DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This application has been transferred to primary examiner Quang Nguyen, Ph.D. in AU 1631.
Claims 22-34, 36, 38-39, 41, 43-45, 58-62 are pending in the present application.
Applicant’s election without traverse of Group I, drawn to a method for producing of cultured tissue comprising the steps recited in independent claim 22, in the reply filed on 01/06/2026 is acknowledged.
Accordingly, claims 58-62 were withdrawn from further consideration because they are directed to non-elected inventions.
Therefore, claims 22-34, 36, 38-39, 41 and 43-45 are examined on the merits herein.
Claim Rejections - 35 USC § 112 (New Matter)
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.
Claims 32-33 are 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.
Claims 32-33 recite the limitations “10 micrograms(mg)/mL insulin” and “10 mg/mL insulin”, respectively. The claims encompass a method for producing of cultured tissue comprising the step of feeding a fiber scaffold into a chamber containing culture medium, wherein the culture medium includes 10 mg/mL insulin. The as-filed specification does not have a written support for the above limitations.
As an initial matter, claims 32-33 have been introduced in the Preliminary Amendment filed on 08/09/2023, so the claims themselves are not part of the original disclosure. 37 CFR § 1.115(a)(2). “New or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. . . . While there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. . . . The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed.” MPEP § 2163, part (I)(B); see also MPEP § 2163.02. In this case, the original specification does not convey the particular invention recited in claims 32-33 with reasonable clarity to skilled artisans. “The trouble is that there is no such disclosure, easy though it is to imagine it.” MPEP § 2163.05, part (II) (quoting In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967)).
In the Preliminary Amendment filed on 08/09/2023 (at page 5, first paragraph), Applicant simply stated that no new matter is added by the amendment without citing specific page number(s) and/or line number(s) that are alleged written support for the limitations “10 micrograms(mg)/mL insulin” and “10 mg/mL insulin” recited in claims 32-33, respectively. It is noted that original claims 32-33 clearly recite the limitations “10 micrograms(μg)/mL insulin” and “10 μg/mL insulin”, respectively. Additionally, the specification teaches clearly the use of 10 μg/mL insulin in a suitable proliferation-differentiation medium (paragraphs [0041] and [0053]). Accordingly, the as-filed specification does not have a written support for the limitations now recited in claims 32-33.
The fact that the person of ordinary skill in the art could have carried out the claimed invention without undue experimentation based on applicants’ disclosure is inadequate to meet this requirement. “The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112.” MPEP § 2163, part (I)(A).
Therefore, given the lack of sufficient guidance provided by the originally filed specification, it would appear that Applicants did not contemplate or have possession of invention as now claimed at the time the application was filed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 32 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 recites the limitation “10 micrograms(mg)/mL insulin”. It is unclear whether the limitation requires 10 micrograms/mL insulin or 10 mg/mL insulin. The unit for microgram is μg and not mg. Clarification is requested because the metes and bounds of the claim are not clearly determined. It is also noted that claim 33 recites specifically the limitation “10 mg/mL insulin”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 22-31 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Koob (US 2013/0105348; IDS) in view of Onoe et al (Nature Materials 12:584-590, 2013, IDS; with attached Supplementary Information) and Larcher et al (WO 2011/130865).
The instant claims encompass a method for producing a cultured tissue, comprising: (i) feeding a fiber scaffold into a chamber containing culture medium; (ii) seeding the chamber with precursor cells; (iii) allowing the precursor cells to proliferate and differentiate on a surface of the fiber scaffold to provide a cell-laden fiber composed of cells adhered to the fiber scaffold; (iv) twisting a plurality of cell-laden fibers to provide a cell-laden yarn; and (v) weaving or knitting the cell-laden yarn into a three dimensional (3D) structure to provide the cultured tissue.
