DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 09/08/2025 has been entered.
Information Disclosure Statement
The information disclosure statement(s) (IDS) were submitted on:
09/08/2025
Accordingly, the information disclosure statement(s) are being considered by the examiner.
Claim Objections
The previous claim objection over claim 25 is withdrawn in light of the amendments.
Claims 12 and 14 are objected to because of the following informalities:
Regarding claim 12, the phrase “wherein the membranes are arranged in layers and spaced apart” could be “wherein the membranes are arranged in layers and are spaced apart”.
Regarding claim 14, the phrase “wherein the mold associated with each of the plurality of elements” is confusingly written, as the phrase “the mold” implies a singular mold. However, it may be more correct to say “each mold” instead, referring to a singular mold per each plurality of elements.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The previous claim rejections over claims 16 and 26-27 are withdrawn in light of the amendments.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 22 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 22, the limitation “with spacers between adjacent layers” does not have written description. The closest written description appears in the specification at paragraph [0087], which describes the spacing of layers of membranes. The language of the specification is “spaced apart from each other by gaps” and that the “arrangement of membranes into layers or arrays are preferably determined and/or measured within the potting heads 142”. Nevertheless, the word “spacer” is not used in the specification.
Claim Rejections - 35 USC § 102 | 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 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1, 3, 13, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited).
Regarding claim 1, Housler discloses a cell culture bioreactor (abstract) comprising a plurality of zones (Fig. 1, there are at least two zones: one for liquids, another for gases) wherein each of the zones has membranes (Fig. 1B, “capillaries” and pg. 134 under Materials and Methods) and wherein a flow of a fluid to each of the zones is separately controllable (Fig. 3 and associated caption for perfusion pump and gas monitor), wherein the bioreactor comprises one or more elements (Fig. 1B, a layer of the capillary network), each element comprising a zone of perfusion membranes (Fig. 1 caption, red and blue perfusion capillaries) that intersects with a zone of gas transfer membranes (Fig. 1 caption, yellow gas capillaries), wherein each element has the membranes of the element potted in a potting material (Fig. 1, beige material between the capillaries) in a plurality of potting cavities (Fig. 1, internal space of Fig. 2, outside surface of the bioreactor) of a mold (Fig. 2, outside surface of the bioreactor), wherein each potting cavity is partially formed by a first part of the mold (Fig. 2, outside surface of the bioreactor, one part of it) and partially formed by a second part of the mold (Fig. 2, outside surface of the bioreactor, second part of it), wherein the first part of the mold (Fig. 2, outside surface of the bioreactor, one part of it) and the second part of the mold (Fig. 2, outside surface of the bioreactor, second part of it) are assembled together (Fig. 2, two parts of an outside surface of the bioreactor are together) and adhered to the potting material by the potting material (Fig. 1, beige material between the capillaries takes up the interior of the bioreactor with the capillaries).
Regarding the phrases “potted”, “formed”, “assembled together”, and “adhered to”, the limitations are a product-by-process limitation. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
Regarding the words “potted”, “formed”, and “adhered to” if it is deemed that these words are patentably distinct, Gerlach discloses these limitations:
Gerlach discloses embedding capillaries using potting techniques (pg. 985, first col., last three paragraphs see especially “The housing encloses the capillaries and flow heads (Fig. 1), which distribute the media to and collect media from the capillaries. Additional openings in the housing enable introduction of cells and temperature and pressure control. The capillaries are embedded in polyurethane (Akzo) using capillary dialyzer potting techniques.”).
In the analogous art of hollow fiber membrane bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the embedding membrane capillary array using potting techniques of Gerlach in order to decentralize metabolite and gas exchange with low gradients (Gerlach, pg. 985, first col., penultimate paragraph).
Alternatively, the phrases “assembled together” and “adhered to” are a method of integration of parts. Integration of parts would have been obvious to one of ordinary skill in the art as a matter of obvious engineering choice. MPEP § 2144.04(V)(B). It would have been obvious to one skilled in the art before the effective filing date to modify the two molds’ parts to be put together in order to have a functioning bioreactor with a cell chamber that is not exposed to the environment.
