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 .
Examiner’s Statement
The Non-Final Office Action dated June 2, 2026, is hereby withdrawn in favor of the present office action. Accordingly, the time period for response is reset based on the date of mailing for the current action.
Status of Claims
Claims 1-20 are pending.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on September 17, 2024, was filed before the mailing of the First Office Action on May 30, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Claim Rejections - 35 USC § 103
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 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 1-20 are rejected under 35 U.S.C. §103 as being unpatentable over Jones et al. [US 2018/0291342 A1], in view of Eibl and Eibl (Hereinafter Eibl) [Chapter 3, Bioreactors for mammalian cells: general overview, Cell and Tissue Reaction Engineering: Principles and Practice, 2009], in view of Jingjing et al. [Advances in large-scale in vitro culture of hybridoma cells: postprint, ChinaRxiv, 2018].
For claim 1, Jones et al. discloses a method for producing T-cells using a cell expansion system [Abstract]. Jones et al. further discloses the cell expansion system is a bioreactor [¶ 0003]. Jones et al. does not disclose the use of a small bioreactor having a surface area of about 2,000 cm2. Regarding the limitation where the small bioreactor has a surface area of about 2,000 cm2, Eibl discloses bioreactors can be as small as a milliliter range up to and above 500 liters [Abstract]. However, Jingjing et al. does disclose hollow fiber systems that provide large surface areas within small volumes. Specifically, Jingjing et al., discussing various sizes, discloses that FiberCell Systems provide a bioreactor system with a surface area of 2200 cm2 [Hollow Fiber System Culture of Hybridoma Cells ¶ 1]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Jones et al. with the further teachings of Jingjing et al. given that small volume bioreactors with large surface areas such as 2200 cm2 were similar in range. This is further made obvious given the disclosure by Eibl, discussing bioreactors and mammalian cells, discloses that bioreactors exist in a multitude of sizes that include as small as a milliliter range up to and above 500 liters [Abstract]. Therefore, there would have been a reasonable expectation of success that a person of ordinary skill would have been able to identify a multitude of value ranges, to include 2000 cm2 surface area of a bioreactor, for the surface area needed for smaller scale bioreactors dependent on need. Lastly, a prima facie case of obviousness exists when a claimed numerical range either overlaps with, falls within, or is sufficiently close to a range disclosed in the prior art. See MPEP § 2144.05(I).
For claim 2 where the intracapillary volume is about 58 milliliters, Jones et al. discloses an intracapillary volume of about 177.1 mL for a bioreactor that has a surface area of about 21,000 cm2 [¶ 0267]. Again, it would have been prima facie obvious to a person of ordinary skill in the art using routine optimization to identify the requisite intracapillary space based on length of the capillary volume for a scaled-down and/or smaller bioreactor based on known engineering parameters, including capillary length and capillary inner diameter given the Jones et al. disclosure in order to adjustment the intracapillary space to accommodate differences in bioreactor scale, surface area, and desired culture capacity.
