DETAILED ACTION
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 .
This action is responsive to papers filed 02/15/2026.
Claims 1 and 17 have been amended. Claims 31-36 have been newly added and claims 10, 12-13, and 16 have been newly canceled.
Claims 1-2, 4-5, 7, 9, 14-15, 17, and 31-36 are currently pending and have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. 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 Objections
Claim 31 is objected to because of the following informalities: Claim 31 does not have a status identifier. The status of claim 31 should have been “new”.
Appropriate correction is required.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4-5, 7, 9, 14-15, 17, 31-36 are rejected under 35 U.S.C. 103 as being unpatentable over Jaques et al (US 2018/0010082 A1- previously cited) in view of Morrissey et al (US 2017/0320027-newly cited).
Regarding claims 1, 17, 31-33, 35-36 Jaques teach a method of using a bioreactor that includes a bioprocess container to form a cell product (abstract, page 3 para 21-24). Methods for culturing the cells for pharmaceutical and biopharmaceutical production purposes are disclosed (page 30 para 325-326) and include wherein the production products are whole cells that must be of high quality to meet or exceed regulatory and customer requirements (page 3 para 18). This would also render obvious any modifications needed for the formulation of a pharmaceutical product comprising living cells. The use of a dual impeller system can ensure a homogeneous environment and provide rapid mixing to maintain homogeneity of the biological material in suspension, such that the mammalian cells are kept in a homogeneous suspension through agitation by the impeller system (page para 167-169).
The method comprises: introducing an initial liquid formulation, comprising said active agent, into a container (adding a cell culture in a fluid medium into a bioprocess container -page 4 para 32); agitating said initial liquid formulation using a container comprising one or more inwardly jutting baffles and an agitation device configured with blades having a diameter less that the widest diameter of the container (page 4 para 29-33, page 5 para 39-40, page 7 para 70, page 8 para 84, Figure 1A); determining a concentration of living cells enabling a calculation of the amount of the dilution solution necessary to achieve a target concentration of the living cells and adding a dilution solution to the initial liquid formulation (pages 7-8 para 74, page 22 para 230, page 22 para 239, page 41 para 391-392), thereby generating a final cell formulation that is repeated removed in a predetermined volume from the container (regarding collection of samples of suspended cells page 41 para 392); wherein the container is operably connected to:
1.a portal for transfer of said dilution solution into said container (regarding feeding fresh medium to the bioreactor container via an inlet port, page 5 para 38, page 5 para 43, page 18 para 195);
2. a portal for transfer of the predetermined volume of the final formulation out of said container (regarding removal of the medium solution with the cells, page 5 para 43, page 18 para 195, page 30 para 328),
3. an apparatus for controlling temperature inside said container (temperature control sensor, pages 3-4 para 23-24, page 6 para 49, para 53).
Regarding the aseptic transfer of the dilution solution, Jaques teach that the tubing designed ensures aseptic transfer of fluids (pages 38-39 para 353).
Jaques further teach mixing the formulation with a rotating device (agitation device) and a baffle that juts inward (rotatable axial rod and blades connected to its bottom and wherein the blades have a diameter less than widest diameter of the container, pages 4-5 para 29-30, 39, page 8 para 84). Since the blades of the impeller are designed for low shear mixing (page 14 para 169) and are not described as touching the sides of the container they are deemed to have a diameter less than the widest diameter of the container (the bladed impeller is specifically described as having a diameter ratio less than the diameter of the tank container-see page 8 para 84).
Jaques disclose that the bioreactor vessel includes at least one harvest port, at least one sample port (page 4 para 35) and a drain outlet at the bottom of the container (page 5 para 45). Any of these outlet ports are intended to be used to remove a cell sample of predefined volume. In addition, the use of concentrations that are substantially the same for dispensing is an obvious selection regardless of whether one is sampling for monitoring cell culture or collecting final products intended for pharmaceutical use in order to provide consistency.