Koob already disclosed at least a method of producing an implantable collagen fibers in a sterile environment, the method comprises: (a) placing at least one elongate collagen fiber in a desired orientation in a tissue culture vessel; (b) seeding the at least one elongate collagen fiber with a plurality of cells while in the vessels; and (c) automatically applying a strain and/or stress to the at least one elongate collagen fiber in the vessel to cause at least one of the following cellular actions: (i) induce the cells to differentiate into tendon or ligament fibroblasts or tendon or ligament phenotype cells; (ii) form an extracellular matrix of some or at least a major portion of collagen; or (iii) both induce the cells to differentiate into tendon or ligament fibroblasts or tendon or ligament phenotype cells and form an extracellular matrix, wherein the extracellular matrix comprises collagen in amount greater than other proteins; wherein the tissue culture vessel can include a flexible pouch that holds the at least one collagen fiber in the desired orientation during the applying step, the seeding step can be carried out by introducing a fluid comprising the plurality of cells into the pouch via a fluid port of the flexible pouch, the seeding step can be carried out by immersing or submerging the at least one elongated collagen fiber into a fluid contained in the flexible pouch, and wherein exemplary cells of the seeding step include embryonic stem cells, determined stem cells, committed progenitors, multipotent stem cells such as mesenchymal stem cells, adult cells of any suitable type such as smooth muscle cells, cardiac muscle cells, epithelial cells, endothelial cells, fibroblasts, myoblasts and any combination thereof (see at least Abstract; Summary of embodiments of the Invention; particularly paragraphs [0015]-[0020], [0090], [0106], [0111]-[0112], [0125], [0161]-[0166]; and Figs. 3D, 11-13). Koop stated “The applying step can be carried out to apply a static initial offset strain to the at least one elongate collagen fiber after the seeding step, then after a sufficient number of cells attach to the at least one fiber and cell proliferation on the at least one collagen fiber to a desired level, the applying step applies a cyclical strain and/or stress” (paragraph [0025] and Fig. 4); “The method can include, prior to the placing step, winding, twisting, braiding or weaving a plurality of the elongate collagen fibers into a collagen fiber construct at a defined tension tf” (paragraph [0027] and Fig. 3D); and “The plurality of elongate collagen fibers can be wound, braided, twisted and/or woven together” (paragraph [0039]). Koop also defined the term “woven” means that a woven construct includes one or more warp and one or more weft yarns, typically between about 10-100 warp and between about 1-10 weft yarns (paragraph [0100]). Koop also taught a tissue formed on a collagen construct (2D or 3D mass of living tissue, or tissue engineered construct) can comprise the same type of cells or different types of cells, and exemplary tissue engineered constructs include but not limited to, a tendon, a ligament, a muscle, an organ, or any combination thereof (paragraph [0151]); and a cell can attach to a collagen construct and/or fibre via a cell adhesion molecule such as, but not limited to, selectins, integrins, and/or cadherins (last sentence of paragraph [0091]). Fig. 16 is a schematic illustration of a system that can provide flow-through fluid while seeding and/or culturing multiple discrete collagen fibers or collagen fiber constructs in sealable packages and at least one tensioner T with an automated stroke cycle in combination with holding members for the sealable packages (paragraph [0172] and Fig. 16).
Koop did not teach specifically at least a method for producing a cultured tissue comprising the steps of twisting a plurality of cell-laden fibers to provide a cell-laden yarn, and weaving or knitting the cell-laden yarn into a three-dimension (3D) structure.
Before the effective filing date of the present application (08/12/2020), Onoe et al already successfully fabricated metre-long core-shell hydrogel microfibres encapsulating ECM proteins (e.g., pepsin-solubilized type-I collagen (PCol), acid-solubilized type-I collagen (Acol) and fibrin) and differentiated cells (e.g., fibroblasts, myocytes, endothelial cells, nerve cells and epithelial cells) or somatic stem cells (e.g., primary mouse neural stem cells); and that the microfibres reconstitute intrinsic morphologies and functions of living tissues (Abstract; sections titled “Cell fibre formation” and “Characterization of fibre morphologies and functions”; particularly Figures 1-2; and Table 1). Moreover, Onoe et al taught to apply these functional cell fibres as building blocks for higher order cellular assembly of various fibre-based 3D macroscopic cellular constructs, including braids (Supplementary Fig. S16) and fabric (Fig. 4b-d, Supplementary Figs S17-S20), or as templates for the reconstruction of fibre-shaped functional tissues that mimic muscle fibres, blood vessels or nerve networks in vivo (Section titled “Higher-order assembly using cell fibres”). Supplementary Fig. S16 shows three-stranded braid/twisting by using NIH/3T3-Acol fibres; Supplementary Fig. S19 shows two types of folded 3D woven fabric while Supplementary Fig. S20 shows the fabrication of double-striped and doubled-layered helical tube structures by reeling two different cell fibres on glass rods. Fig. 4 b is a schematic of a microfluidic weaving machine working in culture medium (see also Supplementary S17-S18). Onoe et al also demonstrated fibres encapsulating primary pancreatic islet cells and transplanted through a microcatheter into the subrenal capsular space of diabetic mice normalized blood glucose concentrations for about two weeks (Section titled “Cell-fibre transplantation for diabetes mellitus”, and Fig. 5).
