 to 7.1 and conditions of applying a temperature change of lowering the culture temperature from the initial temperature of 37 °C to 35 °C were advantageous for increasing antibody productivity of the recombinant cells.
It was confirmed that the CS1 group that was subjected to a temperature change from 37 °C to 35 °C on the 5th day of culture generally exhibited a higher proportion of main active antibodies compared to the CS2 group that was not subjected to a temperature change. In addition, it was confirmed that within a certain range, the lower the pH, the higher the proportion of main active antibodies, and it was confirmed that under the same pH conditions, the proportion of main active antibodies was higher when lactic acid was added to the medium from the 7th day of culture (FIGS. 3A and 3B). The results for the overall effect of pH and temperature conditions on the proportion of main active antibodies are shown in FIG. 3C, and specifically, it was found that pH and temperature changes have a significant effect on the proportion of main active antibodies, and in particular, it was confirmed that pH conditions have a greater effect on the proportion of main active antibodies than temperature conditions. In addition, it was confirmed that within a certain range, the lower the pH and the lower the temperature, the higher the proportion of main active antibodies (FIG. 3C).
The results for the overall effect of pH and temperature conditions on the proportion of acidic isomeric antibodies are shown in FIG. 4C. Specifically, it was found that temperature changes have a greater effect on the proportion of acidic isomeric antibodies than pH changes, and it was confirmed that within a certain range, the lower the temperature, the lower the proportion of acidic isomeric antibodies (FIG. 4C).
The results for the overall effect of pH and temperature conditions on the proportion of basic isomeric antibodies are shown in FIG. 5C, and specifically, it was found that pH and temperature changes have a significant effect on the proportion of basic isomeric antibodies, and in particular, it was confirmed that pH conditions have a greater effect on the proportion of basic isomeric antibodies than temperature conditions. In addition, it was confirmed that within a certain range, the lower the pH and the higher the temperature, the lower the proportion of basic isomeric antibodies (FIG. 5C).
Specifically, in the case of the main active antibody, when lactic acid was added, it was observed that the antibody proportion was increased in both the CS1 group that was subjected to a culture temperature change and the CS2 group that was not subjected to a culture temperature change, and it was found that the antibody proportion increased about 1.5% to 6.6% depending on the pH conditions (FIG. 6A).
In the case of the acidic isomeric antibody, when lactic acid was added, an increase in the antibody proportion of about 0.6% to 3.1% was observed depending on pH conditions in the CS1 group that was subjected to a culture temperature change, and in the CS2 group that was not subjected to a culture temperature change, it was observed that the antibody proportion increased about 0.9% or decreased about 0.8% to 2.1% depending on the pH conditions (FIG. 6B).
In the case of the basic isomeric antibody, when lactic acid was added, it was observed that the antibody proportion decreased in both the CS1 group that was subjected to a culture temperature change and the CS2 group that was not subjected to a culture temperature change, and it was found that the antibody proportion decreased about 2.1% to 4.7% depending on the pH conditions (FIG. 6C).
It was found that under conditions of pH 7.0, when lactic acid was not added, 72.41% of the G0F form, 4.51% of the G0F-N form, and 4.37% of the G0F+GN form were included, and when lactic acid was added, 70.23% of the G0F form, 5.71% of the G0F-N form, and 4.39% of the G0F+GN form were included. The afucosylation results were analyzed to be 4.72% and 4.87%, respectively, and the galactosylation results were analyzed to be 84.52% and 85.47%, respectively.
It was found that under conditions of pH 7.1, when lactic acid was not added, 71.25% of the G0F form, 4.35% of the G0F-N form, and 4.39% of the G0F+GN form were included, and when lactic acid was added, 76.07% of the G0F form, 3.76% of the G0F-N form, and 3.31% of the G0F+GN form were included. The afucosylation results were analyzed to be 5.12% and 4.88%, respectively, and the galactosylation results were analyzed to be 83.39% and 86.60%, respectively (Examples 1-4).
