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 .
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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/9/26 has been entered.
Priority
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application Nos. 62/516,575 and 62/653,332, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The earliest appearance of the use of an open reading frame (ORF) and use of a regulatory factor configured to inactivate a pluripotency gene appears in PCT/US2018/036552, filed 6/7/18. Claims 10, 12-14, are therefore accorded an earliest priority dated of 6/7/18. The earliest appearance of differentiation resulting in generation of myotubes appears in 62/653,332, filed 4/5/18. Claim 19 is therefore accorded and earliest priority date of 4/5/18.
Claim Status
Applicant’s arguments and amendments dated 4/9/26 have been received and entered in the application.
Claims 1, 4-5, 10, 12-14, 19, 21, 32, 35, 43-46, 48-51 are currently pending and examined on the merits.
Claims 1, 44 are currently amended.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections and rejections not specifically reiterated are hereby withdrawn.
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.
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(s) 1, 32, 35, 43-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marga et al., US Publication No. 2015/0079238 (hereinafter Marga) over Donai et al., (2014) Bovine and porcine fibroblasts can be immortalized with intact karyotype by the expression of mutant cyclin dependent kinase 4, cyclin D, telomerase. Journal of Biotechnology, 176: 50-57 (hereinafter Donai) and Furukawa et al., (2001) Formation of human fibroblast aggregates (spheroids) by rotational culture. Cell Transplantation, 10: pp. 441-445 (hereinafter Furukawa 2001).
Regarding claim 1, Marga discloses edible microcarriers appropriate for use in a bioreactor and edible engineered meat products produced thereon (Abstract, [0020]). Marga explains that many microcarriers are not suitable for use in comestible products as the microcarriers are not edible, are not animal product-free, or raise issues of contamination and/or allergies ([0007]). Therefore, the microcarriers must be removed from the cells in order to form a viable meat product ([0007]). Marga discloses forming microcarriers from materials that are derived only from vegetable and/or non-animal sources ([0015], [0038]). The microcarriers may be formed of plant-derived polysaccharides or polypeptides, such as pectin ([0015], [0017]-[0018]). The microcarrier may also include additives such as flavoring, flavor enhancer, or nutritional enhancer ([0019], [0039]). Cells cultured on the microcarriers may comprise any appropriate cells, such as smooth muscle cells, fibroblasts, satellite cells, or adipocyte precursor cells, and may be derived from animal sources, such as cows or fish ([0020], [0069], [0077]). In some embodiments, several cell types may be cultured simultaneously ([0077]). Preferably, the cells and the microcarriers are cultured in a bioreactor ([0053)]. Once the cells have divided and grown for a sufficient time period, the microcarriers may be combined into an appropriate shape to form an edible meat product ([0050], [0053]-[0057]). Marga explains that advantageously the cells do not have to be removed from the microcarriers as the carriers are edible [0070].
Regarding claim 32, cells cultured on the microcarriers may be derived from animal sources, such as cows or fish ([0020], [0069], [0077]).
Regarding claim 44, Marga does not disclose that the stem cells may undergo at least 50 cell divisions during the culturing step. However, Marga discloses that the cells may be grown to the desired number ([0049]). Further, Marga states that the cells may be cultured for at least 12 days ([0049]). Thus, there is a suggestion present in Marga that cell doublings are a result-effective variable. A skilled artisan would understand that the number of doublings could therefore be optimized through routine experimentation requiring no more than ordinary skill in the art (See MPEP § 2144.05).
Regarding claim 45, the microcarriers may be formed of plant-derived polysaccharides or polypeptides, such as pectin ([0015], [0017]-[0018]).
Regarding claim 46 Marga does not explicitly disclose, that the cells may be derived from salmon, tuna, or shrimp. However, Marga discloses, that cells cultured on the microcarriers may be derived from animal sources, such as cows or fish ([0020], [0069], [0077]). A skilled artisan would understand that the species of salmon and tuna would fall within the discloses genus of fish.
Marga does not explicitly disclose that the culture is a serum free culture. However, Marga is directed to animal product-free cultures ([0012]). Marga explains that a key aim of cultured meat products is the requirement that the “final product retains its no animal kill character” ([0009]). As serum is an animal-derived product it is implicit that the cultures disclosed by Marga would thereby be serum-free.
