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 .
Election/Restrictions
Applicant’s election with traverse of Group I (Claims 1-11, 14-16, and 23-26; drawn to a method of expanding cells in a cell expansion system) in the reply filed on December 18, 2025, is acknowledged.
Claims 12-13, 17-22, and 27-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II-IV), there being no allowable generic or linking claim.
Response to Arguments
Applicant's arguments Applicant's election with traverse of Group I in the reply filed on December 18,2025 is acknowledged. The traversal is on the ground(s) that a search for any one group would so overlap the search for the subject matter of the remaining groups that examining all groups can be performed without serious burden (page 1).
Applicant’s arguments have been fully considered but they are not persuasive.
This is not found persuasive because examiner was able to provide art which satisfied the limitations of the method claim of Group I without being able to satisfy the limitations of the product and method claims of Groups II-III thereby demonstrating that a search and/or examination burden exists between the restricted groups (US 111a restriction practice).
The requirement is still deemed proper and is therefore made FINAL.
Rejoinder
The restriction requirement for Group IV has been reconsidered in view of the prior art. Group IV is rejoined.
DETAILED ACTION
The claims filed on August 11, 2023, have been acknowledged. In light of the Applicant’s elected invention and rejoinder of Group IV, claims12-13 and 17-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-11, 14-16, and 23-30 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/399,524, filed on August 19, 2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-11, 14-16, and 23-30 receive domestic benefit from U.S. provisional application No. 63/399,524, filed on August 19, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) filed on September 14, 2023, and November 8, 2023, have been considered.
Claim Objections
Claim 7 is objected to because of the following informalities:
In line 3, the term “the coating agents” should read “the coating agent”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “a plurality of viral cells”” in claim 10 is used by the claim to mean “viral producer or viral host cells,” while the accepted meaning is “a cell that is a virus” and viruses are not cells. The term is indefinite because the specification does not clearly redefine the term.
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 3-4, 7-8, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by United States Patent Application No. 20180142199 (Jones).
Regarding Claim 1, Jones teaches a method of expanding cells in a cell expansion system [CES], comprising:
Loading a first fluid comprising cells is introduced into a bioreactor (also identified as a cell growth chamber);
From step 1220, flow moves to step 1224, where cells are moved toward a wall of the hollow fibers to be attached to an inside surface of the hollow fibers. The hollow fibers may allow fluid ( e.g., liquid) to pass through the fiber wall from an IC side to an EC side. Step 1224 may provide for fluid ( e.g., liquid) to pass through the fiber wall, which may result in the cells being pushed to an inside surface of the hollow fiber wall. The cells may be moved by introducing a second fluid ( e.g., liquid) into the hollow fiber bioreactor. Fluid in first circulation path may flow through the bioreactor. In those embodiments where the bioreactor is a hollow fiber bioreactor, the fluid may flow through the interior of hollow fiber of a hollow fiber membrane disposed in cell growth chamber;
Cells can be kept in suspension in the IC loop by circulating media continuously; and
Expanding the cells (paragraphs 0034, 0077, and 0115-0132 and Figures 1 and 12).
Regarding claims 3-4, Jones teaches that fluid in first fluid circulation path 12 flows through the intracapillary ("IC") space, including the interior, of the hollow fibers in the cell growth chamber 24 and that fluid in second fluid circulation path 14 flows through the extracapillary ("EC") space in the cell growth chamber 24 (paragraph 0036).
Regarding claim 7, Jones teaches that they coated the hollow fibers with fibronectin (paragraphs 0102-0103).
Regarding claim 8, Jones teaches that the hollow fibers may allow fluid ( e.g., liquid) to pass through the fiber wall from an IC side to an EC side. An IC loop
valve ( e.g., valves 290 or 386) may be closed so that the fluid (e.g., liquid) is transported across the fiber wall (e.g., from an IC space to an EC space). The
movement of fluid ( e.g., liquid) thorough the fiber wall is referred to as ultrafiltration (paragraph 0120 and paragraph 0151).
Regarding Claim 11, Jones teaches that a CES can include a device configured to move or "rock" a cell growth chamber relative to other components of the cell expansion system by attaching it to a rotational and/or lateral rocking device.). At sub-step 1216 the hollow fiber bioreactor may be rotated while the fluid with cells is circulated through the bioreactor. For example, in one embodiment, the bioreactor may be rotated between a first initial horizontal position (FIG. 7) through 270 degrees (FIG. 10) and then back to the first position (paragraphs 0106-0107 and 0118).