Regarding the limitation “each element has the membranes of the element potted in a potting material in a plurality of potting cavities of a mold”, if it is deemed that modified Housler does not disclose this product-by-process limitation, Feder discloses this limitation – Feder discloses potting fibers using a potting means such as epoxy (and the like settable organic cement materials) to the sidewalls or the endwalls of the reactor (as well as, alternatively, a removable header) to seal the fiber layers with fluid-tight junctions (Feder, col. 5, lines 47-68). This disclosure also reads on adherence of the mold of the reactor and the perfusion membranes to the potting material by the potting material, as claimed in claim 1 above (see same citation, Feder, col. 5, lines 47-68).
In the analogous art of potting hollow fiber membranes in a mammalian cell culture apparatus, it would have been obvious to one skilled in the art before the effective filing date to modify the potting of modified Housler to take place within the reactor as in Feder in order to create fluid-tight connections so that the perfusion membranes do not leak and the perfusion membranes are able to connect in a fluid-tight manner to media inlet ports or feed ports and a spent media outlet port (Feder, col. 5, lines 40-68).
If it is deemed that Housler does not describe “wherein the first part of the mold and the second part of the mold are assembled together”, the assembly of two parts of a mold is a product-by-process limitation. Additionally, integration and separability of parts are both obvious features, according to MPEP §§ 2144.04(V)(B) and 2144.04(V)(C). If the two parts are not deemed to be disclosed by modified Housler, it would have been obvious to one skilled in the art before the effective filing date to modify the two molds’ parts to be put together in order to have a functioning bioreactor with a cell chamber that is not exposed to the environment.
Regarding claim 3, Housler discloses one or more fluid control modules in communication with the plurality of zones (Figs. 2-3 and their captions).
Regarding claim 13, Housler discloses wherein the first part of the mold (Fig. 2, outside surface of the bioreactor) and the second part of the mold (Fig. 2, outside surface of the bioreactor) define upper and lower surfaces of each of the one or more elements (Fig. 1B a layer of the capillary network wherein an element includes capillaries and the material between the capillaries; Fig. 2, outside surface of the bioreactor).
Regarding claim 22, Housler discloses wherein the membranes are arranged in layers with spacers between adjacent layers (Fig. 1 has beige spacers between membranes that are arranged in vertical layers).
Claim 2 is rejected under 35 U.S.C. 102(a)(1) as anticipated by Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1; or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) applied to claim 1, in view of Zhang (US 20060199260) (previously cited) as; or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Zhang (US 20060199260) (previously cited).
Regarding claim 2, Housler discloses comprising a plurality of sensors (Fig. 2 and its caption, pg. 135-136 under “Measurement of metabolic parameters in bioreactors”) associated with the plurality of zones (Fig. 3 and Table 1 for sensor readings).
If Housler is deemed not to include a plurality of sensors associated with the plurality of zones, Zhang discloses sensors (paragraph [0313] “two sensor foils”) placed inside (paragraphs [0300] and [0313]) a zone of a bioreactor (Fig. 42a and 42b, or paragraph [0313]).
In the analogous art of microbioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Housler with the location of sensor foils inside of a transparent bioreactor in order to obtain information on dissolved oxygen levels and pH (Zhang, paragraph [0313]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Klimant (US 6,602,716) (previously cited), Zhang (US 20060199260) (previously cited), and Langenfeld (US 2018/0127705) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Klimant (US 6,602,716) (previously cited), Zhang (US 20060199260) (previously cited), and Langenfeld (US 2018/0127705) (previously cited).
Regarding claim 4, Housler does not disclose a plurality of light activated sensor foils placed inside the bioreactor on transparent windows.
Klimant discloses a plurality of light activated sensor foils (Fig. 6 and col. 7, line 48 to col. 8, line 10).
