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 .
Applicant’s amendments and arguments of September 4, 2026, are entered.
Claims 1, 20, and 21 have been amended.
Claim 25 has been newly added.
No claims have been canceled.
Status of Claims
Claims 1-14 and 20-25 are pending.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on September 4, 2026, was filed before the mailing of the Non-Final Office Action on September 26, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Claim Objections
Considering Applicant’s amendments for claims 20 and 21, the objection for being substantially duplicate is withdrawn.
Claim Rejections - 35 USC § 112
Considering Applicant’s amendments for claim 1, the §112(b) rejection is withdrawn.
Claim Rejections - 35 USC § 102
The rejection is repeated with regard to claims 1-4, 7-10, 12-14, and 20-24 for the same reasons of record as set forth in the Official action mailed June 4, 2026, and is also applied to newly added claim 25. A response to Applicant’s traversal follows the reiterated rejection below.
Regarding claim 1, Pla et al. teaches a method of producing a protein of interest from a mammalian cell culture comprising [Summary of the invention ¶ 1]: (a) culturing a mammalian cell expressing a protein of interest in a second cell culture media having 0.05 mg/L or less Insulin Like Growth Factor (IGF-1) to express the protein of interest [Para starting with “The IL-18 expressing CHO cell line was cultivated in a growth medium 2xP (SR-371)…”]; (i) comprises a heterologous nucleic acid encoding the protein of interest [Para starting with “The invention also includes a method of producing a protein, e.g., an antibody or antigen-binding portion thereof…”]; (ii) has been directly adapted to grow in a first cell culture media having 0.03 mg/L or less IGF-1 [Para starting with “The invention includes a serum-free culture medium comprising: a basal medium…recombinant human insulin…”]; and (iii) is a progeny of an individual cell isolated from a population of directly adapted mammalian cells by single-cell cloning [Para starting with “Following transformation of a suitable mammalian host cell, e.g., CHO cell, with polynucleotide sequences encoding a recombinant protein…”]; and (b) recovering the protein of interest produced by the mammalian cell [Para starting with “In one embodiment, the invention includes further recovering the anti-TNF[alpha] antibody”].
Regarding claim 2, Pla et al. teaches the method of claim 1, wherein the second cell culture media contains less than 0.03 mg/L of IGF-1 [Para starting with “The invention includes a serum-free culture medium comprising: a basal medium…recombinant human insulin…” and Table 5 and Table 6 showing the absence of IGL-1].
Regarding claim 3, Pla et al. teaches the method of claim 2, wherein the first cell culture media contains no IGF-1 [See citations to claim 2’s rejection].
Regarding claim 4, Pla et al. teaches the method of claim 1, wherein the first cell culture contains no IGF-1 [See citations to claim 2’s rejection].
Regarding claim 7, Pla et al. teaches the method of claim 1, wherein the titer of the expressed protein of interest is at least 50 mg/L at day 10 of the culture [Para starting with “The IL-18 expressing CHO cell line was cultivated in a growth medium 2xP (SR-371), and later in a production medium 3XP (SR-372) for a final titer of approximately 1g/L.”].
Regarding claim 8, Pla et al. teaches the method of claim 1, wherein the protein of interest is an antigen binding protein [See claim 7’s rejection citation].
Regarding claim 9, Pla et al. teaches the method of claim 8, wherein the protein of interest is selected from the group consisting of monoclonal antibodies, bi-specific T cell engagers, immunoglobulins, Fc fusion proteins and peptides [See claim 7’s rejection citation].
Regarding claim 10, Pla et al. teaches the method of claim 1, wherein the mammalian cell culture is fedbatch culture process, a perfusion culture process, or a combination thereof [Summary of the invention ¶ 1].
Regarding claim 12, Pla et al. teaches the method of claim 1 wherein the mammalian cell is a Chinese Hamster Ovary (CHO) cell [Para starting with “In one embodiment, the cell culture media and methods of the invention are for culturing mammalian cells, including Chinese Hamster Ovary (CHO) cells.”].
Regarding claim 13, Pla et al. teaches the method of claim 12, wherein the CHO cell is deficient in dihydrofolate reductase (DHFR-) or is a glutamine synthetase knock out (GSKO) cell [Para starting with “A useful high expression vector, pCAVNOT, has been described by Mosley et al.”].
Regarding claim 14, Pla et al. teaches the method of claim 1, wherein the recovered protein of interest is purified and formulated in a pharmaceutically acceptable formulation [Para starting with “One goal of recombinant protein production is the optimization of cell culture media and conditions…” and “The invention also optionally encompasses further formulating the proteins.”].