For claim 3 where the cell expansion includes a tubing set that is in fluid communication with the small bioreactor and a volume ratio of the tubing set to the bioreactor is about 2.96, Jones et al. discloses a cell expansion system that further includes a tubing set [¶ 0173], where Jones et al. states “START operation 1402 is initiated, and process 1400 proceeds to load a disposable tubing set or pre-mounted fluid conveyance assembly” that is in fluid communication of the bioreactor [¶ 0071]. Additionally, Jones et al. states that fluid flowing throguht the cell growth chamber 24 may be on in contact with the outside of hollow membrane 117 [Fig. 1B] in the cell growth chamber 24 where a hollow fiber membrane comprises multiple hollow fibers. Furthermore, second fluid circulation path 14 may be operably connected to second fluid flow control device with the volume ratio of the tubing set to the bioreactor [¶ 0138]. Furthermore, the limitation reciting a tubing volume of “about 2.96” would have been obvious to a person of ordinary skill in the art in view of the teachings of Jones et al. regarding the design of closed fluidic systems for hollow-fiber bioreactors. Jones et al. further teaches a closed disposable fluid circuit architecture for a hollow-fiber cell expansion system, including a hollow-fiber bioreactor coupled with the tubing, sensors, pumps, and other fluid management components necessary to operate the system. The disposable circuit is configured to circulate fluid through the bioreactor under automated control and necessarily includes a defined internal fluid volume resulting from the physical dimensions and arrangement of the tubing and other fluid-containing components required to perform the selected cell-expansion process. Additionally, Applicant’s specification does not provide evidence that the recited tubing volume of “about 2.96” represents a critical or unexpected discovery. Applicant’s specification recites the value “about 2.96” three separate times. In two instances, the Specification merely states “the small bioreactor being in fluid communication with the tubing set and a volume ratio of the tubing set to the bioreactor is about 2.96” [¶ 0009, 0022]. Likewise, the specification states that “the small bioreactor may have a ratio of tubing to bioreactor volume of about 2.96” [¶ 0050]. However, the Specification contains no discussion explaining why “about 2.96” is a critical value, nor does it identify or explain why values outside this ratio would be unsuitable or would fail to achieve the intended results. Furthermore, the figures present in the present application are identical to those disclosed by Jones et al. [See Figs. 1A, 1B, 1C, and 5A], indicating that the same underlying T-cell expansion architecture, operational workflow, and processing methodology are being implemented. Both applications depict the isolation and expansion of cells, including T-cells, by introducing the cells into a hollow-fiber bioreactor-based cell expansion system. The principal distinction between Applicant’s claimed system and Jones et al. is the size of the bioreactor. As noted in MPEP §2144.05(II)(A), citing In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929), “it is 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”. Accordingly, a person of ordinary skill in the art could have arrived at the tubing volume ratio of “about 2.96” as a result of routine engineering and design considerations dictated by the physical dimensions of the selected bioreactor and associated fluid circuits. The claimed ratio represents a mathematical relationship between the volume of the tubing set and intracapillary volume of the bioreactor, both of which are determined by the selected system geometry. Moreover, Jingjing et al. and Eibl teach that hollow-fiber bioreactor systems were known in the art to be available with a variety of membrane surface areas and corresponding intracapillary volumes.
In view of these teachings, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Jones et al. cell-expansion system by selecting a smaller hollow-fiber bioreactor, including one having an intracapillary volume of 58 mL and a membrane surface area of approximately 2000 cm2, and to configure the associated fluid circuit using routine engineering principles given the physical dimension constraints of the tubing and bioreactor. Therefore, there would have been a reasonable expectation of success for a person of ordinary skill in the art to combine the teachings of Jones et al. with the additional teachings of Jingjing et al. and Eibl to develop a smaller bioreactor suitable for T-cell expansion having an intracapillary volume of approximately 58 mL with a membrane surface area of approximately 2000 cm2 that resulted in a tubing volume ratio of “about 2.96” given the physical parameters and constraints of the Jones et al. cell expansion system.
For claim 4 where the tubing set is in communication with the small bioreactor, Jones et al. discloses placing the tubing set into fluid communication with the bioreactor [¶ 0173].
For claim 5 where the method causes T-cells to flow into a small bioreactor of the cell expansion system, Jones et al. discloses a method where the T-cells flow into a bioreactor
of the cell expansion system [¶ 0061].
For claim 6 where rate at which the T-cells flow into the small bioreactor at a defined rate, Jones et al. discloses the rate of the T-cells flow into the bioreactor where the IC flow rate increases from 0.1 mL/min to 0.2 mL/min to 0.3 mL/min with an increase in cells with growing feeding demands [¶ 0183].
For claim 7 where the T-cells flow into a small bioreactor at about 0.007 µL/min/fiber to less than or equal to about 0.028 µL/min/fiber, it would have been prima facie obvious to a person of ordinary skill in the art to optimize the flow rate of T-cells into the bioreactor fibers as a matter of routine optimization. Applicant’s specification states that the prior art flow rate range of 0.017 µL/min/fiber to 0.0347 µL/min/fiber substantially overlaps with limitations in claim 7 [Applicant’s specification at ¶ 0072].