In the analogous art of optical sensor foils, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the sensor foils of Klimant in order to take readings on different conditions in the bioreactor, including pH, CO2, NH3, and Potassium (Klimant, col. 7, line 48 to col. 8, line 10).
Zhang discloses sensor foils (paragraph [0313]) placed inside (paragraphs [0300] and [0313]) a transparent bioreactor (paragraph [0165]).
In the analogous art of microbioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Housler with the location of sensor foils inside of a transparent bioreactor in order to obtain information on dissolved oxygen levels and pH (Zhang, paragraph [0313]).
Langenfeld discloses a transparent window of a bioreactor (paragraphs [0015]-[0016]).
In the analogous art of bioreactors with a sensor, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Housler with the optical sensor and transparent window of Langenfeld in order to characterize and monitor the tissue and/or cells in the bioreactor (Langenfeld, paragraph [0178]-[0179]).
Regarding the phrases: “sensor foils” and “transparent windows”, mere duplication of parts has no patentable significance unless a new and unexpected result is produced. MPEP § 2144.04(VI)(B). It would have been obvious to one skilled in the art before the effective filing date to modify the sensor foils to be duplicated in order to obtain data from different types of sensor foils (e.g. oxygen, carbon dioxide, pH) in the bioreactor.
Regarding claim 5, Housler does not disclose a moving data collector, the moving data collector having a detector unit adapted to excite the sensor foils with light and record an image of the excited sensor foils.
Modified Housler teaches the sensor foils (see rejection to parent claim 4, modified Housler in view of Zhang).
Langenfeld discloses a moving data collector (paragraph [0178] and Fig. 11C), the moving data collector having a detector unit (paragraph [0178] and Fig. 11C) adapted to … [emit] light and record an image (paragraph [0178] and Fig. 11C, “Sensor/source head 4021 can be used as a source and sensor for multi-photon microscopy and for Raman spectroscopy.”).
In the analogous art of bioreactors with a sensor, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Housler with the optical sensor and transparent window of Langenfeld in order to characterize and monitor the tissue and/or cells in the bioreactor (Langenfeld, paragraph [0178]-[0179]).
Regarding the phrases “adapted to excite the sensor foils with light and record an image of the excited sensor foils”, it would be considered an intended use of the moving data collector of modified Housler to image the excited sensor foils. The manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Housler would be fully capable of operating in this manner given the sensor foils of moving data collector of modified Housler.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Baumfalk (US 2012/0132813) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Baumfalk (US 2012/0132813) (previously cited).
Regarding claim 6, Housler does not disclose having an aperture to hold an optical sensor body in a hole through a wall of the bioreactor.
Baumfalk discloses having an aperture to hold an optical sensor body in a hole through a wall of a bioreactor (Figs. 1-2 and paragraph [0038]).
In the analogous art of mounted optical sensors in bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the aperture holding an optical sensor body in order to mount an optical sensor in the bioreactor to take readings of various parameters such as dissolved oxygen or pH (Baumfalk, paragraph [0009]).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Prabhudharwadkar (US 20190345433) (previously cited) and De Bartolo (“Human hepatocyte functions in a crossed hollow fiber membrane bioreactor”) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Prabhudharwadkar (US 20190345433) (previously cited) and De Bartolo (“Human hepatocyte functions in a crossed hollow fiber membrane bioreactor”) (previously cited).
Regarding claim 9, Housler does not disclose having multiple mixers spaced along a height of the bioreactor.
Prabhudharwadkar discloses having multiple mixers spaced along a height of a bioreactor (Fig. 1 and abstract).
In the analogous art of impellers for bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler to have a multiple-level impeller in order to better reduce the size of air bubbles (with high surface area per unit volume) used for dissolved oxygen in a bioreactor to increase oxygen transfer rate to the media (Prabhudharwadkar, paragraph [0003]). A multiple mixer impeller can also be used to stir media in the bioreactor at various heights in the bioreactor for a well-mixed bioreactor.