Claims 1, 3-6, and 10-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by United States Patent Application No. 20180291342 (Nankervis), as evidenced by United States Patent Application No. 20200392449 (Griffen).
Regarding claim 1, Nankervis teaches a method of expanding cells in a cell expansion system (CES), the method comprising:
loading a first volume of fluid comprising a plurality of cells into the cell expansion system, wherein the cell expansion system comprises a cell growth chamber;
loading a second volume of fluid comprising media into a portion of a first fluid circulation path to position the first volume of fluid in a first portion of the cell growth chamber;
feeding the cells. As can be seen in Figures 11, 13, and 16-17 and disclosed in paragraphs 0065 and 0156-0158, feeding the cells can occur continuously until the expanded cells are ready to proceed to harvest. Embodiments may provide a protocol to shear the colonies by circulating the suspension cell culture through, for example, the hollow fiber Intracapillary (IC) loop (e.g., with hollow fibers of 215 μm inner diameter) during the expansion phase of growth. In embodiments, a colony, micro-colony, or cluster of cells may be sheared to reduce a size of the colony, micro-colony, or cluster of cells. In an embodiment, a colony or cluster of cells may be sheared to provide a single cell suspension and create cell growth/viability. In embodiments, such capabilities may contribute to the continuous perfusion growth of the cells, e.g., T cells or Tregs;
and expanding the cells (claim 1).
Regarding claim 3, Nankervis teaches wherein fluid in the first fluid circulation path flows through an intracapillary space of the cell growth chamber (claim 3).
Regarding claim 4, Nankervis teaches wherein fluid in the second fluid circulation path flows through an extracapillary space of the cell growth chamber (claim 4).
Regarding claim 5, Nankervis teaches wherein the first volume of fluid comprising the plurality of cells is loaded without activating an intracapillary circulation pump (claim 5).
Regarding claim 6, Nankervis teaches wherein the first volume of fluid is the same as the second volume of fluid. (claim 6).
Regarding claim 10, as stated in the 112b rejection above, it is unclear what is meant by viral cells. Due to this uncertainty, cells that are capable of hosting viral vectors are considered to fall within this claim term. As neither claims 1 nor 10 require that the cell comprises any viruses or viral particles, all that is considered to be required by this claim term is that the cells is capable of hosting a virus.
As stated supra, Nankervis teaches that their method can be used to expand T cells (paragraphs 0065 and 0156-0158).
Griffin evidences that T cells can be transduced with lentiviral vectors to express chimeric antigen receptors (paragraphs 0002-0007). Therefore, T cells are capable of being transduced and comprising viral vectors and are considered to fall within the broadest reasonable interpretation of “viral cells”.
Regarding claim 11, the CES may include a device configured to move or "rock" the cell growth chamber relative to other components of the cell expansion system by attaching it to a rotational and/or lateral rocking device. A first rotational rocking component 138 rotates the bioreactor 100 around central axis 142 of the bioreactor. A rocking device may be connected to the bioreactor and after the first time period (and during the second time period), when the first pump is activated at step 1910, the rocking device may be activated to rotate the bioreactor as part of circulating the cells to reduce a number of cells in a cell cluster (paragraphs 0080-0081 and 0228).
Claims 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by United States Patent Application No. 20180291342 (Nankervis).
Regarding Claim 14, Nankervis teaches a method of controlling a cell expansion system (expanding cells in a cell expansion system, Abstract), comprising:
actuating, with a controller, a first pump to flow a first fluid at a first fluid flow rate (The IC inlet pump 920 may be adjusted to produce a first flow rate, Para. [0143]; The one or more controller(s) may be configured, in embodiments, to control the one or more pump(s), Para. [0068]);
and actuating, with a controller, a second pump to flow a second fluid at a second fluid flow rate (and the IC circulation pump may be adjusted 922 to produce a second counter-flow rate or second counter-volumetric flow rate, Para. [0143]; The one or more controller(s) may be configured, in embodiments, to control the one or more pump(s), Para. [0068]);
wherein the first fluid flow rate and the second fluid flow rate are opposite (reducing the loss of cells from a hollow fiber membrane (HFM) bioreactor may be accomplished by matching the IC circulation pump rate to the IC inlet pump rate, but in the opposite direction, during feeding. For example, an IC inlet pump rate of +0.1 ml/min may be matched to a complementary IC circulation pump rate of -0.1 ml/min in order to maintain cells in the bioreactor during the growth phase of the cell culture, Para. [0063]).
Regarding Claims 15-16, Nankervis teaches that a low or minimum feed rate may be ... equal to about 0.01 ml/min (paragraph 0186).
