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 without traverse of Group II (Claims 14-29; drawn to a method of cultivating cells) in the reply filed on December 31, 2024, is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
DETAILED ACTION
The amended claims filed on September 8, 2025, have been acknowledged. Claims 1-13 and 27-28 were cancelled. Claims 14, 16, 20, and 25-26 was amended. Claims 30-33 are new. Claims 14-26 and 29-33 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/132,291, filed on December 30, 2020. 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 14-26 and 29-33 receive domestic benefit from U.S. provisional application No. 62/132,291, filed on December 30, 2020.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 14-29 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 in light of Applicant’s amendments to claim 14 to recite “a plurality of microcarriers”;
amendments to claim 16 to recite "the one or more polymer films" in line 3, “the interior compartment” in line 3, “the inner layer” in line 4, “the outer layer” in line 6, “the first port” in line 7, “the second port” in line 9, and removal of “an plurality of microcarriers” in line 11;
amendments to claim 25 to recite “the interior compartment of the oxygen permeable bag is undivided and removal of the "in fluid communication with the interior compartment" language;
amendments to claim 26 to remove the language "an undivided interior compartment" and "in fluid communication with the interior compartment";
amendments to claim 20 to remove the term substantially; and
amendments to claim 26 to remove the term e.g.
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.
Claims 15 and 22-23 are 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.
Regarding claims 15 and 22-23, they recite the limitation “the microcarriers” while claims 24 and 27-28 recite the limitation “the plurality of microcarriers”. As the applicant uses different terms between claims, it is unclear whether “the microcarriers” of claims 15 and 22-23 have proper antecedent basis and whether “the microcarriers” are the same as the plurality of microcarriers of claim 14. Applicant is recommended to use one set of terminology (a microcarrier and the microcarrier or a plurality of microcarriers and the plurality of microcarriers) for all the relevant claims.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 14-15, 22-23, 27, and 29 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 2014/0287512 (Kaisermayer) is withdrawn in light of Applicant’s amendments to claim 14 to recite that the structure of the tubes.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 14 and 16-21 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2014/0287512 (Kaisermayer) as applied to claim 14 above, and further in view of World Intellectual Property Organization Patent Application No. 2016106290 (Clark) is withdrawn in light of Applicant’s amendments to claim 14 to recite that the structure of the tubes.
The prior rejection of claims 14 and 24 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2014/0287512 (Kaisermayer) as applied to claim 14 above, and further in view of World Intellectual Property Organization Patent Application No. 2016106290 (Clark) and United States Patent No. 8809054 (Borgart) is withdrawn in light of Applicant’s amendments to claim 14 to recite that the structure of the tubes.
The prior rejection of claims 14 and 28 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20190359925 (Lundgren) and United States Patent Application No. 2014/0287512 (Kaisermayer) is withdrawn in light of Applicant’s amendments to claim 14 to recite that the structure of the tubes.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 14-15, 22-23, 25-26, 29, and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2014/0287512 (Kaisermayer) as applied to claim 14 above, and further in view of United States Patent No. 4537860 (Tolbert). This is a new rejection that is substantially similar to a previous rejection. Any aspect of Applicant’s traversal that is considered relevant to the rejection as newly written is addressed below.
Regarding claims 14 and 31, Kaisermayer teaches a method of cultivating cells in a bag, which comprises the steps of:
a) providing a sterile flexible bag:
The sterile flexible bag can be prepared from two flexible sheets joined along their edges to form a "pillow-style bag." The flexible sheets may comprise thermoplastics such as fluoropolymers as multilayer laminates which may further comprise adhesive layers, comprising a filter material which is attached to a wall of the culture bag, wherein the filter material delimits a chamber inside the bag and wherein the chamber is fluidically connected to a first port in a wall of the bag (as can be seen in Figure 5, the first port is formed in the exterior surface of the bag),
b) providing agitation means for the bag,
c) introducing cell culture medium, microcarriers and cells to the bag,
d) cultivating cells in the bag with agitation (i.e. flowing media) provided by the agitation means, allowing formation of a suspension of microcarriers with immobilized cells (i.e. attached cells or anchorage dependent cells) and supplying at least one gas (i.e. oxygen permeable) via a second port (i.e. fluid communication) in a wall of the bag,
e) removing cell debris and/or free cells together with liquid from said suspension of microcarriers through the filter material and the first port (abstract, paragraphs 0025 and 0027-0033, and claim 1).