Additionally, Larcher et al also disclosed an automated cell culture system comprising at least one closed cell culture module with at least one bioreactor, monitoring tool modules (e.g., imaging and sensor devices), manipulator tool modules (e.g., shakers, peristatic pumps, actuators for opening or closing valves, and moving mechanisms), and a robotic pipette device (Abstract; Summary of the Invention; particularly page 5, line 20 continues to line 22 at page 6; and last paragraph of page 15).
Accordingly, it would have been obvious for an ordinary skill in the art to modify the teachings Koop by also subjecting precursor cell seeded collagen fibers to braiding or twisting to provide a cell-laden yarn in a second bioreactor, and weaving or knitting the cell-laden fibers into a 3D structure in a third bioreactor to form a cultured tissue, including automating and/or robotically operating the method, in light of the teachings of Onoe et al and Larcher et al as presented above.
An ordinary skill in the art would have been motivated to carry out the above modifications because Onoe et al already successfully fabricated functional cell fibres as building blocks for higher order cellular assembly of various fibre-based 3D macroscopic cellular constructs, including braids and fabric (e.g., folded 3D woven fabric, double-striped and doubled-layered helical tube structures by reeling two different cell fibres on glass rods). Additionally, Larcher et al already disclosed an automated cell culture system comprising at least one closed cell culture module with at least one bioreactor, monitoring tool modules manipulator tool modules and a robotic pipette device. Moreover, Koop also taught to seed a plurality of cells on a construct comprising a plurality of elongate collagen fibers that are wound, braided, twisted and/or woven together for the fabrication of an implantable collagen construct.
An ordinary skill in the art would have a reasonable expectation of success in light of the teachings of Koob, Onoe et al and Larcher et al as set forth above, coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Koob, Onoe et al and Larcher et al is indistinguishable and encompassed by a method of producing a tissue culture of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 34, 36, 38-39, 41 and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Koob (US 2013/0105348; IDS) in view of Onoe et al (Nature Materials 12:584-590, 2013, IDS; with attached Supplementary Information) and Larcher et al (WO 2011/130865) as applied to claims 22-31 and 45 above, and further in view of Ben-Arye et al (WO 2019/016795), Elfenbein et al (WO 2018/227016; IDS) and Christ et al (WO 2013/049563).
The combined teachings of Koob, Onoe et al and Larcher et al were presented above. However, none of the cited references teach specifically at least that the cultured tissue is cultured meat for consumption (claim 36); the cultured tissue is composed of muscle cell-laden fibers, fat cell-laden fibers, or a combination thereof (claims 39 and 41); the fiber scaffold is edible (claim 43); the fiber scaffold has a tensile strength that ranges from 3 kPa to 40 kPa (claim 44); the cells include tetracycline-responsive promoters for expression of myogenic or adipogenic genes, and wherein the culture medium includes tetracycline (claim 34); or the cells are engineered to produce vital nutrients (claim 38).