Claims 23-26 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20190352589 (Jing).
Jing teaches an automated cell culture system includes a cell culture reactor including a housing; a fluidic circuit for cell culture media, the fluidic circuit disposed in an interior of the housing. The fluidic circuit includes a culture vessel for culturing cells in the cell culture media, a reservoir for the cell culture media, the reservoir fluidically connected to the culture vessel, and a pump configured to pump the cell culture media in the fluidic circuit. The automated cell culture system includes one or more sensors disposed in the interior of the housing, each sensor configured to detect a parameter of one or more of (1) the cell culture media in the fluidic circuit and (2) an environment in the interior of the housing; and a computing device configured to automatically control operation of the cell culture reactor based on one or more of the detected parameters.
Jing teaches that a pump 208a, such as a peristaltic pump, and one or more valves 210, such as pinch valves, can be operable under computer control to pump fresh cell culture from the fresh media source 206 through the supply line and into the fluidic circuit. Cell culture media can be pumped out of the fluidic circuit along a waste line to a waste destination (not shown) by a pump 208b, such as a peristaltic pump. The pumps 208a, 208b can be automatically operable under control of the computing system of the automated cell culture system. In some examples, pumping fresh cell culture media into the fluidic circuit from the fresh media source 206 can occur substantially concurrently with pumping cell culture media out of the fluidic circuit to the waste destination to avoid providing more cell culture media than the capacity of the fluidic circuit. In some examples, cell culture media is pumped into the fluidic circuit from the fresh media source 206 at a higher flow rate (a first fluid at a first fluid flow rate) than cell culture media is pumped out of the fluidic circuit (a second fluid at a second fluid flow rate) to the waste destination, e.g., to increase the volume of cell culture media in the fluidic circuit.
The computing device is configured to control operation of the cell culture reactor based on a comparison between each of one or more of the detected parameters and respective thresholds. The threshold for at least one of the detected parameters is based on a phase of the cell culturing. The computing device is configured to determine the phase of the cell culturing based on one or more of the detected parameters.
A microprocessor-based controller housed in the base portion 102 of the automated cell culture system 100, or connected to the automated cell culture system, can monitor and/or control the operation of the automated cell culture system. One or more sensors housed in the reactor portion 104 of the automated cell culture system 100 are configured to sense parameters of the culture environment in real time and provide signals indicative of the sensed parameters to a local controller.
The sensors can include temperature sensors, pH sensors, dissolved gas sensors, atmospheric gas sensors, glucose sensors, lactate sensors, fluid mass or volume sensors, or other types of sensors. The controller or computing device 100 can automatically, without real time user input, control operation of one or more components of the automated cell culture system, such as heaters, gas flow controllers, pumps, or other components, responsive to the sensed parameters. The real time adjustment of parameters, e.g., in a closed loop feedback system, can enable time- and resource-efficient cell culture. In some examples, the computing device 100 can determine, based on the sensed parameters or historical records of the sensed parameters or both, the phase of the cell culturing, and thereby can control operation of one or more components of the automated cell culture system 100 based on the phase of the cell culturing. The computing device 100 can cause alerts, such as one or more of visual alerts and audio alerts, to be output on a user interface, such as on the display 106, e.g., when a sensed parameter exceeds or falls below a threshold, when a change in the phase of the cell culturing is identified, or for other reasons. The computing system can cause an alert to be output to alert a user of the alarm condition, such as an audible alert, a text or graphical alert on the user interface of the automated cell culture system or on a user interface of a remote computing device, an alert light, or another type of alert (paragraphs 0003-0005, 0071-0088, and 0119).
Claims 27-30 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20190352589 (Jing).
Jing teaches an automated cell culture system includes a cell culture reactor including a housing; a fluidic circuit for cell culture media, the fluidic circuit disposed in an interior of the housing. The fluidic circuit includes a culture vessel for culturing cells in the cell culture media, a reservoir for the cell culture media, the reservoir fluidically connected to the culture vessel, and a pump configured to pump the cell culture media in the fluidic circuit. The automated cell culture system includes one or more sensors disposed in the interior of the housing, each sensor configured to detect a parameter of one or more of (1) the cell culture media in the fluidic circuit and (2) an environment in the interior of the housing; and a computing device configured to automatically control operation of the cell culture reactor based on one or more of the detected parameters.
The computing device is configured to control operation of the cell culture reactor based on a comparison between each of one or more of the detected parameters and respective thresholds. The threshold for at least one of the detected parameters is based on a phase of the cell culturing. The computing device is configured to determine the phase of the cell culturing based on one or more of the detected parameters.