Kaisermayer teaches a culture bag configuration in Figure 6 with two ports 24 that are in the fluid communication with the chamber (i.e. an undivided interior compartment) (paragraphs 48-50). Kaisermayer teaches that ports are equipped with tube fittings (paragraphs 0023 and 0045). Kaisermayer teaches that the fluidic connection of the chamber to a first port in a bag wall enables the removal of non-desired cell debris and free cells from the cell culture together with liquid (paragraph 0034). Kaisermayer teaches that cell culture medium, the microcarriers and the cells can be introduced to the bag via tubing and suitable ports in the bag according to methods known in the art (paragraph 0035).
Kaisermeyer teaches that the bag may also comprise ports in the bag walls for the flow of gases into and out of the reactor, for introduction of cell culture medium, cells and microcarriers, and for sample removal and that the fluidic connection of the chamber to a port in a bag wall may be achieved through tubing (paragraph 0050).
Kaisermayer is silent as to the structure of the tubes.
Tolbert teaches a cell culture vessel 10 for maintenance of animal cells. The reactor shell can be made of rigid plastic materials. The reactor 10 accommodates within its interior chamber first porous tube 19 which is open at its proximal end and in fluid communication with external inlet port 21 for supplying nutrient medium to the cells and a second tube 22 which is concentric to and envelopes porous tube 19 also is disposed within the reactor for passage of expended (spent) media and cell product (i.e. acting as a filter) (column 3, line 19-column 4, line 24). Tolbert also teaches that their reaction vessel can comprise microcarriers for retention of animal cells (column 5, lines 14-31).
Tolbert teaches that in the method of the present invention illustrated by the embodiment shown in FIGS. 1 and 2, nutrient medium is supplied through external inlet port 21 into the lumen of porous tube 19. The nutrient medium can be conveniently pumped from a fresh medium reservoir. The fresh medium perfuses through the porous walls of relatively low porosity tube 19 into the semi-rigid matrix which contains the desired animal cells interspersed between microcarriers or other such finely divided materials which constitute the matrix. By such means, the entire nutrient medium makes cell contact prior to exiting the reactor chamber (column 5, lines 32-50).
Tolbert teaches that a tube assembly comprises a first porous tube (19) defining a central lumen of the tube and enveloped by a second porous tube (22); and a pore size of the second porous tube is 10-150 μM (see claim 1; column 2, lines 15-23; column 3, lines 49-66; column 4, lines 3-14, 20-24; column 7, lines 15-36; figure 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the tube structure of Tolbert for the tubes of Kaisermayer to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to choose the tube structure of Tolbert with a reasonable expectation of success because Tolbert teaches that their tube structure facilitates supplying cell culture medium to the chamber and removal of spent media and cell product (such as cell debris) and that these tubes can be used with microcarriers. Kaisermayer specifically identifies that they use their ports for introducing cell culture medium and removing cell debris and/or free cells together with liquid from the chamber. Furthermore, Tolbert teaches that their tubes allow for the entire nutrient medium to make cell contact prior to exiting the reactor chamber. It would be beneficial to use the tubing identified by Tolbert as Kaisermayer specifically identifies the potential risk of the formation of a filter cake on the filter material if there is not enough agitation. By providing the tubing of Tolbert on either side of the filter material (i.e. a first port and tubing above the filter material and a second port and tubing below the filter material), the tubing of Tolbert could be used to have fluid flow on either side of the filter to prevent filter caking from occurring or to break it up if it occurs.
