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 .
Applicant’s response filed on 05/21/2026 is acknowledged and has been entered into the application file.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 9, 12, and 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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:
Applicants’ amendments filed 05/21/2026 overcome the indefiniteness rejection. Applicants have
specifically amended claims 9, 12, and 13 to remove the exemplary language “such as”. The rejection is therefore withdrawn.
RE: Rejection of claims 1-9, 11-12, 14-17, and 20 under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by PURUSHOTHAMAN et al. (US20150322399A1):
Applicants have traversed the rejection asserting that Purushothaman does not satisfy that standard because it does not disclose the claimed cell detaching solution comprising an enzymatic cocktail nor does it disclose detaching the recited cells "without forming clumps or aggregates," as required by independent claim 1 and similarly required by independent claim 11. Applicants specifically argue that Purushothaman et al. explains that "a chemical agent, such as trypsin, may be used," and similarly gives "trypsin" as the example enzymatic detachment solution and those disclosures do not teach a multi-enzyme cocktail, much less the claimed solution that achieves detachment without forming clumps or aggregates.
This is not persuasive because PURUSHOTHAMAN et al. does specifically teach in paragraph 0044 that an enzymatic detachment solution is circulated through the bed. PURUSHOTHAMAN et al. discloses trypsin only as an example of an enzymatic detachment solution that can be used to detach the cells, not that trypsin is the only enzyme being used in the method. The teaching “enzymatic detachment solution” of PURUSHOTHAMAN et al. permits for the presence of a mixture of enzymes in the solution not just a single-enzyme detachment solution, which reads on the claimed cell detaching solution comprising an enzymatic cocktail. PURUSHOTHAMAN et al. further discloses in paragraph 0018, removing the fluid, vibrating the container to detach the cells from the carrier, and filtering the carrier from the fluid removed from the vessel, such that the detached cells are removed with the fluid, and the carrier is not removed with the fluid. These steps read on the limitation “wherein a substantial portion of the cells are detached from the fixed bed structure without forming clumps or aggregates in the substantial portion of the cells”.
Applicant's arguments filed 05/21/2026 have been fully considered but they are not persuasive. The rejection is therefore maintained.
RE: Rejection of claims 11 and 14, 16-18 under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Zhang et al. (US20040058436A1):
Applicants have traversed the rejection asserting that Zhang et al. does not disclose that the detaching solution prevents or avoids clumps or aggregates in the harvested cells while the present application, by contrast, explains that integrins and extracellular matrix proteins can cause harvested cells to clump even when trypsin is used, and describes the claimed enzymatic cocktail as a mix of different enzymes that cleave integrins and extracellular matrix, such as Accutase or Accumax, to avoid the aggregation issue associated with a single enzyme such as trypsin.
This is not persuasive because although Zhang et al. teaches using trypsin solution as the detaching solution to detach the cells, Zhang et al. discloses in paragraph 0008, after detaching the cells with the, the culture medium containing high concentration of serum is added into the bioreactor to block the trypsin activity, such that the microcarriers with the attached cells are recovered into a sterile receptacle through a vibrating screen under moderate vibration to detach the cells harmlessly. Blocking the trypsin activity of Zhang et al. prevents or avoids clumps or aggregates in the harvested cells as claimed.
Applicant's arguments filed 05/21/2026 have been fully considered but they are not persuasive. The rejection is therefore maintained.
RE: Rejection of claims 1, 10-11 and 19 under 35 U.S.C. 103 as being unpatentable over PURUSHOTHAMAN et al. (US20150322399A1), in view of Pebay et al. (US20180282682A1):
Applicants have traversed the rejection asserting that Pebat et al. in a non-analogous art to the fixed bed bioreactor harvesting problem addressed by the claims and by PURUSHOTHAMAN et al.
In response, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Pebay et al. was only relied upon for the teaching of introducing enzymes that cleave integrins and different enzymes that cleave an extracellular matrix as the enzymatic cocktail. Pebay et al. specifically discloses in paragraph 0108, that any cell releasing solution may be used to detach the cells from the culture plate. This may be dependent of the cell releasing solution used and the mode of action and may be optimized by the skilled addressee familiar with the characteristics of the cell releasing solution or method. Pebay et al. provides motivation to introduce enzymes that cleave integrins and different enzymes that cleave an extracellular matrix as the enzymatic cocktail to allow for the detachment of cells in high yields without the aggregation issue or forming clumps in the substantial portion of the cells.