Quantity of experimentation needed: In light of the above factors, the prior art and the Applicant disclose that careful consideration of the recombinant cell line, the culture media, the antibody being produced, and the process settings affect the unique properties of the produced antibodies. Therefore, a defined protocol is necessary to generate the specified antibody populations of claims 5-8. As such, these essential steps are considered to be missing from claims 5-8. There would be undue experimentation related to any culturing method that does not have a defined protocol in line with the prior art and the Applicant’s specification to practice the full scope of the claim.
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, 3, and 5-6 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20130295613 (Kishishita; referenced in IDS).
Regarding claims 1, 3, and 9, Kishishita teaches that a method of producing an antibody population, comprising:
culturing CHO cells to produce monoclonal antibodies at a normal culture temperature (37°C.) for 4-6 days, and then the culture is continued at a culture temperature lowered to 35°C for 6-8 days, wherein for both culture conditions, the pH is 7.0 (paragraphs 0012-0059).
Regarding claims 5-6, Kishishita teaches that the modulation of the level of heterogeneity components of the desired protein includes reduction of charge heterogeneity. “Charge heterogeneity' refers to a phenomenon where the electric charge of a protein goes heterogeneous due to level of components with a higher p than the main component (basic peaks) and components with a lower pI (acidic peaks), which is caused by differences in deamidated form, amino acid substituted or -deleted form, and sugar chain structure. The modulation of the level of heterogeneity components of the desired protein includes reduction of level of acidic peaks. The acidic peaks of a protein refer to components with a lower pI than the main component and are typically formed due to differences in deamidated form and sugar chain structure. The acidic peaks are determined by ion exchange chromatography and calculated as a proportion (%) to the main component. The resulting monoclonal antibody can be isolated and purified so that the desired protein can be yielded. In cases where the desired protein is an antibody, protein A chromatography is used advantageously but this is not the sole example. Furthermore, by using various affinity based separation or fractionation methods, antibodies can be separated according to their immunoglobulin class or fractionated based on their antigen affinity (paragraphs 0038-0040 and 0062-0063).
As such, Kishishita teaches that the more acidic (isomeric) components can be separated from the main component antibodies using chromatography. Therefore, purification of the main component away from the isomeric, acidic component would lead to a pure fraction of main component antibodies that would be ~100% pure, fulfilling the requirements of claims 5-6.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20130295613 (Kishishita) as applied to claim 1 above, and further in view of Eyster et al. (Biotechnol Progress 37: 1-13. 2021; referenced in IDS).
The teachings of Kishishita are as discussed above.
Kishishita does not teach adding lactic acid to their culture after the temperature shift.
Eyster teaches that process development scientists have several tools at their disposal for modulating mAb glycosylation. One method for rapid modulation of glycosylation is control of nutrient feeds to the bioreactor. Feeds can alter cell metabolism and therefore specific process outcomes such as waste accumulation; an example of one such feed is lactic acid. While it is traditionally thought of as a metabolic waste product in mammalian bioprocesses, and many processes have an explicit goal of reducing its accumulation, feeding a low amount of lactic acid to a CHO bioprocess can lower accumulation of ammonium. Ammonium is a potent metabolic waste product known to negatively affect process outcomes such as cell growth, and correlates with changes to glycosylation to recombinant IgGs and erythropoietin. In addition, increasing ammonium has been noted to negatively impact IgG4 galactosylation. Thus, they examined whether using lactic acid feeding as a process lever for tuning ammonium, and in turn modulating galactosylation. Three feeding strategies were assessed for impact on cell metabolism, productivity, and product quality: bolus-fed glucose, glucose control at 4 g/L, or simultaneous glucose control at 4 g/L and lactate control at 2 g/L using 1.5 M lactic acid. For Raman-controlled reactors, glucose and/or lactate setpoints were maintained by automated delivery of concentrated stock solutions based on the output of the feedback control algorithm described below. The third feeding strategy resulted in a significant reduction in ammonium levels (68%) while increasing mAb galactosylation levels by approximately 50%. They showed that Raman based feeding of lactic acid resulted in a significant impact on CHO metabolism, drastically lowering ammonium accumulation, and increasing galactosylation of a mAb product (abstract, and page 1, column 1, paragraph 1-page 2, column 2, paragraph 1).