As such, it would have been obvious that one could use the tube structure of Tolbert as the tubes of Kaisermayer as they perform the desired function of delivering cell culture medium to the chamber and removing cell debris and expended media. Furthermore, because Tolbert’s tubes have dual functionality, they can be used either solely for removing spent media and debris or delivering cell culture medium or performing both simultaneously, providing a distinct benefit. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the remote location of the second tube, Kaisermayer teaches that the first port is on one side of the filter material. It would have been obvious that the second port could be in an area that would direct fluid flow from the other side of the filter material to facilitate movement of the cell debris and liquid through the filter material and towards the first tube for removal. This would result in a second tube in a location remote from the first tube.
Regarding the flow of the culture medium from the second port to the first port, Kaisermayer specifically identifies that the first port is used for the removal of cell debris. As such, this would lead to fluid from the second port to the first port.
Regarding claim 15, Kaisermayer teaches that when the purpose of cultivation is to produce cells, the method may include between steps d) and e) a step of releasing the cells from the microcarriers. The cells can be released e.g. by treatment with proteases like trypsin or collagenase, alternatively cells can also be released by treatment with chemicals, especially chelating agents like EDTA. After release the cells can be recovered via the filter material, while the microcarriers are retained in the bag (paragraph 0045).
Regarding claims 22-23, Kaisermayer teaches that microcarriers comprise cellulose or crosslinked dextran hydrogel beads of average particle size 125-280 micron (claim 12).
Regarding claim 25, Kaisermayer, as stated supra, teaches a culture bag configuration in Figure 6 with two ports 24 that are in the fluid communication with the chamber (i.e. an undivided interior compartment) (paragraphs 48-50).
Regarding claim 26, Tolbert teaches that a tube assembly comprises a first porous tube (19) defining a central lumen of the tube and enveloped by a second porous tube (22); and a pore size of the second porous tube is 10-150 μM (see claim 1; column 2, lines 15-23; column 3, lines 49-66; column 4, lines 3-14, 20-24; column 7, lines 15-36; figure 3). In regard to the pore size of the tubes, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Regarding claim 29, as stated supra, Kaisermayer teaches that the bag is agitated (abstract).
Regarding claims 32-33, Tolbert teaches that the pore size of the second porous tube (i.e. the outer filter layer) can be from about 10 μm-150 μm (claim 1).
In regard to the pore size of the filter layer, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Response to Arguments
Applicant's arguments filed September 8, 2025, are acknowledged.
Applicant argues that Tolbert describes two separate embodiments, Figures 1-2 (first) and Figures 3-5 (second). Applicant argues that the first embodiment uses their concentric tubular setup for cell culture wherein the space for the cells is in the interior chamber 18 between the first porous and second porous tube while the second embodiment does non-porous rigid tubes for support. Therefore, the combined teachings of Kaisermayer and Tolbert do not teach the claimed arrangement of the tubes of claim 14 (page 1, paragraph 7-page 5, paragraph 5).
Applicant’s argument has been fully considered, but is not persuasive.
The newly written rejection above focuses on embodiment one of Tolbert (Figures 1-2) which, as stated above clearly identify a tubular structure comprising two porous tubes for cultivating cells attached to microcarriers in a chamber enclosed by rigid plastic. Although Tolbert may use it in a chamber where the reaction volume is between the concentric tubes, this is not thew only possible use of these tubular designs. As stated above, the concentric porous tubes design of Tolbert is used for a similar purpose as Kaisermayer and would have been obvious that this tubular design could be used in a similar method of cultivating cells attached to microcarriers in a plastic cell culture system.
Claims 14 and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2014/0287512 (Kaisermayer) and United States Patent No. 4537860 (Tolbert) as applied to claim 14 above, and further in view of World Intellectual Property Organization Patent Application No. 2016106290 (Clark). This is a new rejection that is substantially similar to a previous rejection. Applicant’s traversal has been addressed above.