For claim 8 where the T-cells are maintained in a small bioreactor, Jones et al. discloses maintaining T-cells within a bioreactor using counterflow containment [¶ 0105].
For claim 9 where the counterflow includes a first flow rate in a first direction and a second flow rate in an opposing second direction where the first flow rate is about two times the second flow rate, Jones et al. teaches the counterflow containment includes a first flowrate in a first direction and a second flow rate in an opposing second direction, and the first flowrate is about two times the second flowrate [¶ 0146] in which the negative symbol ("-") used in-0.1 mL/min, for example, indicates a direction of the IC circulation pump (512) to cause or produce a counter-flowrate to maintain cells in the bioreactor during the growth phase of the cell culture [¶ 0148], while table 1018 of FIG. 10B provides example pump rates of ±0.1 to ±0.4 mL/min for feeding the cells while retaining the cells In the bioreactor during the growth phase of the cell culture [Id.].
For claim 10 where the first flow rate is about 0.02 mL/min and second flow rate is about 0.01 ml/min, Jones et al. discloses a low or minimum federate may be greater than or equal to about0.01 mL/min [¶ 0231] where the first flow rate is different from the second flow rate. Terumo does not expressly disclose the first flow rate is about0.02mL/min. However, it would have been prima facie obvious to one of ordinary skill in the art where the artisan would have further optimized using routine optimization based on the scale of the bioreactor allowing an Artisan to identify the needed value for the first flowrate for optimal T-cell expansion.
For claim 11 where T-cells are separated from a source, Jones et al. discloses separating the T-cells from a source [¶ 0123].
For claim 12 where separating the T-cells includes contacting magnetically conjugate antibodies to associate with non-target cells, Jones et al. discloses that the cells may be isolated using any suitable isolation technique including isolating cells using magnetic beads functionalized with antibodies contacted with the cells collected at 706. The functionalized beads may then preferentially attach to the target cell population where a magnetic field may then be used to retain the beads with the attached target cell population allowing the other cells to be removed [¶ 0123].
For claim 13 where the method involves harvesting produced T-cells from the bioreactor, Jones et al. discloses the objective of harvesting Tregs within a specified range [¶ 0320].
For claim 14 where the total viable cell flown into the small bioreactor is greater than or equal to about 20 milliliters to less than or equal to about 60 milliliters, etc., Jones et al. discloses the total cell load for each run, e.g. 4.5-6.5x107 Tregs, may be resuspended, using aseptic technique, in 50mL of complete medium with a Quantum Cell Inlet Bag (Cal.21020) for introduction into the Quantum System bioreactor, and a percent cell viability at harvest is greater than or equal to about 70% to less than or equal to about 100% [¶ 0066] where the viability of the harvested cells maybe above about 65%, above about 70%, above about 75%, above about 80%, above about 85%, above about 90%, or even above about 95%. Jones et al. does not expressly disclose 3 total variable cell of the harvested T-cells is greater than or equal to about 100 milliliters to less than or equal to about 250milliliters. However, It would have been prima obvious to one of ordinary skill in the art would have further optimized using routine experimentation in order to identify the requisite value for the volume of harvested T-cells.
For claim 15 where the method for producing T-cells using a cell expansion system having a tubing set where the small bioreactor being in fluid communication with the tubing set and a volume ratio of the tubing set to the bioreactor is about 2.96, see analysis for the §103 rejection for claim 3.
For claim 16 where the bioreactor has a surface area of about 2,000 cm2 and an intracapillary volume of about 58 milliliters, please see analysis under the §103 rejection for claims 1 and 2.