De Bartolo discloses further reason for this configuration of a bioreactor: the cells can be held in the extra-capillary space (abstract) and the bioreactor is to be considered at least in part well-mixed (pg. 2537, paragraph under equation 9b).
In the analogous art of growing cells in the extra-capillary space of a membrane bioreactor, it would have been obvious to one skilled in the art before the effective filing date to modify Housler to have an extra-capillary space for growing cells in order to have adhesive cells adhere to the capillaries while simultaneously promoting a high mass exchange of cell culture medium (De Bartolo, abstract).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1; or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited), as applied to claim 1, further in view of Funatsu (US 6284451) (newly cited).
Regarding claim 12, Housler discloses wherein the membranes are arranged in layers and spaced apart (Fig. 1B).
Housler does not disclose the limitation “spaced apart by at least 0.2 mm in the layers”.
However, the limitation is obvious as a matter of routine optimization, because the membranes being spaced apart by at least 0.2 mm in the layers is a result-effective variable. The motivation for optimizing this result-effective variable is to permit quick diffusion of gases across the gas transfer membranes into the perfusion membranes, as there is a small distance for the gas to travel in diffusion. MPEP § 2144.05(II).
Alternatively, Funatsu discloses wherein the membranes are arranged in layers (Figs. 1-3) and spaced apart by at least 0.2 mm (col. 5, lines 24-38; alternatively, col. 6, lines 30-37) in the layers (Annotated Figs. 1-3, below).
In the analogous art of cell culture modules with hollow fibers, it would have been obvious to one skilled in the art before the effective filing date to modify the spacing of modified Housler’s perfusion membranes with the spacing of Funatsu’s hollow fibers of 1000 μm or less in order to supply oxygen and nutrients to the cells and to remove waste (Funatsu, col. 5, lines 24-38).
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Funatsu, Annotated Figs. 1-3
Claims 7-8 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1; or, alternatively, under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Gerlach-530 (US 20050003530) (previously cited) and Edwards (US 20110124078) (newly cited); or, alternatively, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Gerlach-530 (US 20050003530) (previously cited) and Edwards (US 20110124078) (newly cited).
Regarding claim 7, Housler discloses a plurality of elements (Fig. 1B a layer of the capillary network) in a stack (Fig. 1B a layer of the capillary network, inset has multiple layers in a stack), each of the plurality of elements having associated membranes (Fig. 1B a layer of the capillary network).
Regarding the phrase “an associated mold”, Housler discloses a mold for the entire bioreactor rather than for each of the plurality of elements.
Housler does not teach the limitation “an associated mold”.
However, having a mold for each of the plurality of elements would be equivalent to having multiples of Housler’s bioreactors, each with their own mold. Therefore, this limitation is rejected under modified Housler, under duplication of parts. Mere duplication of parts has no patentable significance unless a new and unexpected result is produced. MPEP § 2144.04(VI)(B). It would have been obvious to one skilled in the art before the effective filing date to modify one mold associated with each of the one or more elements of Housler and another duplicate mold associated with each of the one or more elements in order to manufacture the entire housing of a larger and more productive bioreactor.
Furthermore, Gerlach-530 discloses multiple elements in a stack, each of the plurality of elements having an associated mold and associated membranes (Figs. 4 and 6-7; paragraphs [0045] and [0050]-[0053]).
In the analogous art of hollow fiber membrane bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the joining of elements from different molds as in Gerlach-530 in order to artificially produce signal transmission similar to signal transmission present in the human body among different organs.
Additionally, Edwards discloses a plurality of elements in a stack, each of the plurality of elements having an associated mold and associated membranes (paragraphs [0053] and [0064]; Annotated Fig. 2, see below).
In the analogous art of scalable cell culture bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify modified Housler with the stackable modular bioreactor of Edwards in order to effectively increasing the membrane surface area and reactor volume linearly (Edwards, paragraph [0064]).