Regarding claim 20, Pla et al. teaches a method of producing a protein of interest from a mammalian cell culture comprising [Summary of the invention ¶ 1]: (a) directly culturing a population of mammalian cells that had been grown in a cell culture media containing Insulin Like Growth Factor (IGF-1) in a first cell culture media having 0.03 mg/L or less IGF-1, without prior serial adaptation of the population in media having progressively reduced concentrations of IGF-1 [Para starting with “The invention includes a serum-free culture medium comprising: a basal medium…recombinant human insulin…”]; (b) obtaining an individual cell from the population of mammalian cells by single cell cloning [Para starting with “Following transformation of a suitable mammalian host cell, e.g., CHO cell, with polynucleotide sequences encoding a recombinant protein…”]; (c) expanding the population of progeny mammalian cells in a second culture media having 0.05 mg/L or less IGF-1 to express a protein of interest, wherein the population of progeny mammalian cells comprises a heterologous nucleic acid encoding the protein of interest [Para starting with “The invention includes a serum-free culture medium comprising: a basal medium…recombinant human insulin…” and “Cells producing the highest levels of recombinant protein may be cloned by methods well-known in the art, for example, by multiple rounds of limiting dilution”]; and € recovering the protein of interest produced by the population of progeny mammalian cells [Para starting with “In one embodiment, the invention includes further recovering the anti-TNF[alpha] antibody”].
Regarding claim 21, Pla et al. teaches the method of claim 20, wherein the mammalian cells are Chinese Hamster Ovary (CHO) cells deficient in dihydrofolate reductase (DHFR-) or are glutamine synthetase knock out (GSKO) CHO cells [Summary of the Invention ¶ 1, Para starting with “Following transformation of a suitable mammalian host cell, e.g., CHO cell, with polynucleotide sequences encoding a recombinant protein”].
Regarding claim 22, Pla et al. teaches the method of claim 20, wherein the recovered protein of interest is purified and formulated in a pharmaceutically acceptable formulation [Para starting with “One goal of recombinant protein production is the optimization of cell culture media and conditions…” and “The invention also optionally encompasses further formulating the proteins.”].
Regarding claim 23, Pla et al. teaches the method of claim 20, wherein the protein of interest is an antigen binding protein [Para starting with “The IL-18 expressing CHO cell line was cultivated in a growth medium 2xP (SR-371), and later in a production medium 3XP (SR-372) for a final titer of approximately 1g/L.”].
Regarding claim 24, Pla et al. teaches the method of claim 20, wherein the protein of interest is selected from the group consisting of monoclonal antibodies, bi-specific T cell engagers, immunoglobulins, Fc fusion proteins and peptibodies [See claim 23’s rejection citations].
Regarding claim 25, Pla et al. teaches the method of claim 20, wherein the mammalian cells are Chinese Hamster Ovary (CHO) cells [Summary of the Invention ¶ 1].
Response to Argument
Applicant’s argument regarding claims 1 and 20 have been considered but have not been found persuasive.
Regarding the IGF-1 concentration limitation, Applicant argues that Pla et al. (‘517 reference) is silent regarding the IGF-1 and that the absence of IGF-1 from a disclosed culture medium does not establish the claimed direct-adaptation process. However, Pla et al. expressly discloses the compositions of the cell culture media used in the disclosed methods [See tables 4 and 5]. Specifically, Table 4 identifies the media used for culturing CHO cells expressing anti-IL18 and anti-EPO/R antibodies. The disclosed media formulations do not identify IGF-1 as a component and instead include recombinant human insulin. Furthermore, Applicant’s own specification expressly states “[i]n direct adaptation, the cells are only adapted to a single culture media having a concentration of IGF-1, which can include no IGF-1” [¶ 0060 Applicant’s specification]. Given this, Applicant has expressly contemplated an IGF-1 concentration of zero. Therefore, the Pla et al. media disclosed by Pla et al. falls within the claimed concentration of 0.03 mg/L or less IGF-1”.
Regarding direct adaptation and the absence of serial adaptation, Applicant argues that cultivation of IGF-1 deficient medium does not necessarily establish direct adaptation and that Pla et al. fails to disclose the claimed adaptation process. However, Pla et al. does not merely disclose cultivation of recombinant mammalian cells in a particular medium. Pla et al. expressly teaches that the cells were passaged for at least five generations until adaptation was observed [Para starting with “To evaluate the growth and titer promoting characteristics of the above combination feeds”]. Here, Pla et al. teaches IGF-1 free media and adaptation of mammalian cells through passaging until a constant growth rate is observed.