Before the effective filing dated of the present application (08/12/2020), Ben-Arye et al already taught at least a method for producing an edible composition, comprising incubating a three-dimensional porous scaffold and a plurality of cell types comprising myoblasts or progenitor cells thereof (e.g., satellite cells), at least one type of extracellular (ECM)-secreting cell and endothelial cells or progenitor cells thereof (e.g., fibroblast progenitors, adipocyte progenitors), and inducing myoblasts differentiation into myotubes; wherein the plurality of cells are derived from a livestock mammal that includes cattle, boar, goat, hare and others (Abstract; Summary of the Invention; particularly paragraphs [061]-[062], [065], [073], [076]; and Examples). Ben-Arye et al also disclosed that the three-dimensional porous scaffold is derived from animal proteins such as casein, collagen (e.g., FDA-approved collagen-based scaffold or Gelfoam) and egg white; vegetable proteins such as a soy protein, a wheat protein and a wheat protein; or a mushroom protein (paragraphs [0101]-[0102] and Example 15). Ben-Arye et al also disclosed an exemplary bovine satellite cell (BSC) proliferation media comprising DMEM/HEPES 43.5%, 43.5% F-10 Nut Mix, 10% FBS, 1% NEAA, 1% GlutaMAX and 1% Penicillin-Streptomycin-Amphotericin B solution, supplemented with 50 μM ZnCl2, 62 ng/ml EGF, 100 ng/ml IGF-1, 10 ng/ml LIF and 10 ng/ml bFGF (paragraph [0120]). Ben-Arye et al also noted that bFGF inhibits myotube formation, and spontaneous myotubes appear in samples that did not contain bFGF (Example 10).
Additionally, Elfenbein et al also disclosed at least method of producing cultured fish meat for human consumption, comprising: a) obtaining a population of self-renewing cells derived from fish (e.g., a population of fish pre-adipocytes and a population of fish satellite cells); b) culturing the population of cell-renewing cells in culture media comprising micro-scaffolds; c) inducing differentiation in the population of cells to form at least one of myocytes and adipocytes; and d) processing the population of cells into fish meat for human consumption (Abstract; Summary of the Invention; particularly paragraphs [004], [013], [086], [092]-[095], [0152]; and Figs. 1-2). Elfenbein et al also taught that in certain instances, the population of self-renewing cells comprises at least one cell that has been modified to undergo inducible differentiation, wherein the at least one cell has been modified to incorporate: a) a first genetic construct comprising an open reading frame (ORF) of at least one pluripotency gene; and b) a second genetic construct comprising an open reading frame (ORF) of a regulatory factor configured to inactivate the at least one pluripotency gene (e.g., a Cre recombinase), wherein the second genetic construct further comprises an inducible promoter (e.g., a tetracycline responsive element or TRE) controlling the expression of the ORF of the regulatory factor, and the ORF of the at least one differentiation gene (e.g., at least one myogenic factor selected from Myogenin (MyoG), Myogenic Differentiation 1 (MyoD), Myogenic Factor 6 (MRF4), and Myogenic Factor 5 (MYF5); or at least one adipogenic factor selected from Fatty Acid Binding Protein 4 (FABP4), Insulin-Responsive Glucose Transporter Type 4 (GLUT4), ADIPOQ, AGPAT2, Perilipin 1 (PLIN1), Leptin and Lipoprotein Lipase (LPL)) (paragraphs [013] and [092]). Elfenbein et al stated “The modified cells can be used to control proliferation, differentiation, cell phenotype (e.g., steatosis/lipid accumulation), or other cellular properties. Exemplary non-limiting examples of such inducible systems are the Tet-on/off systems which utilize tetracycline/doxycycline as the inducing agent” (paragraphs [094]-[095]); “[f]ish pre-adipocytes and satellite cells are isolated and cultured to form cell lines suitable for expansion and differentiation into adipocytes and myocytes, respectively. The differentiated adipocytes and myocytes are usually then cocultured together at a certain ratio to produce a desired final composition of adipocytes and myocytes in the resulting food product” (paragraph [086]); and “Usually, myocytes and adipocytes are cultured separately, and subsequently mixed. Sometimes, the myocytes and adipocytes are homogenously mixed in equal proportions. In other cases, the myocytes and adipocytes are heterogeneously mixed in unequal proportions. For co-culturing or processing, the myocytes and adipocytes are combined at a ratio of at least 1:1, 2:1, 3:1, 4:1, 5:1, 6:1…..90:1, or at least 100:1, respectively” (paragraph [0152]).