Applicant's arguments filed 05/21/2026 have been fully considered but they are not persuasive. The rejection is therefore maintained.
RE: Rejection of claims 11 and 13 under 35 U.S.C. 103 as being unpatentable over PURUSHOTHAMAN et al. (US20150322399A1), in view of CASTILLO et al. (WO2019122239A1):
Applicants have traversed the rejection asserting that Castillo shows that structured beds can support cell growth and media flow. That generic benefit does not supply a reason to make the specific structural retrofit required by claim 13 in the context of Purushothaman's mechanically expandable packed bed.
This is not persuasive because Castillo was specifically relied upon for the teaching of a fixed bed having a plurality of cell immobilization layers, which is explicitly disclosed in paragraph 0074 of Castillo. Castillo provides motivation to modify the bioreactor of PURUSHOTHAMAN et al. to have a plurality of cell immobilization layers with a spacing between adjacent layers to allow cells to adhere and grow upon and forming a cell immobilization section and to allow passage of cells and medium through an open but tortuous path.
Applicant's arguments filed 05/21/2026 have been fully considered but they are not persuasive. The rejection is therefore maintained.
New/Maintained Rejections
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-9, 11-12, 14-17, and 20 are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by PURUSHOTHAMAN et al. (US20150322399A1, filed on 12/11/2013, and published on 11/12/2015).
Regarding claim 1, PURUSHOTHAMAN et al. teaches a method of harvesting cells comprising providing a bioreactor including a fixed bed structure capable of cell entrapment or adherence and cell growth (paragraph 0013, lines 1-3, and paragraph 0035, lines 1-3), adding cells to the bioreactor via media, allowing the cells to become entrapped and/or adhere to the fixed bed structure and grow within the bioreactor (claim 11, paragraph 0025), introducing a cell detaching solution comprising an enzymatic cocktail into the bioreactor (paragraph 0044, lines 4-5), agitating a portion of the bioreactor (paragraph 0061, lines 1-5), and moving a liquid level of the cell detaching solution relative to the fixed bed structure (paragraph 0063, lines 1-5), wherein a substantial portion of the cells are detached from the fixed bed structure without forming clumps or aggregates in the substantial portion of the cells (paragraph 0018, lines 6-9).
Regarding claim 2: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the agitating and moving steps are done simultaneously (paragraph 0018, last 2 lines).
Regarding claim 3: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the moving step comprises at least partially draining the bioreactor of the cell detaching solution (paragraph 0044, lines 1-2, 8-14 and paragraph 0063).
Regarding claim 4: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the moving step comprises moving the liquid level from above or proximate a top of the fixed bed structure to below or proximate a bottom of the fixed bed (paragraph 0063).
Regarding claim 5: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the moving step comprises adding fluid to the bioreactor (paragraph 0025, lines 12-15).
Regarding claim 6: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the adding step comprises adding additional cell detaching solution to the bioreactor (paragraph 0044 and 0059).
Regarding claim 7: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the liquid level is located above the fixed bed structure prior to the moving step (paragraph 0063).
Regarding claim 8: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the moving step comprises raising and lowering the liquid level a plurality of times (paragraphs 0059 and 0063).
Regarding claim 9: Following discussion of claim 1, PURUSHOTHAMAN et al. further teaches that the agitating step comprises directly or indirectly vibrating the fixed bed at a frequency of 50 Hertz and with an amplitude of about 1 millimeter (paragraph 0044, lines 2-7).
Regarding claim 11, PURUSHOTHAMAN et al. teaches a system of harvesting cells comprising a bioreactor including a structure for cell entrapment/adherence and growth (paragraph 0015 and paragraph 0013, lines 1-3, and paragraph 0035, lines 1-3), a cell harvest mechanism adapted to agitate the bioreactor and to move a liquid level relative to the structure (paragraph 0061, lines 1-5, and paragraph 0063, lines 1-5), and a vessel including a cell detaching solution in fluid communication with the bioreactor (paragraph 0044, lines 4-5), the cell detaching solution comprising an enzymatic cocktail for the detachment of cells from the structure for cell entrapment/adherence and growth without producing clumps or aggregates (paragraph 0018, lines 6-9).