A microprocessor-based controller housed in the base portion 102 of the automated cell culture system 100, or connected to the automated cell culture system, can monitor and/or control the operation of the automated cell culture system. One or more sensors housed in the reactor portion 104 of the automated cell culture system 100 are configured to sense parameters of the culture environment in real time and provide signals indicative of the sensed parameters to a local controller.
The sensors can include temperature sensors, pH sensors, dissolved gas sensors, atmospheric gas sensors, glucose sensors, lactate sensors, fluid mass or volume sensors, or other types of sensors. The controller or computing device 100 can automatically, without real time user input, control operation of one or more components of the automated cell culture system, such as heaters, gas flow controllers, pumps, or other components, responsive to the sensed parameters. The real time adjustment of parameters, e.g., in a closed loop feedback system, can enable time- and resource-efficient cell culture. In some examples, the computing device 100 can determine, based on the sensed parameters or historical records of the sensed parameters or both, the phase of the cell culturing, and thereby can control operation of one or more components of the automated cell culture system 100 based on the phase of the cell culturing. The computing device 100 can cause alerts, such as one or more of visual alerts and audio alerts, to be output on a user interface, such as on the display 106, e.g., when a sensed parameter exceeds or falls below a threshold, when a change in the phase of the cell culturing is identified, or for other reasons. The computing system can cause an alert to be output to alert a user of the alarm condition, such as an audible alert, a text or graphical alert on the user interface of the automated cell culture system or on a user interface of a remote computing device, an alert light, or another type of alert (paragraphs 0003-0005, 0071-0088, and 0119).
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.
Claim 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20180142199 (Jones) as applied to claim 1 above.
The teachings of Jones are discussed above.
Jones does not explicitly state that they continuously harvest cells.
However, Jones teaches that cells grown/expanded in bioreactor 201 can be flushed out of bioreactor 201 into harvest bag 299 through valve 298 and line 297. Alternatively, when valve 298 is closed, the cells may be redistributed, e.g., circulated back, within bioreactor 201 for further growth or loading (paragraph 0042).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of expanding cells of Jones to continuously harvest cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Jones already teaches that their device can be used to harvest cells through a valve into a harvest bag or that the valve can be closed to recirculate the cells back into the bioreactor for further growth. As harvesting or recirculating is controlled by a single valve, it would have been obvious that one could harvest a portion of the expanded cells through the valve and then close it to recirculate any remaining cells for further growth, limiting the need to collect and load more cells after each harvest and limiting the risk of potential contamination each time new cells would need to be loaded. Furthermore, this would allow for assessment of a small population of cells to ensure the preferred cells/markers are obtained before performing a larger scale collection. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claim 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20180291342 (Nankervis) as applied to claim 1 above.
The teachings of Nankervis are discussed above.
Nankervis does not explicitly state that they continuously harvest cells.
However, Nankervis teaches that cells grown/expanded in cell growth chamber 501 may be flushed out of cell growth chamber 501 into harvest bag 599 through valve 598. Alternatively, the when valve is closed, the cells may be redistributed within the chamber for further growth (paragraphs 0093 and 0107).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of expanding cells of Nankervis to continuously harvest cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Nankervis already teaches that their device can be used to harvest cells through a valve into a harvest bag or that the valve can be closed to recirculate the cells back into the bioreactor for further growth. As harvesting or recirculating is controlled by a single valve, it would have been obvious that one could harvest a portion of the expanded cells through the valve and then close it to recirculate any remaining cells for further growth, limiting the need to collect and load more cells after each harvest and limiting the risk of potential contamination each time new cells would need to be loaded. Furthermore, this would allow for assessment of a small population of cells to ensure the preferred cells/markers are obtained before performing a larger scale collection. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claim 1 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20180142199 (Jones) as applied to claims 1 and 7-8 above, and further in view of United States Patent Application No. 20170349869 (Frank).
The teachings of Jones are as discussed above. Jones teaches that prior to loading cells in a CES/bioreactor, a protocol may include coating the bioreactor
with a reagent to aid in the attachment of cells (paragraph 0177).
Jones is silent as to the protocol for coating the bioreactor.