Regarding the dispensing of the final formulation as a pharmaceutical product where successive dispensed amounts contain substantially the same concentrations of the cells, Jaques disclose that in one embodiment that the controllers provide increased flexibility, reliability and ease of use in their operation for both research and custom process manufacturing and development projects and specifically in compliance with pharmaceutical industries (page 24 para 259) for production of pharmaceutical and biopharmaceutical products used in cell therapies (page 30 para 325). Monitoring of cell concentrations using sample bioprocess containers attached to the sample line is also suggested (page 41 para 392). These teachings for the formulation of pharmaceuticals and the control of cell concentrations provide a motivation and a reasonable expectation of success for the dispensing of a final formulation as a pharmaceutical product where successive dispensed amounts contain substantially the same concentrations of the cells.
The specific combination of features claimed is disclosed within the broad genera of bioreactor culture conditions and bioreactor features taught by Jaques, but such “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). Where, as here, the reference does not provide any specific teaching to select this specific combination of variables, anticipation cannot be found.
That being said, however, it must be remembered that “[w]hen 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”. KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 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.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
Consistent with this reasoning, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have selected various combinations of culture conditions and bioreactor features from within the disclosure of Jaques to arrive at methods, bioreactors and cell products “yielding no more than one would expect from such an arrangement”.
The motivation and reasonable expectation of success in making these combinations comes from the fact that Jaques suggest that all these cited variables are suitable for inclusion in their method/composition and include methods for culturing the cells for pharmaceutical and biopharmaceutical production purposes (page 30 para 325-326).
Regarding an agitation device comprising an impeller having blades shaped to conform to and align with the container bottom Jaques teach and suggest wherein their agitation device contains an impeller with a blade that can be foldable (page 7 para 70) and thus is deemed to suggest a blade is at least somewhat conformable with the container. Jaques also suggest that there is a disadvantage to flat-bottomed vessels because of the increase in cell sedimentation on the container bottom and thus suggests that having a vessel geometry that prevents this sedimentation collection on the container bottom is preferred (page 2 para 14, page 3 para 20).
Jaques do not specifically disclose wherein the blades of their impeller are shaped to conform to and align with the bottom of the container or mixing across the bottom of the container.
Morrissey is drawn to a container that is a deformable bag having one or more inlets and outlets and one or more impeller assemblies within the container to causing mixing, dispersing, homogenizing and or circulation of the ingredients in the container (abstract, page 2 para 23) and cells are one example of ingredients (page 1 para 7). Locating an impeller assembly towards the bottom of the container is indicated as desirable (page 1 para 11, page 3 para 32). Placing the impeller assembly near the bottom of the funnel shape (concave shaped bottom of the container) allows for mixing even at very low liquid levels in the container and allows for mixing to continue during dispensing as long as possible (page 3 para 32). The number and shape of the blades is not particularly limited provided they provide sufficient agitation of the fluid within the container when actuated (page 3 para 32, para 35).
One of ordinary skill in the art would have been motivated to use blades as close to the bottom of the container as possible in the method of Jaques because Morrissey teach and suggest that this is beneficial and desirable as this allows for mixing even at very low liquid levels in the container and allows for mixing to continue during dispensing as long as possible (page 3 para 32). Shaping the blades to conform to the shape of the container bottom in the method of Jaques would have been obvious because Morrissey teach and suggest that the number and shape of the blades is not particularly limited provided they provide sufficient agitation of the fluid within the container when actuated and Jaques indicate that their impeller can be made to conform to the container (page 7 para 70). The mixing during dispensing is indicated as desirable and beneficial by Morrissey as well and clearly would have provided dispensed products with the benefit of a homogenous composition. One of ordinary skill in the art would have had a reasonable expectation of success because Jaques and Morrissey are both directed to deformable containers that include the ability to mix their contents with impellers and are usable with biopharmaceuticals such as cells.
Regarding claim 2, Jaques teach wherein the cells are in suspension and the container is operably connected to a sensor (probe) for determining concentrations of the living cells (viable cell concentrations) in the suspension (pages 3-4 para 23-24, page 22 para 230, page 41 para 391-392)
Regarding claim 4, Jaques teach that cell's viability is being supported and measured by the system (page 22 para 230).