Regarding claim 12: Following discussion of claim 11, PURUSHOTHAMAN et al. further teaches that the structure for cell entrapment/adherence and growth comprises a fixed bed (paragraph 0013, lines 1-3).
Regarding claim 14: Following discussion of claim 11, PURUSHOTHAMAN et al. further teaches that the cell harvest mechanism comprises a device for vibrating the bioreactor (paragraph 0012, lines 1-3).
Regarding claim 15: Following discussion of claim 11, PURUSHOTHAMAN et al. further teaches that the cell harvest mechanism comprises a pump for moving the liquid level (paragraph 0016, lines 1-3).
Regarding claim 16: Following discussion of claim 11, PURUSHOTHAMAN et al. further teaches that
the cell harvest mechanism comprises a device for applying vibratory energy to the bioreactor and, in particular, to the structure for cell entrapment/adherence and growth (vibration table 302 of Fig. 12, paragraph 0061).
Regarding claim 17: Following discussion of claim 11, PURUSHOTHAMAN et al. further teaches that the cell harvest mechanism forms part of a docking station for the bioreactor (see vibration table 302 of Fig. 12 as part of a docking station, paragraph 0061).
Regarding claim 20: Following discussion of claim 11, PURUSHOTHAMAN et al. further teaches that the system further includes a compactor for compacting the structure for cell entrapment/adherence and growth, either internal or external thereto (See compression of the fixed bed shown in Figures 3-6 and paragraph 0040).
Claim(s) 11 and 14, 16-18 are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Zhang et al. (US20040058436A1, filed on 06/05/2003, and published on 03/25/2004).
Regarding claim 11, Zhang et al. teaches a system of harvesting cells comprising a bioreactor including a structure for cell entrapment/adherence and growth (Claim 1, paragraph 0039, lines 1-4, Figures 1-3, paragraph 0040, last two lines), a cell harvest mechanism adapted to agitate the bioreactor and to move a liquid level relative to the structure (claim 1 of Zhang et al.), and a vessel including a cell detaching solution in fluid communication with the bioreactor (claim 1 of Zhang et al.), cell detaching solution comprising an enzymatic cocktail for the detachment of cells from the structure for cell entrapment/adherence and growth without producing clumps or aggregates (paragraph 0028, lines 9-13).
Regarding claim 14: Following discussion of claim 11, Zhang et al. further teaches that the cell harvest mechanism comprises a device for vibrating the bioreactor (paragraph 0008, last 4 lines).
Regarding claim 16: Following discussion of claim 11, Zhang et al. further teaches that
the cell harvest mechanism comprises a device for applying vibratory energy to the bioreactor and, in particular, to the structure for cell entrapment/adherence and growth (vibration screen, paragraph 0008, last 4 lines).
Regarding claim 17: Following discussion of claim 11, Zhang et al. further teaches that the cell harvest mechanism forms part of a docking station for the bioreactor (see vibration screen as part of a docking station, paragraph 0008).
Regarding claim 18: Following discussion of claim 11, Zhang et al. further teaches that the bioreactor comprises a harvest vessel for harvesting cells for introduction to another bioreactor (see downstream bioreactor, left side end of Fig. 3 and paragraph 0029).
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 10-11 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over PURUSHOTHAMAN et al. (US20150322399A1, filed on 12/11/2013, and published on 11/12/2015), in view of Pebay et al. (US20180282682A1, filed on 04/04/2017, and published on 10/04/2018).
Regarding claims 1 and 11, the teachings of PURUSHOTHAMAN et al. are set forth in detail above.
Regarding claim 10: Following discussion of claim 1, PURUSHOTHAMAN et al. fails to teach that the method further comprises introducing enzymes that cleave integrins and different enzymes that cleave an extracellular matrix as the enzymatic cocktail.