However, Frank teaches that a coating agent may be applied to a surface, such as the cell growth surface of a hollow fiber, by controlling the movement of a fluid in which a coating agent is suspended. Using ultrafiltration, the fluid may be pushed through the pores of a hollow fiber from a first side, e.g., an intracapillary (IC) side, of the hollow fiber to a second side, e.g., an extracapillary (EC) side, while the coating agent is actively promoted to the surface of the hollow fiber. In so doing, the coating agent may be hydrostatically deposited onto a wall e.g., inner wall, of the hollow fiber. Frank teaches that this procedure can be completed in 10 minutes for coating with fibronectin (abstract and Example 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the coating protocol of Frank for coating the hollow fiber membrane with fibronectin to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use this protocol with a reasonable expectation of success because Jones and Frank use similar cell expansion systems that use extracapillary and intracapillary fluid paths to grow cells attached to hollow fiber membranes and Frank teaches a known method for coating the hollow fiber membranes with fibronectin. Furthermore, Frank teaches that their protocol can be completed in 10 minutes allowing for expansion of cells to begin quickly. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-7, and 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11629332 in view of United States Patent Application No. 20180142199 (Jones), as evidenced by United States Patent Application No. 20200392449 (Griffin).
Regarding claim 1, ‘332 claims a method of expanding cells in a cell expansion system, the method comprising: loading a first volume of a first fluid into the cell expansion system, wherein the first fluid comprises a plurality of cells, and wherein the cell expansion system comprises a cell growth chamber (a hollow fiber membrane);
based on the first volume of the first fluid, determining a second volume of a second fluid to load into a portion of a first fluid circulation path to position the first volume of the first fluid in a first portion of the cell growth chamber,
based on the determining the second volume of the second fluid, loading the second volume of the second fluid into the cell expansion system to position the first volume of the first fluid in the central portion of the cell growth chamber;
loading a third volume of a third fluid for feeding the plurality of cells; and
expanding the plurality of cells (claims 1 and 8).
‘332 does not explicitly state that the third fluid for feeding the plurality of cells continuously circulates about an intracapillary loop.
However, Jones teaches a method of expanding cells in a cell expansion system [CES], comprising:
Loading a first fluid comprising cells is introduced into a bioreactor (also identified as a cell growth chamber);
From step 1220, flow moves to step 1224, where cells are moved toward a wall of the hollow fibers to be attached to an inside surface of the hollow fibers. The hollow fibers may allow fluid ( e.g., liquid) to pass through the fiber wall from an IC side to an EC side. Step 1224 may provide for fluid ( e.g., liquid) to pass through the fiber wall, which may result in the cells being pushed to an inside surface of the hollow fiber wall. The cells may be moved by introducing a second fluid ( e.g., liquid) into the hollow fiber bioreactor. Fluid in first circulation path may flow through the bioreactor. In those embodiments where the bioreactor is a hollow fiber bioreactor, the fluid may flow through the interior of hollow fiber of a hollow fiber membrane disposed in cell growth chamber;
Cells can be kept in suspension in the IC loop by circulating media continuously; and
Expanding the cells (paragraphs 0034, 0077, and 0115-0132 and Figures 1 and 12).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘332 to continuously feed the cells through an intracapillary loop to maintain them in suspension, as identified by Jones, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘332 and Jones use similar cell expansion systems to grow cells in hollow fiber membrane growth chambers and Jones reduces to practice that feeding a fluid continuously through an intracapillary loop can be used in such a system to maintain the cells in suspension rather them causing them to settle. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 3, ‘332 claims wherein the second volume of the second fluid in the first fluid circulation path flows through an intracapillary space of the cell growth chamber (claim 3).
Regarding claim 4, ‘332 claims wherein a fourth fluid in the second fluid circulation path flows through an extracapillary space of the cell growth chamber (claim 4).
Regarding claim 5, ‘332 claims wherein the first volume of the first fluid is loaded without activating an intracapillary circulation pump (claim 5).
Regarding claim 6, ‘332 claims wherein the first volume of the first fluid is the same as the second volume of the second fluid (claim 6).
Regarding claim 7, ‘332 does not teach using a coating agent.
However, Jones teaches that they coated the hollow fibers with fibronectin to enhance cell growth and/or adherence of the cells to the lumen wall (paragraphs 0102-0103). Jones teaches that prior to loading cells in a CES/bioreactor, a protocol may include coating the bioreactor with a reagent to aid in the attachment of cells. The purpose of this protocol may be to enable adherent cells to attach to the bioreactor membrane while allowing flow on the EC circulation loop (paragraphs 0177-0178).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘332 to coat the hollow fiber membranes with fibronectin, as identified by Jones, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘332 and Jones use similar cell expansion systems to grow cells in hollow fiber membrane growth chambers and Jones teaches that coating the hollow fiber membranes with fibronectin can improve enhance cell growth and/or adherence of the cells to the lumen wall while allowing flow on the EC circulation loop. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 10, as stated in the 112b rejection above, it is unclear what is meant by viral cells. Due to this uncertainty, cells that are capable of hosting viral vectors are considered to fall within this claim term. As neither claims 1 nor 10 require that the cell comprises any viruses or viral particles, all that is considered to be required by this claim term is that the cells is capable of hosting a virus.