Regarding claims 16-17, the teachings of Kaisermayer and Tolbert are as discussed above.
Although Kaisermayer teaches that the oxygen-permeable bags comprising multiple polymer films that can be made of fluoropolymers, it is silent to an inner layer of fluoropolymers that are fluorinated ethylene-propylene (FEP).
However, Clark teaches a gas permeable inner fluoropolymer and outer silicone material used in the construction of cell culture bags (abstract [017, 034]). Clark teaches that the fluoropolymer layer is FEP with a thickness of .0254 mm and the elastomer layer is silicone (also known as silicone rubber) with a thickness of .127 mm to .254 mm (paragraphs 0075-0076).
Clark teaches that silicone films for cell culture bags have high oxygen permeability, good optical clarity, good resistance to puncture, typically do not bind cells, and can be easily fabricated into a wide variety of shapes. Fluoropolymer films have desirable characteristics that make them a popular choice for culture bags. Compared to silicone, fluoropolymer films are more biologically, chemically and immunologically inert, as well as being hydrophobic. Fluoropolymer films like FEP (fluorinated ethylene-propylene) do not trigger immune responses in immune cells and progenitor immune cells. However fluoropolymer films are more expensive and less gas permeable than silicone films. Clark generated the cell culture bags with the combined gas permeable fluoropolymer and silicone material to take advantage of the beneficial properties of fluoropolymer and elastomer films (paragraphs 011-012 and 056).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the inner fluoropolymer layer as FEP, as identified by Clark, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to choose FEP as the inner layer with a reasonable expectation of success because Clark teaches that fluoropolymer films like FEP (fluorinated ethylene-propylene) do not trigger immune responses in immune cells and progenitor immune cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 18-19, as stated supra, Clark teaches that their cell culture bags have an inner layer of FEP and an outer layer of silicone rubber (an elastomer) (paragraphs 0075-0076)
Clark, as stated supra, teaches that silicone films for cell culture bags have high oxygen permeability, good optical clarity, good resistance to puncture, typically do not bind cells, and can be easily fabricated into a wide variety of shapes. Fluoropolymer films have desirable characteristics that make them a popular choice for culture bags. Compared to silicone, fluoropolymer films are more biologically, chemically and immunologically inert, as well as being hydrophobic. However fluoropolymer films are less gas permeable than silicone films. Clark generated the cell culture bags with the combined gas permeable fluoropolymer and silicone material to take advantage of the beneficial properties of fluoropolymer and elastomer films.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the fluoropolymer inner and outer layers of Kaisermayer with the FEP and silicone rubber bag construction of Clark to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Clark teaches that fluoropolymer films are more biologically, chemically and immunologically inert but less gas permeable than silicone films. As such, it would have been obvious to generate a cell culture bag with an inner layer of a fluoropolymer (such as FEP) because they are more biologically, chemically, and immunologically inert than silicone rubbers and an outer layer of silicone rubber because they are more gas permeable than fluoropolymer layers, as done by Clark. This configuration takes advantage of the benefits of both layers while minimizing the downsides of the layers. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 20-21, as stated supra, Clark teaches that the fluoropolymer layer is FEP with a thickness of .0254 mm and the elastomer layer is silicone (also known as silicone rubber) with a thickness of .127 mm to .254 mm (paragraphs 0075-0076).
Regarding the limitation of claim 21 stating the layers comprise at least 95% of their respective polymer, as Clark teaches the layers are made up of FEP and silicone rubber without any other components associated with those layers, the FEP and silicone layers of Clark are considered to have above 95% FEP and silicone rubber, respectively. As such, the FEP and silicone layers of Clark would fulfill the limitations of claim 21. In regard to the thickness of the films, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Claims 14 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2014/0287512 (Kaisermayer) and United States Patent No. 4537860 (Tolbert) as applied to claim 14 above, and further in view of World Intellectual Property Organization Patent Application No. 2016106290 (Clark) and United States Patent No. 8809054 (Borgart). This is a new rejection that is substantially similar to a previous rejection. Applicant’s traversal has been addressed above.