For claim 17 where the method further includes causing T-cells to flow into a small bioreactor of the cell expansion system at greater than or equal to about 0.007 µL/min/fiber to less than or equal to about 0.0281 µL/min/fiber, again, it would have been prima facie obvious to a person of ordinary skill in the art to optimize the flow rate of T-cells into the bioreactor fibers as a matter of routine optimization. Applicant’s specification states that the prior art flow rate range of 0.017 µL/min/fiber to 0.0347 µL/min/fiber substantially overlaps with limitations in claim 7 [Applicant’s specification at ¶ 0072].
For claim 18 where the counterflow includes a first flow rate in a first direction and a second flow rate in an opposing second direction where the first flow rate is about two times the second flow rate, Jones et al. teaches the counterflow containment includes a first flowrate in a first direction and a second flow rate in an opposing second direction, and the first flowrate is about two times the second flowrate [¶ 0146] in which the negative symbol ("-") used in-0.1 mL/min, for example, indicates a direction of the IC circulation pump (512) to cause or produce a counter-flowrate to maintain cells in the bioreactor during the growth phase of the cell culture [¶ 0148], while table 1018 of FIG. 10B provides example pump rates of ±0.1 to ±0.4 mL/min for feeding the cells while retaining the cells In the bioreactor during the growth phase of the cell culture [Id.].
For claim 19, Jones et al. teaches where the cells, i.e. T-cells, may be isolated 708 as part of the preparation 704 where the cells may be isolated using any suitable isolation technique which can include isolating T-cells using immunomagnetic separation where magnetic beads functionalized with antibodies are contacted with the cells collected at 706. The functionalized beads may preferentially attach to the target cell population. A magnetic field may then be used to retain the beads with the attached target cell population, while the other cells may be removed, e.g. allowing the non-conjugate antibodies to pass there through [¶ 0123].
For claim 20 where the method of claim 15 further includes harvesting T-cells from the bioreactor and further steps, Jones et al. discloses that the objective is to harvest Tregs within a specified range [¶ 0320], and in addition the total cell load for each run, e.g. 4.5-6.5x107 Tregs, may be resuspended, using aseptic technique, in 50mL of complete medium with a Quantum Cell Inlet Bag (Cal.21020) for introduction into the Quantum System bioreactor, and a percent cell viability at harvest is greater than or equal to about 70% to less than or equal to about 100% [¶ 0066] where the viability of the harvested cells maybe above about 65%, above about 70%, above about 75%, above about 80%, above about 85%, above about 90%, or even above about 95%. Jones et al. does not expressly disclose 3 total variable cell of the harvested T-cells is greater than or equal to about 100 milliliters to less than or equal to about 250milliliters. However, It would have been prima obvious to one of ordinary skill in the art would have further optimized using routine experimentation in order to identify the requisite value for the volume of harvested T-cells.
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods as taught by Jones et al. where Jones et al. discloses a method for cell expansion, including T-cells, using a bioreactor with the additional teachings of Jingjing et al. and Eibl where a general overview of bioreactors was provided that included commercial size bioreactors as well smaller bioreactors that range from milliliters up to 10 liters that included bioreactor sizes around 2000 cm2. Additionally, the figures in the current application are identical to the figures listed in Jones et al. indicating that the same underlying T-cell expansion architecture, operational workflow, and processing methodologies are being implemented [Figs 1A, 1B, 1C, and 5A]. Both applications depict the isolation of cells, including T-cells, by introducing the cells into a bioreactor-based cell expansion system, then expanded the cells within the bioreactor, and harvesting the expanded cells. Applicants claims appear to differ only in the scale of the bioreactor system. Thus, there is a reasonable expectation of success that a person of ordinary skill could reasonably combine the teachings of Jones et al. with the additional teachings generic teachings of Eibl in order to modify a known bioreactor system to a smaller-scale bioreactor system given that smaller systems are routinely employed based on need. Furthermore, modification of a known system to a smaller system would be merely routine engineering optimization within known scaling of existing bioreactor parameters. This would have included reactor surface area, intracapillary volume, flow characteristics, as well as using known methods, including the use of immunomagnetic separation beads that could be used to contact either the targeted cells or the non-target cells as a means for isolating the target cells.
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.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights