DETAILED ACTION
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 final rejection. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 02/22/2026 has been entered.
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 .
Status of the Claims
Claims 1, 13, 15, 17-24, 34-35, and 38-44 are pending (claim set as filed on 02/22/2026).
Applicant’s election without traverse of Group II, method claims, in the reply filed on 12/14/2024 is acknowledged. The product claim is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Therefore, only method claims 13, 15, 17-24, 34-35, and 38-44 are presented for examination.
Priority
This application is a CON of 16/088,676 (now abandoned) filed 09/26/2018, which is a 371 of PCT/IB2017/051692 filed 03/23/2017, which has a PRO 62/318,275 filed 04/05/2016.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/23/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Withdrawal of Rejections
The response and amendments filed on 02/22/2026 are acknowledged. Any previously applied minor objections and/or minor rejections, not explicitly restated herein for brevity, have been withdrawn necessitated by Applicant’s formal corrections and/or amendments.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 13, 15, 17-24, 34-35, and 38-44 are rejected under 35 U.S.C. 103 as being unpatentable over Luan (US Patent no. 8,232,075) in view of Mukai (JP S49-4454-B) - previously cited references.
Luan’s general disclosure relates to methods for rationally designing cell culture media for use in cell cultures, e.g., cell cultures employed in polypeptide production; cell culture media
designed with the disclosed methods; methods of producing a polypeptide of interest, e.g., an antibody, using such media; polypeptides produced using the methods and media (see abstract & col. 1-2, lines 13-7).
Luan teaches large-scale cell culture (e.g., 500 L) (see col. 2, lines 11-24, & col. 6, lines 39-61). In particular, Luan teaches a method of cell culture comprising: providing a cell culture, comprising: cells; and a desired cell culture medium, comprising a concentration of an amino acid that is calculated for use in cell
mass and a concentration of the amino acid that is calculated for use in cell maintenance; and maintaining the cell culture under conditions that allow growth and replication of the cells
in the cell culture (see col. 3-4, lines 61-2).
Regarding the amino acids, Luan discloses “it is known that modification of the total cumulative concentration of amino acids, the concentration of individual amino acids, and the ratios of individual amino acids to each other and to total amino acids in the media of a large-scale cell culture can result in substantially improved large-scale polypeptide production” (see col. 1, lines 53-59, and col. 2, lines 25-30, and col. 18-19, lines 42-29). Luan teaches “the desired cell culture medium comprises greater than or equal to about 3 mM tyrosine. In another embodiments of the methods disclosed herein, the desired cell culture medium comprises: between about 7 mM and about 30 mM leucine; between about 7 mM and about 30 mM lysine; between about 7 mM and about 30 mM threonine; between about 7 mM and about 30 mM praline; and/or between about 7 mM and about 30 mM valine. In a further embodiment of the methods disclosed herein, the combined concentration of leucine, lysine, threonine, praline, and valine in the desired cell culture medium is between about 35 mM and about 150 mM. In yet another embodiment, the combined concentration of leucine, lysine, threonine, and valine in the desired cell culture medium is between about 60% and about 80% of the concentration of the total essential amino acids in the desired cell culture medium” (see col. 3, lines 24-40).
Regarding the cell density, Luan teaches “the terms "cell density," "cell concentration," or the like, as used herein, refer to that number, weight, mass, etc. of cells present in a given volume of medium. "Peak cell density" or the like refers to the maximum number of cells that can be reached in a given volume of medium, and "desired peak cell density" or the like refers to the maximum number of cells” (see col. 6, lines 62-67). Luan teaches 106 cells/mL and also teaches “another aspect of the invention provides a method for determining an optimized concentration of an amino acid used in a cell culture medium for the production of a polypeptide of interest in a cell culture, comprising: determining the amino acid concentration required for the cell mass of the cells in the cell culture at a target cell density” (see col. 4, lines 47-59, & Figures).
Regarding the recombinant protein, Luan teaches methods of producing a polypeptide of interest, e.g., an antibody, or a recombinant fragment thereof (see abstract, & col. 8, lines 5-30).
Regarding the cells, Luan teaches a number of mammalian cell lines are suitable host cells for recombinant expression of polypeptides including CHO cells, HepG2 cells, et. al. (see col. 9, lines 35-54, & Figures).
Luan teaches various methods of preparing mammalian cells for production of polypeptides by batch and fed-batch culture are well known in the art (see col. 25, lines 40-45).
However, Luan does not particularly teach: PVA and wherein the concentration is at least 2.5 g/L or between 0.5 - 5 g/L.
