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 .
Claims 1-16, of record 6/5/2024, are pending and subject to prosecution.
Priority
The instant application is a national stage entry of PCT/US2022/080875 (filed 12/5/2022). Acknowledgement is made of the applicant’s claim for benefit to provisional application 63/264994 (filed 12/6/2021).
Specification
The use of the terms Sephadex, LIVE/DEAD, RNeasy, Triton-X, Matrigel, HyStem, and CellTiter-Glo, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 5, 8-11, 13, and 16 are objected to because of the following informalities:
In line 4 of claim 1, the article “a” should be inserted after “microcarrier”, and “the microcarrier and cell mixture” in line 6 should be replaced with “the microcarrier, human stromal cell, and second cell line” or the like.
Additionally, claim 1 recites a “second cell line”, however, a first cell line is not recited, only a human stromal cell. Applicant should amend the terminology to recite a first cell line or a single cell line in addition to the human stromal cell and extend the same language to claims 8-11 and 13.
In claim 5, “adding during the adding step a modified adhesion protein” should be replaced with “adding a modified adhesion protein with the human stromal stem cell and second cell line” or the like.
In claim 16, “defined” in line 3 should be deleted, and “human derived ECM” should be inserted in front of “biomaterial” in lines 4-5 for consistency.
Appropriate correction is required.
Claim Interpretation
Claim 13 recites the limitation “[a] panel of multiple unique human derived ECM biomaterials prepared according to the method of claim 1”. The biomaterials are defined using product-by-process language. Product-by-process limitations are considered only in so far as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product as claimed is the same or obvious over a product of the prior art (i.e., is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113. In the instant application, because the method of claim 1 does not appear to distinguish the resulting ECM biomaterials structurally (e.g., whether the microcarrier is required to be present/undegraded in the end product is not recited), the biomaterials are interpreted as comprising any human-derived ECM biomaterials.
Additionally in claim 13, the limitation “panel” is not defined in the instant specification. The broadest reasonable interpretation is therefore considered to be a group of multiple unique human-derived ECM biomaterials.
Claim Rejections - 35 USC § 112
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 4 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 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.
Claim 4 recites the limitations “collagen analog” and “collagen mimetic”. While the claim recites a number of biomolecules that the microcarrier can comprise, the instant rejection is based upon the genera denoted by these particular limitations.
To satisfy the written description aspect of 35 U.S.C. 112a) for a claimed genus, it must be clear that: (1) the identifying characteristics of the claimed genus have been disclosed (e.g., structure or other physical and/or chemical properties by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics; or (2) a representative number of species within the genus must be disclosed.
Regarding disclosure of identifying characteristics of the claimed genera, a review of the instant specification fails to provide a definition of what structural or functional characteristics the members of the claimed genera must have. It is unclear whether a collagen analog or mimetic must resemble collagen in terms of physical structure or composition, functional activity, or both structurally and functionally. Because the applicant has not identified any particular core structure or function that must be shared by all members of the genera, one of ordinary skill in the art would not immediately envisage all members of the genera as claimed.
Regarding disclosure of a representative number of species, a review of the specification reveals no examples of either a collagen analog or a collagen mimetic. Therefore, the applicant has not disclosed a representative number of species required to support the description and show possession of the entire claimed genus.
One of ordinary skill in the art would not have been able to determine that the applicant was in possession of the invention, as claimed, at the time the application was filed. Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 U.S.C. 112(a).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-3 and 9-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation “the mixture” in line 3. There is insufficient antecedent basis for this limitation in the claim.
In claim 3, the limitation “efficient at secreting extracellular matrix” includes a relative term which renders the claim indefinite. The term “efficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 9-10 recites the limitation “wherein the second cell line is an established organoid” and “wherein the second cell line is a… organoid”. What is being claimed by these limitations is unclear, as a cell line consists of one clonal type of cell and an organoid comprises multiple types of differentiated cells to mimic an organ. The scope of the claims thus cannot be determined.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-4, 7, and 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Naughton et al. (US 20130344161 A1) in view of Skardal et al. (Biomaterials, 2010).