The teachings of Kaisermayer and Tolbert are as discussed above.
Kaisermayer is silent as to the surface area of their cell culture bag and the amount/surface area of the microcarriers.
Clark teaches that they made a cell culture bag with an FEP layer that had an internal surface area of 650 cm2- and a volume of 214 mL (abstract, paragraph 0110, and Example 2).
Borgart teaches a method of expanding adherent cells by allowing adherent cells to attach to microcarriers during the seeding phase. Microcarriers are particles that have a high Surface to Volume ratio, to allow a large grow surface area for the adherent cells in a small volume (column 5, lines 1-17). Borgart teaches that the purpose of the microcarriers is to provide an increased growing surface for the adherent cells. Borgart teaches that seeding volume can be around 200 mL and the microcarriers can provide a growth surface area up to 60,000 cm2 (column 12, line 62-column 13, line 10).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one could use a plurality of microcarriers that had at least 1000% the surface area of the interior compartment to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use a plurality of microcarriers that had at least 1000% the surface area of the interior compartment with a reasonable expectation of success because Borgart teaches that the purpose of the microcarriers is to provide an increased growing surface for the adherent cells. Borgart teaches that the seeding volume for adherent culture can be around 200 mL and the microcarriers can provide a growth surface area up to 60,000 cm2. More microcarriers means more surface area for attachment and increased potential for initial cell attachment during the seeding phase and increased expansion potential. As such, it would have been obvious that one would want to optimize the procedure to produce the most expanded cells by using as many microcarriers as possible. As the FEP bag identified by Clark has a surface area of 650 cm2 and volume of 214 mL, it would have been possible to achieve a microcarrier surface area of up to 60,000 cm2 in the FEP bag of Clark, well above the 1000% increase (6500 cm2) of claim 24. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 14 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2014/0287512 (Kaisermayer) and United States Patent No. 4537860 (Tolbert) as applied to claim 14 above, and further in view of United States Patent No. 6881336 (Johnson) and United States Patent No. 10876090 (Castillo). This is a new rejection made in response to new claim 30.
The teachings of Kaisermayer and Tolbert are as discussed above.
The combined teachings of Kaisermayer and Tolbert do not teach wherein the first inner support structure is a spiral-wound element.
However, Johnson teaches that spiral-wound elements are a common configuration for filtration system and represent a low cost, low polarization, and low pressure drop across the element compared to other configurations (column 1, lines 51-62).
Castillo teaches that spiral-wound tubular chamber units have been used for cell culture allowing the culture media and cells to travel within and about the center of the spiral and can also be used with a spacer membrane to facilitate gas flow (column 1, lines 56-67).
As applicant has not defined a spiral wound filament, the spiral wound element of Johnson is considered to fall within the broadest reasonable interpretation of a spiral wound filament.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the first porous internal support structure of the combined teachings of Kaisermayer and Tolbert with a spiral-wound element to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Johnson teaches that spiral wound filaments are commonly used for filtration and represent a low cost, low polarization, and low pressure drop across the element compared to other configurations. Furthermore, Castillo teaches that spiral-wound tubular chamber units have been used for cell culture allowing the culture media and cells to travel within and about the center of the spiral and can also be used with a spacer membrane to facilitate gas flow. As Kaisermayer and Tolbert discuss using their tubes for filtration of cell debris and spent media and Castillo teaches that spiral-wound tubular chmabers have been previously used as part of a cell culture system for movement of media and cells, it would be obvious that the spiral wound element, a known element used for improved filtration and that has been used as part of cell culture method, could be used in a similar method for filtration of cell debris and spent media. 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 14-23, 25, 27 and 29-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11959056 in view of United States Patent Application No. 2014/0287512 (Kaisermayer) and World Intellectual Property Organization Patent Application No. 2016106290 (Clark).