Mukai discloses that tyrosine is known to be one of the most poorly soluble amino acid in water in a pH region in the vicinity of neutrality (see page 1, last ¶). Mukai teaches a method of obtaining a concentrated aqueous solution of tyrosine by causing polyvinyl alcohol (PVA) to be present in an alkaline or acidic aqueous solution followed by neutralization (see page 1: 1st ¶ of Detailed Description of the Invention) wherein “tyrosine can be achieved without precipitating a tyrosine crystal” (see page 2, 1st ¶). The method of the present invention can be applied to, for example, preparation of a culture solution (see page 2, 2nd ¶).
Mukai further teaches “1 g of L-tyrosine is dissolved in 12 ml of a 1N-NaOH aqueous solution or 20 ml of a 1N-HCl aqueous solution, and the resulting solution is appropriately diluted with water to prepare an aqueous solution having a tyrosine concentration of 10 mg/ml. The pH of this aqueous solution is about 13 for an alkaline solution or about 1 for an acidic solution. To this solution, 10 mg/ml of a polyvinyl alcohol powder having a degree of polymerization of about 500 was added, and the resulting mixture is stirred for 30 minutes or more to dissolve the powder” (see page 2: Example 1). Mukai teaches “In the case of adding no polyvinyl alcohol, cloudiness was observed during neutralization” (see page 3, 2nd ¶). Examiner’s note: it is not definitively clear if the concentration values of PVA fall within the claimed concentration ranges because the prior art employs a different unit of measurement and moreover, the degree of polymerization and additive concentration of the PVA appears to affect the degree of cloudiness (see, e.g., Table 1 of Mukai).
It would have been obvious to one of ordinary skill in the art to employ or add polyvinyl alcohol (PVA) such as taught by Mukai in the method of Luan. The ordinary artisan would have been motivated to do so is because Mukai teaches that PVA helps with tyrosine stability or solubility in the cell culture media. If not expressly taught by the references with respect to the concentration ranges of the claimed elements, the MPEP at 2144.05 (I) states: “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists”. Moreover, one of ordinary skill in the art would recognize that the concentrations are a result effective variable dependent upon “calculated for use in cell mass, a concentration of the amino acid that is calculated for use in cell maintenance, and a concentration of the amino acid that is calculated for incorporation into the polypeptide of interest” as evidenced by Luan. Furthermore, the MPEP at 2144.05 states that:
II. ROUTINE OPTIMIZATION
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
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."
(a change in form, proportions, or degree "will not sustain a patent"); ("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.").
Therefore, one of ordinary skill following the guidance of cited references would recognize the concentrations of ingredients can be calculated, adjusted, and optimized. This is motivation for someone of ordinary skill in the art to practice or test the parameter values widely to find those that are functional or optimal which then would be inclusive or cover those values as instantly claimed. Absent any teaching of criticality by the Applicant concerning the concentrations of the ingredients, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variable which can be met as a matter of routine optimization (MPEP 2144.05 II).
Regarding claim 44 pertaining to the turbidity, claim interpretation: this claim is interpreted as a functional limitation which describes the claimed invention by its innate functions or properties rather than its distinctive structures or specific ingredients (MPEP 2173.05). The reference of Mukai is silent with respect to this functional language but there is reason to believe it should meet the claimed characteristics because Mukai discloses that in the case of adding polyvinyl alcohol, no cloudiness or precipitation was observed. The guidance of the specification discloses “in the presence of PVA, the turbidity remained low and no precipitate is observed” (see instant pre-grant specification ¶ [0087]). Therefore, since both the claimed invention and the prior art utilizes a medium comprising PVA and tyrosine, this is the technical reasoning for an inherency rationale that the prior art naturally includes functions that are newly cited or is identical to a product instantly claimed (unless it is due to unclaimed features or conditions not recited in the claims).
Examiner’s Response to Arguments
Applicant’s arguments filed on 02/22/2026 have been fully considered but they are not persuasive and deemed insufficient to overcome the prior arts of record over Luan in view of Mukai.
In response to Applicant’s argument (addressing page 13 of the remarks) that “no where does Luan hint that higher tyrosine concentrations can cause precipitation, or that this could be prevented by adding PVA to the medium--the problem and solution respectively identified by the instant inventors”: this argument is not persuasive where the fact that the Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious (MPEP 2145(II)). Even if the reason is different from Applicant’s invention, there is still suggestion in the prior art to adjust the concentration of the amino acid such as, for example, to support optimal cell development or viability. Furthermore, it is improper to import limitations from the specification into the claims where the claimed invention, as a whole, is drawn to a method of cell culture as denoted by claim 13’s preamble.
In response to Applicant’s argument (addressing pages 13-14 of the remarks) that while Mukai describes that it can be applied to preparation of a culture solution and the Office action reads too much into that statement”: this argument is not persuasive because the MPEP 2123 stats that “a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art”. It is maintained that Mukai reasonably suggests that PVA may be added for the set forth herein and in the prior office action.
Conclusion
No claims were allowed.
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653