‘332 claims that their method can be used to expand T cells (claims 13-15).
Griffin evidences that T cells can be transduced with lentiviral vectors to express chimeric antigen receptors (paragraphs 0002-0007). Therefore, T cells are capable of being transduced and comprising viral vectors and are considered to fall within the broadest reasonable interpretation of “viral cells”.
Regarding claim 11, ‘332 does not teach using a rocking device.
However, Jones teaches that in addition to structural features, some embodiments provide for creating conditions in a CES controlled by fluid flow that optimizes growth of cells. As one example, a CES can include a device configured to move or "rock" a cell growth chamber relative to other components of the cell expansion system by attaching it to a rotational and/or lateral rocking device.). At sub-step 1216 the hollow fiber bioreactor may be rotated while the fluid with cells is circulated through the bioreactor. For example, in one embodiment, the bioreactor may be rotated between a first initial horizontal position (FIG. 7) through 270 degrees (FIG. 10) and then back to the first position (paragraphs 0106-0107 and 0118).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘332 to include using a rocking device to rotate the cell expansion system, as identified by Jones, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘332 and Jones use similar cell expansion systems to grow cells in hollow fiber membrane growth chambers and Jones teaches that using a rocking device to rotate the cell expansion system optimizes the growth of cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1-2 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11629332 in view of United States Patent Application No. 20180142199 (Jones) as applied to claim 1 above.
The teachings of ‘332 and Jones are discussed above.
‘332 and Jones do not explicitly state that they continuously harvest cells.
However, Jones teaches that cells grown/expanded in bioreactor 201 can be flushed out of bioreactor 201 into harvest bag 299 through valve 298 and line 297. Alternatively, when valve 298 is closed, the cells may be redistributed, e.g., circulated back, within bioreactor 201 for further growth or loading (paragraph 0042).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of expanding cells of ‘332 and Jones to continuously harvest cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Jones already teaches that their device can be used to harvest cells through a valve into a harvest bag or that the valve can be closed to recirculate the cells back into the bioreactor for further growth. As harvesting or recirculating is controlled by a single valve, it would have been obvious that one could harvest a portion of the expanded cells through the valve and then close it to recirculate any remaining cells for further growth, limiting the need to collect and load more cells after each harvest and limiting the risk of potential contamination each time new cells would need to be loaded. Furthermore, this would allow for assessment of a small population of cells to ensure the preferred cells/markers are obtained before performing a larger scale collection. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 7-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11629332 in view of United States Patent Application No. 20180142199 (Jones) as applied to claims 1 and 7 and further in view of United States Patent Application No. 20170349869 (Frank).
The teachings of ‘332 and Jones are as discussed above. ‘332, as stated supra, claims fluid circulation paths that are extracapillary and intracapillary (claims 3-4) but does not identify that moving a fluid through a hollow fiber membrane and intro the extracapillary circulation loop using ultrafiltration. Jones, as stated supra, teaches that prior to loading cells in a CES/bioreactor, a protocol may include coating the bioreactor with a reagent to aid in the attachment of cells (paragraph 0177).
Jones is silent as to the protocol for coating the bioreactor.
However, Frank teaches that a coating agent may be applied to a surface, such as the cell growth surface of a hollow fiber, by controlling the movement of a fluid in which a coating agent is suspended. Using ultrafiltration, the fluid may be pushed through the pores of a hollow fiber from a first side, e.g., an intracapillary (IC) side, of the hollow fiber to a second side, e.g., an extracapillary (EC) side, while the coating agent is actively promoted to the surface of the hollow fiber. In so doing, the coating agent may be hydrostatically deposited onto a wall e.g., inner wall, of the hollow fiber. Frank teaches that this procedure can be completed in 10 minutes for coating with fibronectin (abstract and Example 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the coating protocol of Frank for coating the hollow fiber membrane with fibronectin to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use this protocol with a reasonable expectation of success because ‘332, Jones, and Frank use similar cell expansion systems that use extracapillary and intracapillary fluid paths to grow cells in a hollow fiber membranes cell growth chamber and Frank teaches a known method for coating the hollow fiber membranes with fibronectin. Furthermore, Frank teaches that their protocol can be completed in 10 minutes allowing for expansion of cells to begin quickly. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 3-4, 7-8, and 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11608486 in view of United States Patent Application No. 20180142199 (Jones).