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Edwards, Annotated Fig. 2
Regarding claim 8, Housler discloses each of the plurality of the elements having associated ports (Figs. 2-3) wherein the ports of each element separately connect (Figs. 1 and 3, the hollow fiber membranes of Fig. 1 separately connect to the bioreactor’s input and output manifolds for the perfusion loop of Fig. 3) each of the elements to one or more gaseous and/or liquid media (Fig. 3).
Regarding claim 14, Housler discloses wherein the mold (Figs. 1-3, outside surface of the bioreactor) associated with each of the plurality of elements (Fig. 1B a layer of the capillary network) is joined to another device (Figs. 2 and 3, joined to perfusion device, noted in dashed-line box in Fig. 3).
Housler does not disclose wherein the mold associated with each of the one or more elements is joined to another mold associated with another element, a base, a top plate, a harvest layer, or a mixing layer.
Arguably, the limitation “is joined to” is a product-by-process limitation (how the bioreactor is assembled or made). “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
Regarding the limitation “another mold”, mere duplication of parts has no patentable significance unless a new and unexpected result is produced. MPEP § 2144.04(VI)(B). Additionally, regarding the limitation “the mold … is joined to another mold”, integration of parts would have been obvious to one of ordinary skill in the art as a matter of obvious engineering choice. MPEP § 2144.04(V)(B). It would have been obvious to one skilled in the art before the effective filing date to modify one mold associated with each of the one or more elements of Housler to be joined to another duplicate mold associated with each of the one or more elements in order to manufacture the entire housing of a larger and more productive bioreactor.
Regarding the limitation “associated with another one of the plurality of elements, a base, a top plate, a harvest layer, or a mixing layer”, these features are claimed in the alternative. Because a duplication of the first mold would be associated with a duplication of another element, the remaining features claimed in the alternative need not be rejected at this time.
If it is deemed that Housler does not disclose wherein the mold associated with each of the plurality of elements is joined to another mold associated with another one of the plurality of elements, a base, a top plate, a harvest layer or a mixing layer, Gerlach-530 discloses this limitation.
Gerlach-530 discloses wherein the mold associated with each of the plurality of elements (each of the molds of the corresponding element are, respectively, the surfaces of the bioreactor 1b with the elements being zones of membranes of bioreactor 1b) is joined to another mold associated with another one of the plurality of elements (each of the molds of the corresponding element are, respectively, the surfaces of the bioreactor 1a with the elements being zones of membranes of bioreactor 1a).
In the analogous art of hollow fiber membrane bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify Housler with the joining of elements from different molds as in Gerlach-530 in order to artificially produce signal transmission similar to neuronal strands; to help model the mathematical signaling of neurons for models of artificial intelligence; and to replicate whole sections of the nervous system (Gerlach-530, paragraph [0045]).
Additionally, Edwards wherein the mold associated with each of the one or more elements is joined to another mold associated with another element, a base, a top plate, a harvest layer, or a mixing layer (paragraphs [0053] and [0064]; Annotated Fig. 2).
In the analogous art of scalable cell culture bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify modified Housler with the stackable modular bioreactor of Edwards in order to effectively increasing the membrane surface area and reactor volume linearly (Edwards, paragraph [0064]).
Regarding the limitation “a base, a top plate, a harvest layer, or a mixing layer”, these features are claimed in the alternative. Because a duplication of the first mold would be associated with a duplication of another element, the remaining features claimed in the alternative need not be rejected at this time.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Toner (US 6562616) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Toner (US 6562616) (previously cited).
Regarding claim 15, Housler discloses wherein the mold has ribs (Fig. 2, spider-web-like ribs on the bioreactors); and a membrane assembly (Fig. 1B “capillaries” and pg. 134 under Materials and Methods).
Housler does not disclose wherein the mold has ribs adapted to locate a membrane assembly inside the mold.
Toner discloses wherein the mold has ribs (col. 8, lines 53-65; Fig. 8A) adapted to locate plates (col. 8, lines 53-65) inside the mold (col. 8, lines 53-65).