Regarding claims 5, 7, 9 and 14, Jaques teach a sensor for monitoring pH, oxygen and automated control of all functions (pages 3-4 para 23-24, page 6 para 49-52, page 22 para 230). Jaques teach that the functions, such as feeding fresh medium, perfusing the reactor vessel, collecting samples of fluid from the reactor, are automatically and/or robotically controlled, wherein a peristaltic pump maybe used for executing said functions (page 22 para 230).
Regarding claim 15, Jaques further teach that the system is maintained in sterile conditions (pages 8-9 para 87-91, page 15 para 174, pages 38-39 para 353).
Regarding claim 34, Jaques further teach wherein the container bottom has a concave shape (page 12 para 141, page 13 para 153-156).
Therefore, the combined teachings of Jaques et al and Morrissey et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 02/15/2026 have been fully considered but they are not persuasive.
Applicant’s arguments, see page 9 last paragraph to page 10 first paragraph, filed 02/15/2026, with respect to the rejection(s) of claim(s) 1 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Jaques in view of Morrissey as described above under 35 USC 103.
Applicant argues that Jacques merely describes a bioreactor system for cell culture and expansion and that there is no disclosure in Jacques for formulating a pharmaceutical product comprising living cells while maintaining a homogenous suspension of the living cells during dispensing as now required by amended claim 1. Applicant argues that Jaques does not disclose the claimed container configuration having a bottom and an agitation device comprising an impeller having blades shaped to conform to and align with the container bottom for mixing across the surface of the container bottom to prevent sedimentation of living cells during container depletion.
This was found persuasive, however a new rejection in view of additional teachings of Jaques and the newly cited Morrissey reference addresses the new limitations that Applicant has added to their claims as described above. However, the characterization of Jaques as being limited to a bioreactor only culture and expansion is not persuasive. Jaques specifically teach that the systems, devices, facilities and/or methods described in their reference are suitable for production operations configured for production of pharmaceutical and biopharmaceutical products (see page 30 para 325).
Applicant argues that Jaques further fails to teach adding an amount of dilution solution necessary to achieve a target concentration of living cells for a pharmaceutical product as opposed to media exchange or perfusion during culture expansion. Applicant asserts that Jaques does not teach dispersing one or more amounts of a final pharmaceutical formulation wherein successive dispersed amounts contain substantially the same concentration of living cells. Applicant asserts that the sampling ports of Jaques are limited to monitoring culture conditions and cannot be applied to dispensing successive pharmaceutical doses while maintaining uniform concentrations during depletion.
This is not found persuasive. Jaques specifically teach that the systems, devices, facilities and/or methods described in their reference are suitable for production operations configured for production of pharmaceutical and biopharmaceutical products (see page 30 para 325). In response to applicant's argument that sampling for monitoring is not equivalent to dispensing therapeutic doses, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In this case, the sampling for monitoring provides for the withdrawal of a dose of the product for evaluation and unless this results in a product that cannot be used for the intended use as a pharmaceutical product (which Jaques has stated that they are suited for this purpose and thus can be used as a pharmaceutical), then it is deemed to meet the claim requirements.
In addition, the use of concentrations that are substantially the same is an obvious selection regardless of whether one is sampling for monitoring cell culture or collecting final products intended for pharmaceutical use in order to provide consistency.
Applicant argues that the successive dispensed amounts contain substantially the same concentration of living cells is not a mere statement of intended result and that it is tied to the coordinated impeller and container bottom configuration and to agitation during dispensing which Jaques does not disclose.
This is not found persuasive because Morrissey discloses the benefits of the impeller configuration at the bottom of the container that provides the feature of agitation during dispensing that provides the dispensed product with a homogenous mixture as described above. The use of concentrations that are substantially the same is an obvious selection regardless of whether one is sampling for monitoring cell culture or collecting final products intended for pharmaceutical use in order to provide consistency.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Benz, Gregory, “Piloting Bioreactors for Agitation Scale-Up”, CEP, 2008, https://cmbe.engr.uga.edu/bche3180/Benz%202008%20Chem%20Eng%20Prog.pdf, pp. 32-34.
Benz disclose that agitation can affect the rate of production, yield and maximum product titer in a cell culture (page 34).
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 LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached on 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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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631
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