DETAILED ACTION
Notice of Pre-AIA or AIA Status
The text of those sections of Title 35, U.S. Code not included in this action can
be found in a prior Office action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to the papers filed on 06/18/2026. Claims 24, 25, 28-33, and 47-49 are currently pending as per claims filed on 06/18/2026. Claims 26 and 27 are cancelled and Claim 24, 25, 28, 29, 31-33 and have been amended by Applicants’ amendment filed on 06/18/2026. Claims 47-49 are newly added claims by Applicants’ amendment filed on 06/18/2026.
Applicant’s election without traverse of Group III, claims 24-33 in the reply filed on 01/16/2026 was previously acknowledged.
Therefore, claims 24, 25, 28-33, and 47-49 are under examination to which the following grounds of rejection are applicable. Claim 24 is an independent claim.
Priority
Applicant's claim for the benefit of prior-filed application 63/315,897 filed 03/02/2022, 63/411,899 filed 09/30/2022, 63/417,873 filed 10/20/2022, 63/436,854 filed 01/03/2023, and 63/448,655 filed 02/27/2023 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is 03/02/2022.
Withdrawn objections/rejection in response to Applicants’ arguments or Amendment
Claim Objections
In view of Applicants’ amendment of claim 28 and 31, the claim objection has
been withdrawn.
Claim Rejections - 35 USC § 112(b)
In view of Applicants’ amendment of claim 32 removing the phrase “configured to”, the claim rejections under 35 U.S.C. 112(b) has been withdrawn
Double Patenting
In view of Applicants’ amendment of claim 24 by requiring increasing an agitation rate and having an uppermost impeller below a surface of an initial working volume, the claim rejections under provisional double patenting has been withdrawn.
New rejections in response to Applicants’ arguments or
Amendment
Applicant amended claim 24 to include limitations recited in previously presented claims 26 and 27. The inclusion of these limitations necessitated the Examiner to conduct a new search of the prior art, hence revealing new prior art that reads on the amended claim 24.
Claim Rejections - 35 USC § 112
Claim 47 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 47 recites “feed days”. It is unclear what constitutes “feed days” as the specification does not provide a definition or explanation of what is a “feed day”.
Claim Rejections - 35 USC § 103
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Matthiessen (US 20110229455 A1) and further in view of Kim et al (WO 2020/096381 A1; as cited in IDS), and O’Connor et al (Biotechnology Techniques, 1992, pages 323-328; as cited in office action filed 03/18/2026), and evidence by He et al (Biochemical Engineering Journal, 2019, page 173-181)H
Regarding claim 24, Kim teaches a method of producing an anti-ILR4α antibody (page 1, abstract) wherein the method includes “(a) culturing the cells; and (b) recovering an antibody or antigen-binding fragment thereof from the cultured cells” (page 14, para 7), “the cells can be cultured in various media. Any commercially available medium can be used as a culture medium without limitation” (page 14, para 8), and provides examples of culturing cells expressing anti-ILR4α antibody (page 16-27; Example 1).
As to methods of production, the art is replete with known methods using the same CHO cell culture. Matthiessen teaches a method of producing proteins, the method comprising culturing cells expressing the protein in culture medium wherein the culture medium contains a polyamine such as putrescine at concentration ranging from 2 mg/L to 8 mg/L (i.e. 0.02 mM to 0.9 mM) (para 0186 and 0196). Matthiessen teaches that the cells can be cultured in a stirred-tank reactor system for batch and continuous cell cultures and the stirred-tank reactor system uses an agitator such as a Rushton, hydrofoil, pitched blade, or marine (i.e. types of impellers; see Example 1, para 0334 recited a Rushton-type impeller) (para 0184).
While Matthiessen does not teach explicitly teach that the method comprises the step of controlling dissolved gas concentrations in said cell culture, Matthiessen does recite that the cells were cultured in a bioreactor with Rushton type impellers under an inlined controlled pH of 7.15-7.20 at 37 degree C with a dissolved oxygen concentration of 20% air saturation (para 0334). He provides evidence that in bioreactor-based cell culture, oxygen supply and accumulated CO2 removal need to be well controlled (page 174, left col). Based on Matthiessen teaching that the dissolved oxygen concentration is 20% air saturation, signifying control of dissolved gas concentration, and with consideration of the importance of controlling gasses as evidenced by He, the teaching of Matthiessen reads on the limitation step (c), controlling dissolved gas concentrations in said cell culture.
Matthiessen does not teach that the agitation rate is increased during said culturing and that the method produces an anti-IL-4Rα antibody.
However, one of ordinary skill in the art would have considered the teachings of
O’Connor and Kim as these references are analogous prior art pertaining to increasing the rate of agitation during cell culture for biologics production and methods for producing anti-IL-4Rα antibody using cell culture techniques.
O’Connor teaches culturing of CHO cells in spinner-flask bioreactors and “all cultures were initially grown at 100 rpm. The impeller speed (i.e. agitation rate) in the spinner flasks was increased 20 hr (100 - 340 rpm) or 26 hr (400 rpm) after inoculation” (page 325, para 1) and the increase in impeller speed showed greater number of viable cells (Figure 1B, page 325). O’Connor also teaches that increasing agitation from 100 rpm to 270 also led to an increase in concentration of viable cells as shown in Figure 2A (page 327).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of the cell culture bioreactor system for protein production taught by Matthiessen to instead culture cells which express anti-ILR4α antibody as taught by Kim and increase the agitation speed during the culture as taught by O’Connor since O’Connor teaches that the increase in agitation speed leads to higher number of viable of cells. Hence, the combined teachings of Matthiessen, Kim, and O’Connor would lead one of ordinary skill in the art to develop a method of culturing cells for production of anti-IL-4Rα antibody and said cells are able to maximally divide and grow. One would be motivated to do so to the grow the maximum number of cells that can subsequently produce the maximal amount of antibody of interest in a cell culture system. As using agitation in cell culture bioreactor systems and producing anti-IL-4Rα antibody through cell culture techniques are known in the art, one would have reasonable expectation of success.
Claim Rejections - 35 USC § 103
Claim 25, 28-33, 47-49 are rejected under 35 U.S.C. 103 as being unpatentable over Matthiessen (US 20110229455 A1), Kim et al (WO 2020/096381 A1; as cited in IDS), and O’Connor et al (Biotechnology Techniques, 1992, pages 323-328; as cited in office action filed 03/18/2026), and evidence by He et al (Biochemical Engineering Journal, 2019, page 173-181), as recited in the 103 above, and further in view of Floris et al (Applied Microbiology and Biotechnology, 2018, pages 5495–5504; as cited in office action filed 03/18/2026), Schulz et al (WO 2021/069353 A1; as cited in IDS; as cited in office action filed 03/18/2026), and Hoshan et al (Biotechnol. Prog, 2018, pages 1-7). H
Regarding claim 25, the teachings of Matthiessen, Kim, and O’Connor render obvious claim 24.
While Matthiessen teaches heat treatment of the resulting ADAMTS13 formulation for viral inactivation (para 0232), the combined teachings of Matthiessen, Kim, and O’Connor do not explicitly teach wherein said cell culture medium has been subjected to High Temperature Short Time (HTST) treatment at about 101 C to about 106°C for 8 to 15 seconds.
Floris teaches that, in cell culture media bioprocessing for biopharmaceutical production, “high-temperature short-time (HTST) pasteurization is recognized as an effective protective barrier against viral contaminants” and during HTST “culture media are continuously processed and maintained at elevated temperatures of approximately 100 °C for short time intervals (generally 10 s), facilitating the denaturation of viral protein capsids” (page 1, right col, para 2).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of the agitated cell culture method for anti-IL-4Lα antibody production taught by the combined teachings of Matthiessen, Kim, and O’Connor, to additionally apply HTST as Floris teaches that HTHS is an effective protective barrier against viral contaminants in cell culture media and Matthiessen recites heat treatment of the resulting protein. One would be motivated to combine the teachings of Matthiessen, Kim, O’Connor, and Floris to ensure that the cell culture media is not contaminated with viruses when culturing cells/harvesting resulting antibodies for human therapeutic purposes. As using HTST and cell culture bioreactor methods are known in the art, one would have reasonable expectation of success.
Applicant is reminded that 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.") See MPEP 2144.05 II. A.
Regarding claim 28 and 48, the teachings of Matthiessen, Kim, and O’Connor render obvious claim 24. Moreover, O’Connor teaches cell cultures were initially cultured at 60 rpm and then increased to 100 or 150 rpm (page 324, Results and Discussion, Cell Growth.
While O’Connor does not explicitly recite the agitation rate is at initially 20 rpm (claim 28) and is increased from about 22 rpm to about 40 rpm during said culturing, a person of ordinary skill in the art would have been motivated to determine an appropriate initial agitation rate and increase rate through routine optimization within a cell culture method, in order to effectively achieve a desired population of cells and at desirable viability. Further, a person of ordinary skill in the art would also be aware of the effect of agitation in cell culture as it pertains to cell health and growth and would have been motivated to determine an initial agitation rate and increased rate through routine optimization to achieve a desired population of cells and, therefore, antibody production
Regarding claim 29, the teachings of the teachings of Matthiessen, Kim, and O’Connor render obvious claim 24. Moreover, O’Connor teaches cell cultures were initially cultured at 60 rpm and then increased to 100 or 150 rpm (i.e. 150%) after 20 hours post-inoculation (page 324, Results and Discussion, Cell Growth), rendering obvious wherein said agitation rate is increased by 150% on day 0.5 or 1 of said culturing.
Regarding claim 30-32 and 49, the teachings of the teachings of Matthiessen, Kim, and O’Connor render obvious claim 24
The combined teachings of Matthiessen, Kim, and O’Connor do not teach wherein said dissolved gas concentrations are controlled by one or more spargers (claim 30), wherein said one or more spargers are configured at an initial sparging rate of about 25-75 standard liters per minute (slpm), (claim 31), wherein said sparging rate is increased from the initial sparging rate by 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% on one or more days selected from the group of day 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, and 11 of said culturing (claim 32), and wherein a sparging rate of said one or more spargers is increased during said culturing (claim 49).
However, one of ordinary skill in the art would have considered the teachings of
Schulz and Hoshan as these references are analogous prior art pertaining to use of spargers in bioreactor cell culture systems and the need to increase sparging rate.
Schulz teaches spargers in a bioreactor for cell culture and the spargers provide oxygen and/or air bubbles into the liquid phase wherein cells or microorganisms are cultivated (page 17, line 13-15). Schulz teaches additional spargers “supply additional air bubbles and/or additional oxygen gas bubbles continuously to the liquid medium” and this “has a variety of advantages for the culturing process” (page 17, line 23-25). Moreover, Schulz teaches sparger gas flow rates can be from 0, 20, 60, 120 L/min and the gas flow rate can be adjusted (page 36).
Hoshan teaches bioreactors for cell culture provide excellent control of critical parameters for optimal cell growth and protein production such as temperature, dissolved oxygen (DO), and pH and that feedback control is important as dissolved CO2 levels can greatly affect culture pH (Page 1-2, Introduction). Hoshan teaches that control of pH can be accomplished by changing sparging rate; for instance, when pH is lower than the setpoint, sparging air (or N2) is automatically ramped up to improve CO2 stripping and increase culture pH (Page 1-2, Introduction). Hoshan teaches that the sparging rate is increased from the initial sparging rate between about day 3 and 4 and the increase is about 0.01 to about 0.05 (i.e. 500%; See Figure 1(a)).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of the agitated cell culture method for anti-IL-4Lα antibody production taught by the combined teachings of Matthiessen, Kim, and O’Connor to use spargers to supply and control dissolved gas concentrations as taught by Schulz and increase the sparging rate since Hoshan teaches that increasing sparging rate is beneficial in cell culture bioreactors to control pH. One would be motivated to do so to maximize the cell culture output (i.e. the cells and, therefore, the respective antibodies produced by the cells). As use of bioreactors with spargers for cell culture and increasing the sparging rate is known in the art, one would have a reasonable expectation of success.
Regarding claim 33, the teachings of Matthiessen, Kim, O’Connor, and Schulz
render obvious claim 24 and 30.
However, the combined teachings of Matthiessen, Kim, O’Connor, and Schulz do not teach a sparging rate of said one or more spargers is automatically configured based on dissolved oxygen levels in said cell culture.
It would have been prima fascie obvious to one of ordinary skill in the art prior to the filing of the instant application to use automation for optimizing a system (e.g. sparging rate that is automatically configured based on dissolved oxygen levels and removal of carbon dioxide). Providing mechanical or automated approaches to replace manual labor would accomplish the same result of culturing cells expressing an anti-IL-4Rα antibody. Motivation to do so would be to increase efficiency and throughput of culturing cells expressing an anti-IL-4Rα antibody and, ultimately, producing a maximal amount of anti-IL-4Rα.
Regarding claim 47, no reasonable interpretation could be made pertaining to the phrase “feed days”, hence no rejection could be made for prior art purposes.
Response to Applicant’s arguments as they apply to rejection of claims
24-25 and 28-33 under 35 USC § 103
Applicant’s arguments filed 06/18/2026 have been fully considered but not
persuasive. Applicant’s arguments with respect to Xing and Roca have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant asserts that:
1) Kim is directed to the development of testing of a novel antibody and not antibody manufacturing methods, therefore Kim does not teach or suggest anything about culturing cells in a cell culture medium comprising the claimed concentrations of polyamines, agitation, having an impeller, or controlling dissolved gas concentrations in cell culture, as required by claim 24 (page 6, Applicant’s Remarks);
2) Schultz is directed to a bioreactor and optimizing oxygen and carbon dioxide distribution based on sparging positioning and does not disclose, teach or suggest anything about anti-IL-4Rα antibodies and there is no motivation to combine Kim and Roca with Schulz and also relies on improper hindsight (page 9-10, Applicant’s remarks);
3) Floris is directed to small-scale devices for cell culture media development, and there is no motivation to combine with Roca and Kim, thus also relying on improper hindsight (page 10-12, Applicant’s remarks); and the four-reference combination is an extraordinary number of references for combination.
4) O’Connor teaches that higher agitation rate results in lower viable cell concentrations and percent viability, thus teaching away from increasing agitation rate in suspension cultures (page 12-13, Applicant’s remarks); and
Regarding argument 1, the Examiner directs the applicant to para 0083-0085 and para 0111 (Example 1: Expression of recombinant human interleukin-4 receptor α (hIL-4Rα)) of Kim which recites that this invention discloses method of producing a IL4Rα antibody by culturing cells expressing the antibody and collecting the antibody from the cultured cells. Indeed, Kim teaches that the expression vector for hIL-4Rα was expressed in CHO cells (page 14), the cells were cultured, for the goal of antibody purified from the media supernatant (para 0111), therefore Kim does teach a method of producing an anti-IL-4Rα antibody. It is noted that the claims do not recite that the production is for “antibody manufacturing”, therefore Kim reads on at least part of claim 1 that recites “a method of producing an anti-IL-4Rα antibody comprising culturing a cell culture comprising cells expressing an anti-IL-4Rα antibody in a cell culture medium” and the art of Kim is combined with the art of O’Connor and newly cited Matthiessen which remedy the deficiencies as described in the above 103. It is further noted that the teachings of Kim are not read in a vacuum, but rather in view of the teachings of the secondary references Matthiessen and O’Connor.
Regarding argument 2 and 3, Schulz recites a bioreactor system for cell culture which comprises a stirrer/impeller for agitation and the positioning of the impellers is below the surface of the working volume of cell culture media (as recited in office action filed 03/18/2026, page 10). While Schulz teaches industrial-scale bioreactors, the claims do not recite that the cell culture cannot take place at an industrial-scale level. Moreover, the newly applied art of Matthiessen teaches that the protein production can occur in batch stirred bioreactors which encompass industrial-scale level. Furthermore, the art of O’Connor and Kim do not indicate the agitation increase and the production of the anti-IL-4Rα antibody cannot be conducted in an industrial-bioreactor, hence Matthiessen, O’Connor, Kim, and Schulz combined to read on a method of producing anti-IL-4Rα antibodies with a bioreactor system comprising impeller assemblies as recited in the claims. It is noted that the teachings of Schulz are not read in a vacuum, but rather in view of the teachings of the secondary references Matthiessen, O’Connor, and Kim. In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Similarly, Floris teaches the importance of High Temperature Short Time treatment for reducing viral contaminants in cell culture media and teaches that the small-scale studies are necessitated prior to scale-up for commercial manufacturing operations (abstract, page 1), emphasizing its applicability in protein production. Furthermore, Matthiessen recites a heat treatment for inactivation of viruses in the resulting protein formulation, providing further support of combining Floris with Matthiessen for decreasing viral contamination. Hence, Floris indeed provides motivation to want to combine with the teachings of Kim, Roca, and Schulz.
Regarding argument 4, while examiner acknowledges that O’Connor indeed teaches that percent of viable cells decreases with agitation (Figure 1C), there is nevertheless an overall increase in number of viable suspension cells, as shown in Figure 1B and 2B. In Figure 1B, when agitation was increased from 60 rpm to 100 or 150 rpm, the concentration of viable cells rose, indicating that increasing the agitation had a beneficial effect in producing a greater number of viable cells. In Figure 2B, when agitation was raised from 100 rpm to 270 rpm and showed no decrease in viable cell concentration. Finally, despite O’Connor implying that the agitation describes adverse conditions for culturing the CHO cells, O’Connor also recites that their results “demonstrate that agitation altered DNA synthesis in CHO cells and that these cells have the capacity to adapt to adverse conditions.”(page 327, DNA synthesis). Therefore, O’Connor demonstrated that agitation could aid in increasing over viable cell number for cells in suspension culture and cells can adapt to the increased agitation, providing motivation to implement such parameter with the combined teachings of Kim, Roca, and Schulz.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA MARVICH/ Primary Examiner, Art Unit 1634
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