As can be seen in Figure 5, lactic acid reaches the 2 g/L control point around day 4.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the antibody production method of Kishishita by adding lactic acid every day from the first day of culture at the second temperature to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Eyster teaches that while it is traditionally thought of as a metabolic waste product in mammalian bioprocesses, and many processes have an explicit goal of reducing its accumulation, feeding a low amount of lactic acid to a CHO bioprocess can lower accumulation of ammonium. Ammonium is a potent metabolic waste product known to negatively affect process outcomes such as cell growth, and correlates with changes to glycosylation to recombinant IgGs and erythropoietin. In addition, increasing ammonium has been noted to negatively impact IgG4 galactosylation. The third feeding strategy involving lactate control at 2 g/L resulted in a significant reduction in ammonium levels (68%) while increasing mAb galactosylation levels by approximately 50%. This showed that feeding of lactic acid resulted in a significant impact on CHO metabolism, drastically lowering ammonium accumulation, and increasing galactosylation of a mAb product.
Regarding the timing of adding the lactic acid, Figure 5 of Eyster shows that lactic acid buildup reaches its peak around day 5 and above the lactic acid control amount of 2 g/L on day 4. As the temperature shift can occur after 4 days of culturing, it would have been well understood that the lactic acid could be added on day 5, when it reaches its peak to control lactic acid and ammonia levels for the entirety of the second culture step.
Regarding the specific concentration of lactic acid being added (80 to 120 μl of 0.1 to 2 M lactic acid per 10 ml of a medium every day), Eyster does not identify the specific concentration of lactic acid added each day as part of their method. However, it would have been obvious to one of ordinary skill in the art that they could undertake routine optimization and reach the concentration of the lactic acid addition. MPEP 2144.05 (II) discloses that, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 155, Song teaches that ex vivo modification of cells has been used to treat cancer (Table 2, row 6).
Claims 3 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20130295613 (Kishishita) as applied to claim 1 above, and further in view of United States Patent Application No. 20160115225 (Chumsae).
Regarding claim 3, the teachings of Kishishita are as discussed above.
Kishishita is silent regarding the monoclonal antibodies that can be produced using their method.
However, Chumsae teaches a method of producing adalimumab antibodies comprising:
Culturing recombinant cells for four days at 35°C then shifting the temperature to 33°C to alter the amount of acidic species formed as part of their method (paragraphs 0009-0017).
Therefore, it was already well understood that adalimumab monoclonal antibodies could be produced using a culture method incorporating a temperature shift 2°C below the original culture temperature. As such, one of ordinary skill in the art would readily understand that adalimumab could be produced using the antibody production method outlined by Kishishita.
Regarding claims 7-8, Figure 7 and Example 4 of the instant specification identify that an adalimumab production method at pH 7.0 with a temperature shift from 37°C to 35°C at day 4 of culture without the addition of lactic acid led to the specific antibody properties of claims 7-8. As the combined method of Kishishita and Chumsae is the same as that used in the specification, it naturally flows that the adalimumab antibodies produced by the combined method of Kishishita and Chumsae would have the same properties.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20130295613 (Kishishita) and Eyster et al. (Biotechnol Progress 37: 1-13. 2021) as applied to claim 1 above, and further in view of United States Patent Application No. 20160115225 (Chumsae).
The teachings of Kishishita and Eyster are as discussed above.
Kishishita and Eyster are silent regarding the monoclonal antibodies that can be produced using their methods.
However, Chumsae teaches a method of producing adalimumab antibodies comprising:
Culturing recombinant cells for four days at 35°C then shifting the temperature to 33°C to alter the amount of acidic species formed as part of their method (paragraphs 0009-0017).
Therefore, it was already well understood that adalimumab monoclonal antibodies could be produced using a culture method incorporating a temperature shift 2°C below the original culture temperature. As such, one of ordinary skill in the art would readily understand that adalimumab could be produced using the antibody production method outlined by Kishishita and Eyster.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KEENAN A BATES/Examiner, Art Unit 1631
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