Marga does not disclose that the fibroblasts are immortalized.
Donai discloses methods of immortalizing cattle and pig fibroblasts (Abstract). Donai explains that cattle and pigs comprise the most economically important livestock animals (Abstract, Introduction). Bovine and porcine fibroblasts are limited in public cell banks, and the cost of sampling to start primary cultures is a further limitation (Introduction). Donai explains that livestock derived fibroblasts may be successfully immortalized allowing for production of large quantities of fibroblasts (Discussion).
A skilled artisan would be motivated to use the immortalized fibroblasts of Donai in the methods of Marga as Donai teaches that primary fibroblasts from livestock species have limited availability, and may be cost prohibitive for large scale uses. Therefore, immortalized fibroblasts provide an easy and lower cost option. Further, Marga explicitly states that any suitable cell type may be used in the discloses methods.
Regarding claim 43, Donai does not explicitly disclose that the media may contain certain components. However, Donai discloses that immortalized fibroblasts are cultured in DMEM ([Cell culture]). DMEM contains pyruvic acid (i.e., pyruvate). Therefore, it is implicit that Donai discloses culturing the cells in a media containing pyruvate.
The combination of Marga and Donai does not disclose that fibroblasts are cultured in a suspension bioreactor without the use of a scaffold prior to seeding on the plant based scaffold.
Furukawa 2001 discloses methods of making human fibroblast aggregates (Abstract, Introduction). Furukawa 2001 explains that aggregates of anchorage dependent cells, like fibroblasts, demonstrate higher retention and viability in suspension cultures than in two dimensional culture (Introduction). Furukawa explains that cells grown in aggregate are consequently highly useful for large scale culture applications (Introduction). Furukawa 2001 discloses suspending individual cells in rotational culture for at least 12 hours (Cell culture). Furukawa 2001 explains that the diameter of aggregates increases over time (Formation of aggregates of normal human skin fibroblasts). The resultant aggregates demonstrate good viability and ability to migrate onto scaffolds (Discussion).
A skilled artisan would be motivated to use the fibroblasts of Furukawa 2001 in the methods of the combination, as Furukawa 2001 discloses that large numbers of cells may be effectively produced using the disclosed methods. Furukawa also discloses that the cells demonstrate good migratory ability onto scaffolds for further applications.
Claim(s) 1, 4-5, 10, 12, 14, 19, 21, 32, 35, 43-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marga, Donai, and Furukawa 2001 as applied to claims 1, 32, 35, 43-46 above, and in further view of Boularaoui et al, (2017) Efficient transdifferentiation of human dermal fibroblasts into skeletal muscle. Tissue Engineering and Regenerative Medicine, 12(2): pp. e918-e936 (hereinafter Boularaoui).
Regarding claims 4-5, 12, 14, 19, 21 the combination does not disclose that the immortalized fibroblasts are transdifferentiated into skeletal muscle cells.
Boularaoui discloses methods of efficiently transdifferentiating fibroblasts into skeletal muscle (Abstract). Boularaoui explains that there is a need for a cell population with in vitro myogenic differentiation capacity which is easily accessible and readily expandable as compared to pluripotent stem cells or satellite cells (i.e., muscle stem cells) (Abstract, Introduction). Boularaoui discloses transducing human dermal fibroblasts with lentiviral vectors, such as MYOD1, on several extracellular matrix (ECM) components (2.1, 2.5, 2.10). Use of ECM substrates, such as laminin and fibronectin, induces a significant increase in conversion to myotubes (3.3, Fig. 3). Boularaoui concludes that fibroblasts may be efficiently transdifferentiated into skeletal muscle via induced transgenic expression of MYOD1 (Discussion). Boularaoui further suggests that the disclosed methods may be used to generate large numbers of skeletal muscle cells for the generation of skeletal biosynthetic tissue (e.g., ex vivo meat products).
A skilled artisan would be motivated to combine the methods of Boularaoui and the combination to generate large quantities of skeletal muscle tissue for the production of tissue engineered meat products.
Claim(s) 1, 32, 35, 43-46, 48-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marga, Donai, and Furukawa 2001 as applied to claims 1, 32, 35, 43-46 above, and in further view of Lin et al., (2008) Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnology Journal, 3:pp. 1172-1184 (hereinafter Lin 2008).