Pla et al. further teaches that the disclosed medium was developed into two production platforms used in two separate projects for culturing recombinant CHO cells. One platform was directed to production of anti-IL18, while the other was directed to production of anti-EPO/R, therefore establishing that the disclosed culture media was employed in recombinant production platforms.
Regarding the single-cell cloning, progeny expansion, and MPEP §2113, Applicant argues that Pla et al. fails to disclose isolation of an individual cell from directly adapted population, single-cell cloning, and subsequent expansion and passaging of progeny to provide a production-cell population. However, Pla et al. expressly teaches that, following transformation of a suitable mammalian host cell, such as CHO cells, with polynucleotide sequences encoding a recombinant protein, cells demonstrating stable recombinant protein expression are identified and isolated. Pla et al. further teaches transfection of dihydrofolate reductase-deficient CHO cells, followed by isolation and testing of individual clones demonstrating the highest recombinant protein expression, and selection of a specific cell line for manufacturing based on growth and production in small-scale spinners and larger-scale bioreactors [Para starting with “Following transformation of a suitable mammalian host cell”]. This disclosure expressly teaches expansion of a clone from an individual cell that necessarily produces progeny derived from that founding cell. Pla et al. additionally teaches subsequent cultivation and evaluation of selected cell lines for recombinant manufacturing. Additionally, under MPEP § 2113, the “single cell cloning” language is merely describing the provenance of the starting cell line and does not meaningfully distinguish he claimed method over Pla et al. absent a claimed resulting difference in the cell itself. More specifically, Pla et al. describes a DHFR- CHO cell that is similar to Applicant’s DHFR- CHO cell given that Applicant states at paragraph [0065] CHO cells are widely used to produce complex recombinant proteins. Furthermore, both Pla et al. and Applicant specifically cite CHO strain DX-B11 as a CHO line that is deficient in DHFR citing to the exact same reference. Based on this, claims 1-4, 7-10, 12-14, and 20-25 remain rejected under §102.
Claim Rejections - 35 USC § 103
This rejection is repeated for claims 5-6 and 11 for the same reasons of record as set forth in the Official action mailed on June 4, 2026. A response to Applicant’s traversal follows the reiterated rejection below.
Claims 5-6 and 11 remain rejected under 35 U.S.C. §103 as being unpatentable over Pla et al. [WO 2008 033517 A2].
Regarding claims 1-4, Pla et al. teaches each and every limitation recited in claims 1-4. However, Pla et al. does not specifically teach the limitations of claims 5 and 6.
Regarding claims 5 and 6, Pla et al. teaches improved cell culture media for growing mammalian cells and optimized methods and media formulations for achieving high recombinant protein expression [Background of the Invention]. Pla et al. further teaches optimizing culture conditions, including temperature, pH, culture duration, and medium composition to achieve desired cell growth and production characteristics and expressly teaches selecting an optimal clone based on growth characteristics that include fast doubling times and highest cell density in culture for protein production [Para starting with “Cells producing the highest levels of recombinant protein may be cloned”]. Pla et al. also teaches the use of passaging cells until adaptation is observed through constant growth [Para starting with “To evaluate the growth and titer promoting characteristics of the above combination feeds”]. Although, Pla et al. does not expressly disclose comparing the adapted cells with cells of the same lineage that have not undergone direct adaptation, Pla et al. recognizes growth rate and cell doubling time as important characteristics for selecting suitable recombinant protein-producing cell lines.
Regarding claim 11 where the mammalian cell culture is established by inoculating a bioreactor of at least 100 L with specified cell culture concentration in a serum-free culture media with 0.03 mg/L or less of IGF-1, please see the analysis for claims 5 and 6. Furthermore, MPEP § 2144.05(II)(A) states “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).” Additionally, Pla et al. contemplates the use of shake flasks, small scale bioreactors, and/or large-scale bioreactors [Para starting with “Typically, cell culture is performed under sterile, controlled temperature and atmospheric conditions”]. Furthermore, Applicant’s specification merely recites the claimed bioreactor size and cell concentration without identifying and particular criticality or unexpected results associated with the recited values.