Regarding claims 14, 16, 25, and 29, ‘056 teaches a method for cultivating cells, comprising providing a cell culture bag comprising one or more polymer films, having edges bonded together to form edges around an undivided interior compartment of the bag; a first port formed in an exterior surface of the bag; a first liquid-permeable tube extending into and in fluid communication with the interior compartment of the bag, the first liquid-permeable tube being operatively coupled to the first port; a second port formed in an exterior surface of the bag; a second liquid-permeable tube extending into and in fluid communication with the interior compartment of the bag, the second liquid-permeable tube being operatively coupled to the second port; and optionally, a third port formed in an exterior surface of the bag, the third port being in fluid communication with the interior compartment of the bag; wherein the first liquid-permeable tube comprises: a first inner support structure defining a central lumen of the first liquid-permeable tube, wherein the first inner support structure comprises a first porous tube having an average pore size in the range of 250 to 5000 μm; and a first outer filter layer surrounding the first inner support structure, wherein the first outer filter layer has an average pore size of less than 50 μm. ‘056 teaches that the liquid permeable tube can comprise a spiral-wound filament or porous tube. ‘956 teahces that the pore size of the outer filter can be 50 microns.
‘056 is silent as to what polymer is used and does not teach using microcarriers and anchorage dependent cells.
However, Kaisermayer teaches a method of cultivating cells in a bag, which comprises the steps of:
a) providing a sterile flexible bag:
The sterile flexible bag can be prepared from two flexible sheets joined along their edges to form a "pillow-style bag." The flexible sheets may comprise thermoplastics such as fluoropolymers as multilayer laminates which may further comprise adhesive layers,
comprising a filter material which is attached to a wall of the culture bag, wherein the filter material delimits a chamber inside the bag and wherein the chamber is fluidically connected to a first port in a wall of the bag (as can be seen in Figure 5, the first port is formed in the exterior surface of the bag),
b) providing agitation means for the bag,
c) introducing cell culture medium, microcarriers and cells to the bag,
d) cultivating cells in the bag with agitation (i.e. flowing media) provided by the agitation means, allowing formation of a suspension of microcarriers with immobilized cells (i.e. attached cells or anchorage dependent cells) and supplying at least one gas (i.e. oxygen permeable) via a second port (i.e. fluid communication) in a wall of the bag,
e) removing cell debris and/or free cells together with liquid from said suspension of microcarriers through the filter material and the first port (abstract, paragraphs 0025 and 0027-0033, and claim 1).
Clark teaches a gas permeable inner fluoropolymer and outer silicone material used in the construction of cell culture bags (abstract [017, 034]). Clark teaches that the fluoropolymer layer is FEP with a thickness of .0254 mm and the elastomer layer is silicone (also known as silicone rubber) with a thickness of .127 mm to .254 mm (paragraphs 0075-0076).
Clark teaches that silicone films for cell culture bags have high oxygen permeability, good optical clarity, good resistance to puncture, typically do not bind cells, and can be easily fabricated into a wide variety of shapes. Fluoropolymer films have desirable characteristics that make them a popular choice for culture bags. Compared to silicone, fluoropolymer films are more biologically, chemically and immunologically inert, as well as being hydrophobic. Fluoropolymer films like FEP (fluorinated ethylene-propylene) do not trigger immune responses in immune cells and progenitor immune cells. However fluoropolymer films are more expensive and less gas permeable than silicone films. Clark generated the cell culture bags with the combined gas permeable fluoropolymer and silicone material to take advantage of the beneficial properties of fluoropolymer and elastomer films (paragraphs 011-012 and 056).