Regarding claims 48, the combination does not disclose that the bioreactor is a hanging drop bioreactor or a stirred tank bioreactor.
Lin 2008 reviews methods of performing non-adherent, suspension cultures (Abstract). Lin 2008 discloses that rotary systems, hanging drop systems, and spinner flasks are all known means by which to perform suspension culture (4.1, 4.4, Table 1, Fig. 3). Lin 2008 further discloses that spinner flasks and roller bottles are both simple to use and allow for the production of large quantities of cells (4.4, Table 1, Fig. 3). Lin also explains that hanging drop culture allows for precise control of spheroid formation, is inexpensive, and simple to perform (4.1, Table 1, Fig. 3).
As Furukawa 2001 and Lin each disclose methods of suspension culture it would be obvious to one of ordinary skill in the art that the references could be combined. Lin discloses that each of rotary systems, hanging drop systems, and spinner flasks are well-known equivalents for the formation of spheroid cultures. Therefore, it would be obvious to one of ordinary skill in the art that the systems could be substituted for each other with a reasonable expectation of producing suspension cultures.
Regarding claims 49-51, the combination does not disclose that the culture produces a certain amount of cells or that the bioreactor has a certain volume. However, as per MPEP § 2144.04 changes in size or proportion are considered routine expedients requiring no more than ordinary skill in the art. Further, Lin 2008 discloses that both spinner flasks and rotary cultures may be used for large scale production of cells. Therefore, there is a suggestion present in Lin that the culture may be scaled-up as needed.
Response to Arguments
Applicant’s arguments and amendments dated 4/9/26 have been fully considered but are moot in part and not persuasive in part due to the new grounds of rejection necessitated by applicant’s amendments. To the extent that the arguments are pertinent to the current grounds of rejection they are responded to below.
Claim(s) 1, 4-5, 10, 12, 14, 19, 21, 32, 35, 44-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marga, Donai, and Furukawa 2001.
Applicant argues that Furukawa 2001 teaches that serum-free culture conditions cannot be used to successfully culture fibroblasts under suspension cultures (Response p13-14).
Applicant appears to be arguing that Furukawa 2001 constitutes a teaching away from utilizing serum-free conditions. To constitute a teaching away the reference must criticize, discredit, or otherwise discourage the solution claimed. See MPEP §§ 2123, 2143.01. The section to which applicant points in Furukawa 2001 does not criticize, discredit, or otherwise discourage utilizing serum free conditions. The section merely states that another was unable to culture fibroblasts in non-adherent culture using a lower cell density, orbital shaking, a lower rotational speed, different culture plates, and a different culture media. Therefore, Furukawa 2001 is considered to teach away from utilizing serum free conditions for aggregate culture.
Applicant argues that Furukawa 2001 fails to disclose or suggest that the fibroblasts do not require adherence; applicant argues that the aggregate culture is fundamentally different from single cell suspension culture (Response p14).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., single cell culture) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims as presented merely require that the cells do not require adhesion to an extracellular scaffold, substrate, or matrix, none of which the cells of Furukawa 2001 require.
Applicant argues that neither Marga nor Furukawa 2001 discloses immortalized, fish-derived fibroblasts for serum free suspension culture (Response p14).
In response, references are relevant for prior art for all they contain; a reference may be relied upon “for all that it would have reasonably suggested”. See MPEP § 2123. Marga explicitly discloses that cells cultured on the microcarriers may be derived from fish. Marga also discloses that cultured on the microcarriers include fibroblasts. Therefore, Marga reasonably suggests that, at least in some embodiments, the cells could be fish-derived fibroblasts.
Claim(s) 1, 4-5, 10, 12, 14, 19, 21, 32, 35, 44-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marga, Donai, Furukawa 2001, and Boularaoui.
Applicant argues that Boularaoui expressly teaches that ECM components are important for efficient transdifferentiation (Response p15).
Applicant appears to be arguing that the transdifferentiation step occurs during suspension culture. However, nothing in the claims requires that the transdifferentiation occur prior to seeding on a plant-based scaffold. Therefore, the combination reads on the claims as currently presented.
Allowable Subject Matter
Claim 13 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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