Moreover, Christ et al already disclosed a skeletal muscle cell scaffold comprising a polymeric matrix (e.g., a collagen, a hydrogel) or a collagen support, and seeded muscle cells such as myoblast cells or satellite cells, wherein the scaffold has sufficient mechanical integrity for skeletal muscle applications and wherein the scaffold has a tensile strength of from 10 kPa to 1000 kPa, or a tensile strength of at least 10, 50, 100 or 300 kPa (see at least Summary of the Invention, particularly lines 9-16 at page 2; and lines 13-19 and lines 27-30 at page 8).
Accordingly, it would have been obvious for an ordinary skill in the art to further modify the combined teachings Koop, Onoe et al and Larcher et al by also fabricating at least a 3D cultured tissue that is composed of muscle cell-laden fibers and/or fat cell-laden fibers at a desirable ratio as cultured meat for consumption, including using modified cells comprising tetracycline responsive promoters for expression of myogenic or adipogenic genes with a culture medium containing tetracycline, as well as a fiber scaffold having a tensile strength ranging from 3 kPa to 40 kPa; in light of the teachings of Ben-Arye et al, Elfenbein et al and Christ et al as presented above.
An ordinary skill in the art would have been further motivated to carry out the above modifications because Ben-Arye et al already taught successfully at least a method for producing an edible composition, comprising incubating a three-dimensional porous scaffold (e.g., collagen-based scaffold or Gelfoam) and a plurality of cell types comprising myoblasts or progenitor cells thereof (e.g., satellite cells), at least one type of extracellular (ECM)-secreting cell and endothelial cells or progenitor cells thereof (e.g., fibroblast progenitors, adipocyte progenitors), and inducing myoblasts differentiation into myotubes; wherein the plurality of cells are derived from a livestock mammal that includes cattle, boar, goat, hare and others. Additionally, Elfenbein et al also successfully taught a method of producing cultured fish meat for human consumption, comprising: a) obtaining a population of self-renewing cells derived from fish (e.g., a population of fish pre-adipocytes and a population of fish satellite cells); b) culturing the population of cell-renewing cells in culture media comprising micro-scaffolds; c) inducing differentiation in the population of cells to form at least one of myocytes and adipocytes; and d) processing the population of cells into fish meat for human consumption. Moreover, Elfenbein et al also taught the self-renewing cells are modified to control proliferation, differentiation, cell phenotype (e.g., steatosis/lipid accumulation), or other cellular properties with a genetic construct comprising an inducible promoter for controlling the expression of at least one myogenic differentiation gene or at least one adipogenic gene, and wherein the inducible promoter is the Tet-on system that utilizes tetracycline as an inducing agent. Elfenbein et al also taught that differentiated adipocytes and myocytes are usually cocultured together at a certain ratio to produce a desired final composition of adipocytes and myocytes in the resulting food product. Moreover, Christ et al also taught a skeletal muscle cell scaffold having a tensile strength of at least 10 kPa, or from 10 kPa to 1000 kPa for sufficient mechanical integrity for skeletal muscle applications. Furthermore, please note that Onoe et al already taught using at least functional cell fibres as templates for the reconstruction of fibre-shaped functional tissues that mimic muscle fibres.
An ordinary skill in the art would have a reasonable expectation of success in light of the teachings of Koop, Onoe et al, Larcher et al, Ben-Arye et al, Elfenbein et al and Christ et al as set forth above, coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Koop, Onoe et al, Larcher et al, Ben-Arye et al, Elfenbein et al and Christ et al is indistinguishable and encompassed by the claimed method of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Forgacs et al (US 10,669,524) disclosed a large-scale cell culture system for making meat and associated products, wherein different cell types (e.g., muscle and adipose cells) are cultured in a single culturing vessel/bioreactor or separating culturing vessels/bioreactors that are connected in parallel or in series (Abstract; Summary of the Invention; and Figs. 1-4).
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/
Primary Examiner, Art Unit 1631