Given this, it would have been prima facie obvious to a person skilled in the art prior to the filing of the claimed invention to modify the systems and methods of Pla et al. that discloses methods for expanding transfected CHO cells expressing a recombinant protein of interest where Pla et al. specifically teaches optimizing culture conditions, including temperature, pH, culture duration, and medium composition to achieve desired cell growth and production characteristics and expressly teaches selecting an optimal clone based on growth characteristics that include fast doubling times and highest cell density in culture for protein production and Pla et al. also teaches the use of passaging cells until adaptation is observed through constant growth where Pla et al. expressly discloses that spinner flasks, small-scale bioreactors, and/or large scale bioreactors can be used in cell expansion. Based on this, a person of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed size of the bioreactor based on need with the claimed cell concentration given cell concentration could be adjusted based on need and the selected method for expanding and/or production of the recombinant protein of interest. This is especially true given 100 L size bioreactors are well known in the art since commercial size bioreactors can be as large as 2000 L.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument
Applicant argues that routine optimization of the parameters recited in claims 5, 6, and 11 would not yield a mammalian cell directly adapted to low IGF-1 medium and derived from a single cell isolated by single-cell cloning. Examiner does not find the argument persuasive. Examiner’s routine-optimization rationale is directed to the additional limitations recited in dependent claims 5, 6, and 11. Although these limitations do inherent all of the limitations of claim 1, the rejection and response to argument as been separately addressed for the rejection in claim 1. Furthermore, Applicant’s argument does not address the core rational of examiner’s rejection under §103 that are directed to the additional growth and production parameters. Applicant further argues that Pla et al. does not establish routine optimization would predictably yield the claimed growth characteristics. However, Pla et al. expressly teach an improved cell culture media and optimized methods and media formulations for achieving high recombinant protein expression in mammalian cell cultures. Pla et al. further teaches the optimizing culture conditions that include temperature, pH, culture duration, and medium composition. More importantly, Pla et al. expressly teaches selecting optimal clone based on growth characteristics, including the fastest doubling time and highest cell density for use in recombinant protein production. Applicant’s own specification describes expanding and passaging cells until adaptation is achieved, characterized by viability of at least 90% and a normal growth rate, such as doubling time of 30 hours or less [¶ 0009]. However, Pla et al. provides motivation to optimize growth characteristics and select cells exhibiting desirable proliferation and production characteristics. Routine-optimization is based on the recognized relationship between these parameters and cell culture performance, rather than the assertion that any parameter may be routinely optimized [See MPEP § 2144.05]. Applicant further argues that table 12 does not represent an experiment isolating temperatures as a variable and does not establish that temperature optimization would predictably yield the claimed growth characteristics. However, claims 5, 6, and 11 do not recite a particular temperature or temperature range. Furthermore, the examiner’s rationale is not predicated solely on temperature. The teachings in Pla et al. are directed to a multitude of variables that are such as temperature, pH, cell density, type of expansion system, culture media, etc. that are known variables when optimizing growth characteristics.
Regarding the absence of comparative growth data, Applicant argues that Pla et al. does not provide comparative growth data demonstrating that directly adapted cells exhibit growth rates comparable to cells of the same lineage that have not undergone direct adaptation. However, Pla et al. does teach selecting optimal clones exhibiting desirable growth characteristics including rapid doubling times and high cell densities. Pla et al. also teaches that passaging cells until adaptation is observed through constant growth rate. This disclosure establishes that growth rate was a recognized characteristic for evaluating adapted cells and selecting recombinant protein-producing cell lines. Here, the rational is directed to the obviousness of selecting and optimizing cells for desirable growth characteristics.
Regarding Applicant’s alleged unexpected results, Applicant argues that the experimental results described in the specification demonstrate that the claimed direct-adaptation and clonal-selection procedures were not routine or predictably successful. In particular, Applicant relies on results showing that cells subjected to gradual adaptation through 110 population doubling levels did not perform as well as parental host cells. For this, Applicant has not established that the gradual-adaptation procedure employed in these experiments correspond to the adaptation procedures disclosed by Pla et al. where the prior art teaches passaging cells until adaptation is observed through a constant growth rate, whereas Applicant’s comparative experiments concern a particular gradual adaptation procedure involving 110 population doublings. Also, Applicant is relying on experimental results obtained using GSKO host cells. However, the claims are not limited to GSKO cells and additionally encompass DHFR-deficient CHO cells which are expressly disclosed by Pla et al.
Applicant further relies on experimental results obtained using a 200 L production-scale bioreactor reporting comparable growth and recombinant protein titer. However, claim 11 recites a 100 L bioreactor. The reported results demonstrate that Applicant’s process was successfully implemented as a different production scale but does not establish that the specifically claimed 100 L bioreactor provides unexpected results or that the claimed size is critical.
For these reasons, the §103 rejection for claims 5, 6, and 11 are being maintained.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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