In the analogous art of ribs in cell culture systems, it would have been obvious to one skilled in the art before the effective filing date to modify the mold of Housler with the mold and ribs of Toner in order to maintain a minimal dead volume within the mold of the bioreactor while allowing a cell growth spaces to be placed in the bioreactor while having manufactured the bioreactor with injection/molding techniques (Toner, col. 8, lines 53-65).
Additionally, the limitation “adapted to locate a membrane assembly inside the mold” is a product-by-process limitation. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
Claims 17 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Wilkerson (US 2012/0149091) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1, further in view of Wilkerson (US 2012/0149091) (previously cited).
Regarding claim 17, Housler discloses the mold (Fig. 2, outside surface of the bioreactor).
Housler does not disclose comprising panels separating the potting cavities of the mold and a sensor attached to at least one of the panels.
Wilkerson discloses comprising panels separating cavities (paragraphs [0122] and [0139] “stackable algae panels” and Fig. 7) and a sensor attached to at least one of the panels (paragraph [0104]).
In the analogous art of photobioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the interior stackable panels of Wilkerson in order to individually and separately control each potting cavity’s environmental conditions.
Regarding the word “potting”, the limitation is a product-by-process limitation. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
Regarding claim 24, Housler discloses the potting cavities and the mold (see rejection to claim 1, above); and some of the potting material (Fig. 1, inset, beige material between the different types of membranes) extends between the potting cavities (Fig. 1, large picture is zoomed in with the inset, but the zoomed-in portion is between at least two opposing cylindrical ends of the bioreactor and thus between at least two potting cavities).
Housler does not disclose the potting cavities are separated by panels of the mold and some of the potting material extends between the potting cavities across the panels.
Wilkerson discloses panels separating cavities (paragraphs [0122] and [0139] “stackable algae panels” and Fig. 7).
In the analogous art of photobioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the interior stackable panels of Wilkerson in order to individually and separately control each potting cavity’s environmental conditions.
Modified Housler does not disclose some of the potting material extends between the potting cavities across the panels. However, this is a design choice and would not have modified the function of the device. Regarding this limitation, rearrangement of parts would have been obvious to one of ordinary skill in the art as an obvious matter of design choice and would not have modified the operation of the device. MPEP § 2144.04(VI)(C). It would have been obvious to one skilled in the art before the effective filing date to modify the potting material to extend across the panels in order to hold the panels in place within the potting cavities.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) as applied to claim 1, in view of Feder (US 4087327) (previously cited); or, in the alternative, under 35 U.S.C. 103 as obvious over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited) and Feder (US 4087327) (previously cited) as applied to claim 1.
Regarding claim 25, Housler discloses the first part of the mold and the second part of the mold are together (see rejection to claim 1).
Housler does not disclose “are assembled together by an adhesive”.
This limitation is a product-by-process limitation (assembled together). “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
However, the adhesive used in the product-by-process limitation lends structure to the invention. To this end, Feder discloses an adhesive that bonds to molded plastic and/or metal parts in a reactor housing (col. 2, lines 63-68 and col. 6, lines 7-19).
In the analogous art of mammalian cell culture processes, it would have been obvious to one skilled in the art before the effective filing date to modify the mold of Housler to be assembled together with an adhesive as in Feder in order to make a fluid-tight reactor that uses potting means such as epoxy (Feder, col. 5, lines 54-68).
Alternatively, regarding the limitation, integration of parts would have been obvious to one of ordinary skill in the art as a matter of obvious engineering choice. MPEP § 2144.04(V)(B). It would have been obvious to one skilled in the art before the effective filing date to modify the mold of Housler with an adhesive in order to combine the parts together in a fluid-tight manner (Feder, col. 5, lines 54-68).