However, Pebay et al. teaches an automated system for sterile passaging of cells, said system comprising a platform for receiving and moving a cell culture plate from a housing, a manipulator arm for moving the culture plate between the housing and the platform and placing the culture plate on the platform, a disposable tip carrier for providing sterile disposable tips for dispensing the solution or the cell releasing solution from the receptacle to the culture plate, a controlling system to automate and program any one of the manipulator arm, the platform, and the liquid handling system such that the liquid handling system controllably and sterilely delivers and removes predetermined aliquots of solution and cell releasing solution to and from the culture plate sufficient to detach the cells from the culture plate for further passaging (claim 15 of Pebay et al.) Also, Pebay et al. teaches in paragraph 0104 introducing a mix of different enzymes to allow detachment of cells, such as ethylenediaminetetraacetic acid (EDTA), trypsin, ReLeSR Trypsin-EDTA, TrypLE Express, TrypLE Select, Collagenase, Dispase, Phosphate Buffered Saline, Accutase, Accumax, Cell dissociation solution (Sigma-Aldrich), Cell dissociation buffer (Thermofisher).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have used a mix of enzymes in the fixed bed reactor of PURUSHOTHAMAN et al. that cleave integrins and the extracellular matrix, such as accutase and accumax with a reasonable expectation of success. One would have been motivated to have done so in order to allow for the detachment of cells in high yields without the aggregation issue or forming clumps in the substantial portion of the cells as taught by Pebay et al.
Regarding claim 19: Following discussion of claim 11, PURUSHOTHAMAN et al. fails to teach that the bioreactor is tilted relative to a horizontal plane to facilitate draining of liquid from the structure for cell entrapment/adherence and growth.
However, Pebay et al. teaches an automated system for sterile passaging of cells, said system comprising a platform for receiving and moving a cell culture plate from a housing, a manipulator arm for moving the culture plate between the housing and the platform and placing the culture plate on the platform, a disposable tip carrier for providing sterile disposable tips for dispensing the solution or the cell releasing solution from the receptacle to the culture plate, a controlling system to automate and program any one of the manipulator arm, the platform, and the liquid handling system such that the liquid handling system controllably and sterilely delivers and removes predetermined aliquots of solution and cell releasing solution to and from the culture plate sufficient to detach the cells from the culture plate for further passaging (claim 15 of Pebay et al.) Also, Pebay et al. teaches shaking and tilting the platform so that the solutions pool to enable aspiration of the solutions from the culture plate (paragraph 0059).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have tilted the fixed bed reactor of PURUSHOTHAMAN et al. relative to a horizontal plane with a reasonable expectation of success. One would have been motivated to have done so in order to facilitate draining of the solution or liquids from the fixed bed of the bioreactor as taught by Pebay et al.
Claim(s) 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over PURUSHOTHAMAN et al. (US20150322399A1, filed on 12/11/2013, and published on 11/12/2015), in view of CASTILLO et al. (WO2019122239A1, filed on 12/20/2018, and published on 06/27/2019).
Regarding claim 11, the teachings of PURUSHOTHAMAN et al. are set forth in detail above.
Regarding claim 13, PURUSHOTHAMAN et al. fails to teach that the structure for cell entrapment/adherence and growth comprises a fixed bed having a plurality of cell immobilization layers, such as arranged in a stack or a spiral configuration, and either in direct contact or with a spacing between adjacent layers.
However, CASTILLO et al. teaches a fixed bed reactor, wherein the structured fixed bed can comprise one or more cell immobilization layers having a surface which allows cells to adhere and grow upon and forming a cell immobilization section. In some embodiments, adjacent to the cell immobilization layers are one or more spacer layers (paragraph 0074).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the bioreactor of PURUSHOTHAMAN et al. to have a plurality of cell immobilization layers with a spacing between adjacent layers with a reasonable expectation of success. One would have been motivated to have done so to allow cells to adhere and grow upon and forming a cell immobilization section, allow passage of cells, and facilitate cell and cell medium incursion into the immobilization layers as taught by CASTILLO et al.
Conclusion
THIS ACTION IS MADE FINAL. 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 HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