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 cultivating cells in an oxygen permeable bag of ‘056 by using fluoropolymers as the inner layer and using it with microcarriers and anchorage dependent cells, as identified by Kaisermayer and Clark, 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 ‘056 and Kaisermayer both use culture bags for culturing cells with a filter membranes within the bag. Kaisermayer has successfully reduced to practice that adherent cells can be cultured in a fluoropolymer bag with microcarriers with two compartments separated by a filter membrane. As such, it would have been obvious to one of ordinary skill in the art that adherent cells and microcarriers could also be cultivated in the culture bag of ‘056. One of ordinary skill in the art would have a reason to choose FEP as the inner layer with a reasonable expectation of success because Clark teaches that fluoropolymer films like FEP (fluorinated ethylene-propylene) do not trigger immune responses in immune cells and progenitor immune cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 15, Kaisermayer teaches that when the purpose of cultivation is to produce cells, the method may include between steps d) and e) a step of releasing the cells from the microcarriers. The cells can be released e.g. by treatment with proteases like trypsin or collagenase, alternatively cells can also be released by treatment with chemicals, especially chelating agents like EDTA. After release the cells can be recovered via the filter material, while the microcarriers are retained in the bag (paragraph 0045).
Regarding claims 16-17, Clark teaches a gas permeable fluoropolymer and silicone material used in the construction of cell culture bags (abstract). Clark teaches that the fluoropolymer layer is FEP with a thickness of .0254 mm and the elastomer layer is silicone (also known as silicone rubber) with a thickness of .127 mm to .254 mm (paragraphs 0075-0076).
Clark teaches that silicone films for cell culture bags have high oxygen permeability, good optical clarity, good resistance to puncture, typically do not bind cells, and can be easily fabricated into a wide variety of shapes. Fluoropolymer films have desirable characteristics that make them a popular choice for culture bags. Compared to silicone, fluoropolymer films are more biologically, chemically and immunologically inert, as well as being hydrophobic. Fluoropolymer films like FEP (fluorinated ethylene-propylene) do not trigger immune responses in immune cells and progenitor immune cells. However fluoropolymer films are more expensive and less gas permeable than silicone films. Clark generated the cell culture bags with the combined gas permeable fluoropolymer and silicone material to take advantage of the beneficial properties of fluoropolymer and elastomer films (paragraphs 011-012 and 056).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the inner fluoropolymer layer as FEP, as identified by Clark, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to choose FEP with a reasonable expectation of success because Clark teaches that fluoropolymer films like FEP (fluorinated ethylene-propylene) do not trigger immune responses in immune cells and progenitor immune cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 18-19, as stated supra, Clark teaches that their cell culture bags have an inner layer of FEP and an outer layer of silicone rubber (an elastomer) (paragraphs 0075-0076)
Clark, as stated supra, teaches that silicone films for cell culture bags have high oxygen permeability, good optical clarity, good resistance to puncture, typically do not bind cells, and can be easily fabricated into a wide variety of shapes. Fluoropolymer films have desirable characteristics that make them a popular choice for culture bags. Compared to silicone, fluoropolymer films are more biologically, chemically and immunologically inert, as well as being hydrophobic. However fluoropolymer films are less gas permeable than silicone films. Clark generated the cell culture bags with the combined gas permeable fluoropolymer and silicone material to take advantage of the beneficial properties of fluoropolymer and elastomer films.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the fluoropolymer inner and outer layers of ‘056 and Kaisermayer with the FEP and silicone rubber bag construction of Clark to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Clark teaches that fluoropolymer films are more biologically, chemically and immunologically inert but less gas permeable than silicone films. As such, it would have been obvious to generate a cell culture bag with an inner layer of a fluoropolymer (such as FEP) because they are more biologically, chemically, and immunologically inert than silicone rubbers and an outer layer of silicone rubber because they are more gas permeable than fluoropolymer layers, as done by Clark. This configuration takes advantage of the benefits of both layers while minimizing the downsides of the layers. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 20-21, as stated supra, Clark teaches that the fluoropolymer layer is FEP with a thickness of .0254 mm and the elastomer layer is silicone (also known as silicone rubber) with a thickness of .127 mm to .254 mm (paragraphs 0075-0076).