Claims 16 and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Housler (“Compartmental Hollow Fiber Capillary Membrane–Based Bioreactor Technology for In Vitro Studies on Red Blood Cell Lineage Direction of Hematopoietic Stem Cells”) (previously cited) in view of Gerlach (“Bioreactor for a Larger Scale Hepatocyte in vitro Perfusion”) (previously cited), Feder (US 4087327) (previously cited), Gerlach-530 (US 20050003530) (previously cited), and Edwards (US 20110124078) (newly cited).
Regarding claim 16, Housler discloses a cell culture bioreactor (abstract) comprising
a plurality of zones (Fig. 1, there are at least two zones: one for liquids, another for gases), the plurality of zones including a zone of perfusion membranes (Fig. 1 caption, red and blue perfusion capillaries) and a zone of gas transfer membranes (Fig. 1 caption, yellow gas capillaries), wherein a flow of a fluid to each of the zones is separately controllable (Fig. 3 and associated caption for perfusion pump and gas monitor), and
wherein the perfusion membranes (Fig. 1 caption, red and blue perfusion capillaries) and the gas transfer membranes (Fig. 1 caption, yellow gas capillaries) are potted in a potting material in a plurality of potting cavities of the mold (Fig. 1, beige material between the capillaries), the mold having a surface of the mold comprising an aperture (Figs. 2-3 ports on the sides of the bioreactor); whereby [there is] an extra-capillary space (ECS) within the mold (pg. 134, second col., under “Size-scaling of the bioreactor technology”, specifically “transport of culture medium in a decentralized pattern in the cell compartment”).
If it is deemed Housler does not disclose an extra-capillary space within the mold, Gerlach discloses an extra-capillary space within the mold (pg. 985, first col., under “Materials and Methods”, see especially: “The hepatocytes are seeded on the outer surface of, and between, the capillaries”; “decentralized perfusion of the cells between these capillaries”; and “The housing encloses the capillaries and flow heads (Fig. 1), which distribute the media to and collect media from the capillaries. Additional openings in the housing enable introduction of cells and temperature and pressure control. The capillaries are embedded in polyurethane (Akzo), using capillary dialyzer potting techniques.”).
In the analogous art of hollow fiber membrane bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of Housler with the embedding membrane capillary array using potting techniques of Gerlach in order to decentralize metabolite and gas exchange with low gradients (Gerlach, pg. 985, first col., penultimate paragraph).
Additionally, regarding the limitation “wherein the perfusion membranes and the gas transfer membranes are potted in a potting material in a plurality of potting cavities of the molds”, if it is deemed that modified Housler does not disclose this product-by-process limitation, Feder discloses this limitation – Feder discloses potting fibers using a potting means such as epoxy (and the like settable organic cement materials) to the sidewalls or the endwalls of the reactor (as well as, alternatively, a removable header) to seal the fiber layers with fluid-tight junctions (Feder, col. 5, lines 47-68). This disclosure also reads on adherence of the mold of the reactor and the perfusion membranes to the potting material by the potting material, as claimed in claim 1 above (see same citation, Feder, col. 5, lines 47-68).
In the analogous art of potting hollow fiber membranes in a mammalian cell culture apparatus, it would have been obvious to one skilled in the art before the effective filing date to modify the potting of modified Housler to take place within the reactor as in Feder in order to create fluid-tight connections so that the perfusion membranes do not leak and the perfusion membranes are able to connect in a fluid-tight manner to media inlet ports or feed ports and a spent media outlet port (Feder, col. 5, lines 40-68).
Housler does not disclose:
a plurality of molds stacked together;
wherein a first surface comprising a first aperture of a first one of the molds is inserted into and connected to a second surface of a second aperture of the second one of the molds;
whereby an extra-capillary space (ECS) within the first one of the molds is fluidly connected to an ECS within the second one of the molds.
Regarding feature 1, a plurality of molds would be obvious under duplication of parts. Mere duplication of parts has no patentable significance unless a new and unexpected result is produced. MPEP § 2144.04(VI)(B). It would have been obvious to one skilled in the art before the effective filing