Regarding claim 1, ‘486 claims a method of growing cells in a hollow fiber bioreactor comprising a longitudinal axis, the method comprising: loading cells into the hollow fiber bioreactor, wherein the loading comprises:
introducing a first fluid comprising the cells into a plurality of hollow fibers in the hollow fiber bioreactor;
maintaining the longitudinal axis of the hollow fiber bioreactor at an angle greater than zero degrees from a first position, wherein the longitudinal axis is substantially horizontal when in the first position; and while maintaining the longitudinal axis of the hollow fiber bioreactor at the angle, moving the cells toward an inside wall of at least one of the plurality of hollow fibers by introducing a second fluid into the hollow fiber bioreactor, wherein a portion of the second fluid passes through a wall of the at least one of the plurality of hollow fibers and a portion of the cells attach to a lumen wall of the at least one of the plurality of hollow fibers, wherein the first fluid and the second fluid are different;
expanding the cells by circulating media in the hollow fiber bioreactor to feed the cells, wherein during the expanding the media is circulated at a first flow rate that subjects the cells to a fluid shear stress greater than about 0.01 dynes/cm2 for a first predetermined period of time (i.e. continuously) (claims 1 and 7).
‘486 does not explicitly state that the fluid for feeding the plurality of cells continuously circulates about an intracapillary loop.
However, Jones teaches a method of expanding cells in a cell expansion system [CES], comprising:
Loading a first fluid comprising cells is introduced into a bioreactor (also identified as a cell growth chamber);
From step 1220, flow moves to step 1224, where cells are moved toward a wall of the hollow fibers to be attached to an inside surface of the hollow fibers. The hollow fibers may allow fluid ( e.g., liquid) to pass through the fiber wall from an IC side to an EC side. Step 1224 may provide for fluid ( e.g., liquid) to pass through the fiber wall, which may result in the cells being pushed to an inside surface of the hollow fiber wall. The cells may be moved by introducing a second fluid ( e.g., liquid) into the hollow fiber bioreactor. Fluid in first circulation path may flow through the bioreactor. In those embodiments where the bioreactor is a hollow fiber bioreactor, the fluid may flow through the interior of hollow fiber of a hollow fiber membrane disposed in cell growth chamber;
Cells can be kept in suspension in the IC loop by circulating media continuously; and
Expanding the cells (paragraphs 0034, 0077, and 0115-0132 and Figures 1 and 12).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘486 to continuously feed the cells through an intracapillary loop to maintain them in suspension, as identified by Jones, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘486 and Jones use similar cell expansion systems to grow cells in hollow fiber membrane growth chambers and Jones reduces to practice that feeding a fluid continuously through an intracapillary loop can be used in such a system to maintain the cells in suspension rather them causing them to settle. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 3-4, ‘486 claims wherein the plurality of hollow fibers are part of an intracapillary space of the hollow fiber bioreactor and wherein the portion of the second fluid passes from the intracapillary space to an extracapillary space of the bioreactor (claim 2).
Regarding claim 7, ‘486 does not teach using a coating agent.
However, Jones teaches that they coated the hollow fibers with fibronectin to enhance cell growth and/or adherence of the cells to the lumen wall (paragraphs 0102-0103). Jones teaches that prior to loading cells in a CES/bioreactor, a protocol may include coating the bioreactor with a reagent to aid in the attachment of cells. The purpose of this protocol may be to enable adherent cells to attach to the bioreactor membrane while allowing flow on the EC circulation loop (paragraphs 0177-0178).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘486 to coat the hollow fiber membranes with fibronectin, as identified by Jones, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘486 and Jones use similar cell expansion systems to grow cells in hollow fiber membrane growth chambers and Jones teaches that coating the hollow fiber membranes with fibronectin can improve enhance cell growth and/or adherence of the cells to the lumen wall while allowing flow on the EC circulation loop. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 8, ‘486, as stated supra, claims that wherein the plurality of hollow fibers are part of an intracapillary space of the hollow fiber bioreactor and wherein the portion of the second fluid passes from the intracapillary space to an extracapillary space of the bioreactor (claim 2). Although ‘486 does not identify this as ultrafiltration, Jones evidences that the movement of fluid ( e.g., liquid) thorough the fiber wall is ultrafiltration (paragraph 0120 and paragraph 0151).