Regarding the limitation of claim 21 stating the layers comprise at least 95% of their respective polymer, as Clark teaches the layers are made up of FEP and silicone rubber without any other components associated with those layers, the FEP and silicone layers of Clark are considered to have above 95% FEP and silicone rubber, respectively. As such, the FEP and silicone layers of Clark would fulfill the limitations of claim 21.
Regarding claims 22-23, Kaisermayer teaches that microcarriers comprise cellulose or crosslinked dextran hydrogel beads of average particle size 125-280 micron (claim 12).
Regarding claim 27, ‘056 does not teach wherein the culture bag contains a porous membrane.
Kaisermayer teaches a configuration (Figure 6) wherein the cell culture bag comprises a filter material (i.e. a porous membrane) attached to the bottom wall of the bag delimiting a chamber (a first portion) and comprising two ports fluidically connected to the chamber. Kaisermayer teaches that liquid and smaller particles such as free cells and cell debris can only pass into the chamber via the pores of the filter material, while the larger microcarrier particles are retained in the bag outside the chamber (a second portion).
As such it would have been obvious to include a porous membrane in the culture bag of ‘056 to hold the cells attached to the microcarrier in a separate compartment and only filter out smaller free cells and cell debris for removal, as successfully done by Kaisermayer.
Regarding claim 29, as stated supra, Kaisermayer teaches that the bag is agitated (abstract).
Response to Arguments
Applicant's arguments filed September 8, 2025, are acknowledged.
Applicants request that the Examiner hold this rejection in abeyance until claims are otherwise allowable.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The rejection cannot be held in abeyance, and it is maintained for the reasons of record until the aforementioned issues are resolved.
Claims 14 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15-17 of U.S. Patent No. 11959056 in view of United States Patent Application No. 2014/0287512 (Kaisermayer) and World Intellectual Property Organization Patent Application No. 2016106290 (Clark) as applied to claim 14 above, and further in view of United States Patent No. 8809054 (Borgart).
The teachings of ‘056, Kaisermayer, and Clark are as discussed above. Clark teaches that they made a cell culture bag with an FEP layer that had an internal surface area of 650 cm2- and a volume of 214 mL (abstract, paragraph 0110, and Example 2).
‘056 and Kaisermayer are silent as to the surface area of their cell culture bag and the amount/surface area of the microcarriers.
Borgart teaches a method of expanding adherent cells by allowing adherent cells to attach to microcarriers during the seeding phase. Microcarriers are particles that have a high Surface to Volume ratio, to allow a large grow surface area for the adherent cells in a small volume (column 5, lines 1-17). Borgart teaches that the purpose of the microcarriers is to provide an increased growing surface for the adherent cells. Borgart teaches that seeding volume can be around 200 mL and the microcarriers can provide a growth surface area up to 60,000 cm2 (column 12, line 62-column 13, line 10).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one could use a plurality of microcarriers that had at least 1000% the surface area of the interior compartment to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use a plurality of microcarriers that had at least 1000% the surface area of the interior compartment with a reasonable expectation of success because Borgart teaches that the purpose of the microcarriers is to provide an increased growing surface for the adherent cells. Borgart teaches that the seeding volume for adherent culture can be around 200 mL and the microcarriers can provide a growth surface area up to 60,000 cm2. More microcarriers means more surface area for attachment and increased potential for initial cell attachment during the seeding phase and increased expansion potential. As such, it would have been obvious that one would want to optimize the procedure to produce the most expanded cells by using as many microcarriers as possible. As the FEP bag identified by Clark has a surface area of 650 cm2 and volume of 214 mL, it would have been possible to achieve a microcarrier surface area of up to 60,000 cm2 in the FEP bag of Clark, well above the 1000% increase (6500 cm2) of claim 24. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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 t