Regarding claim 10, as stated in the 112b rejection above, it is unclear what is meant by viral cells. Due to this uncertainty, cells that are capable of hosting viral vectors are considered to fall within this claim term. As neither claims 1 nor 10 require that the cell comprises any viruses or viral particles, all that is considered to be required by this claim term is that the cells is capable of hosting a virus.
‘486 claims that their method can be used to expand endothelial cells (claim 17).
Endothelial cells are known to be capable of hosting viruses. Therefore, endothelial cells considered to fall within the broadest reasonable interpretation of “viral cells”.
Regarding claim 11, although ‘486 claims rotating their device, they do not specifically recite using a rocking device.
However, Jones teaches that in addition to structural features, some embodiments provide for creating conditions in a CES controlled by fluid flow that optimizes growth of cells. As one example, a CES can include a device configured to move or "rock" a cell growth chamber relative to other components of the cell expansion system by attaching it to a rotational and/or lateral rocking device.). At sub-step 1216 the hollow fiber bioreactor may be rotated while the fluid with cells is circulated through the bioreactor. For example, in one embodiment, the bioreactor may be rotated between a first initial horizontal position (FIG. 7) through 270 degrees (FIG. 10) and then back to the first position (paragraphs 0106-0107 and 0118).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘486 to use a rocking device to rotate the cell expansion system, as identified by Jones, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘486 and Jones use similar cell expansion systems to grow cells in hollow fiber membrane growth chambers and Jones teaches that using a rocking device to rotate the cell expansion system optimizes the growth of cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1-2 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11608486 in view of United States Patent Application No. 20180142199 (Jones) as applied to claim 1 above.
The teachings of ‘486 and Jones are discussed above.
‘486 and Jones do not explicitly state that they continuously harvest cells.
However, Jones teaches that cells grown/expanded in bioreactor 201 can be flushed out of bioreactor 201 into harvest bag 299 through valve 298 and line 297. Alternatively, when valve 298 is closed, the cells may be redistributed, e.g., circulated back, within bioreactor 201 for further growth or loading (paragraph 0042).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of expanding cells of ‘486 and Jones to continuously harvest cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Jones already teaches that their device can be used to harvest cells through a valve into a harvest bag or that the valve can be closed to recirculate the cells back into the bioreactor for further growth. As harvesting or recirculating is controlled by a single valve, it would have been obvious that one could harvest a portion of the expanded cells through the valve and then close it to recirculate any remaining cells for further growth, limiting the need to collect and load more cells after each harvest and limiting the risk of potential contamination each time new cells would need to be loaded. Furthermore, this would allow for assessment of a small population of cells to ensure the preferred cells/markers are obtained before performing a larger scale collection. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 7-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11608486 in view of United States Patent Application No. 20180142199 (Jones) as applied to claims 1 and 7-8 and further in view of United States Patent Application No. 20170349869 (Frank).
The teachings of ‘486 and Jones are as discussed above. ‘486, as stated supra, claims fluid circulation paths that are extracapillary and intracapillary (claim 2) but does not identify that moving a fluid through a hollow fiber membrane and into the extracapillary circulation loop using ultrafiltration. Jones, as stated supra, teaches that prior to loading cells in a CES/bioreactor, a protocol may include coating the bioreactor with a reagent to aid in the attachment of cells (paragraph 0177).
Jones is silent as to the protocol for coating the bioreactor.
However, Frank teaches that a coating agent may be applied to a surface, such as the cell growth surface of a hollow fiber, by controlling the movement of a fluid in which a coating agent is suspended. Using ultrafiltration, the fluid may be pushed through the pores of a hollow fiber from a first side, e.g., an intracapillary (IC) side, of the hollow fiber to a second side, e.g., an extracapillary (EC) side, while the coating agent is actively promoted to the surface of the hollow fiber. In so doing, the coating agent may be hydrostatically deposited onto a wall e.g., inner wall, of the hollow fiber. Frank teaches that this procedure can be completed in 10 minutes for coating with fibronectin (abstract and Example 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the coating protocol of Frank for coating the hollow fiber membrane with fibronectin to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use this protocol with a reasonable expectation of success because ‘486, Jones, and Frank use similar cell expansion systems that use extracapillary and intracapillary fluid paths to grow cells in a hollow fiber membranes cell growth chamber and Frank teaches a known method for coating the hollow fiber membranes with fibronectin. Furthermore, Frank teaches that their protocol can be completed in 10 minutes allowing for expansion of cells to begin quickly. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631