Regarding claims 1, 3-4, 7, 10, 12, and 14-15: Naughton et al. teach methods for producing extracellular matrix compositions for clinical and therapeutic applications (See Abstract and ¶0022). Cells can be cultured on scaffolds or supports, such as microcarriers, comprising gelatin, collagen, and hyaluronic acid (See ¶0049, 0054-0055, and 0061). The supports can be coated with proteins to enhance cell growth (which reads on “preparing a microcarrier”) (See ¶0076). The cells can be stromal cells comprising human fibroblasts (which reads on “human stromal cell characterized by secreting an ECM”), with or without other cells (See ¶0071-0073 and 0078). The cells can be derived from a patient’s own tissues (See ¶0076). Additional cell types can be included to confer beneficial effects such as enhancing synthesis of growth factors and promoting attachment of cells to the scaffold (which reads on “a second cell line specific for driving the stromal cell-based ECM secretion”) (See ¶0080). The cells can secrete molecules such as VEGF (See ¶0112-0113). Secreted ECM proteins and biological components are deposited on the scaffolds and can be collected and further processed along with soluble active agents (See ¶0050, 0115, and 0123). The collected ECM can be filtered or subjected to chromatography (which reads on “purifying”), precipitated, and/or lyophilized (See ¶0115-0119). In an embodiment, the cultures were lysed and washed to remove all living cells and cellular debris (which reads on “decellularizing”) (See ¶0188).
Naughton et al. do not expressly teach culture of the cells to form an organoid or culture in a rotational wall vessel.
Skardal et al. teach the culture of 3D tissue aggregates on microcarriers in a 50 ml rotating wall vessel bioreactor (RWV) (See Abstract and page 8428, col. 1, ¶1). The RWV can promote differentiation and proliferation and enhance expression of extracellular matrix proteins (See page 847, col. 1, full ¶1). Cell aggregates cultured in RWVs acquire and recapitulate properties of differentiated cells and tissues (which reads on “organoids”) (See page 847, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Naughton et al. to comprise the use of a RWV, as taught by Skardal et al. One would be motivated to make this modification because Skardal et al. teach RWVs as capable of promoting cell proliferation and differentiation as well as ECM protein production (See page 847, col. 1, full ¶1). There would be a reasonable expectation of success in doing so because Skardal et al. demonstrate that cells on microcarriers can be cultured in a RWV (See fig. 3-4). Additionally, organoids formed by differentiation during the culturing process would serve as a natural endpoint for ECM collection.
Regarding claims 11 and 13: Following the discussion of claims 1, 3-4, 7, 10, 12, and 14-15, Naughton et al. teach that the cells used to inoculate the culture supports can be fibroblasts in combination with other cell types such as muscles cells, endothelial cells, adipocytes, and immune cells, which can be selected in order to synthesize particular collagen types found in the their native tissues (which reads on “characteristics specific for the second cell line” and “defined by a unique characteristic of a unique second cell line”) (See ¶0080 and 0103 and table 1). The use of different cell combinations would yield ECM products that would read on “[a] panel”.
Regarding claim 16: Following the discussion of claims 1, 3-4, 7, 10, 12, and 14-15, Naughton et al. and Skardal et al. do not expressly teach the formation of an organoid using the collected organoid-derived ECM. However, one of ordinary skill would recognize that it would be well-suited to and could be readily used for the further generation of organoids.
Claims 1-7 and 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Naughton et al. (US 20130344161 A1) in view of Skardal et al. (Biomaterials, 2010), further in view of Votanopoulos et al. (Annals of Surgical Oncology, 2020).
The teachings of Naughton et al. and Skardal et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 2 and 5-6: Following the discussion of claims 1, 3-4, 7, and 10-16, Naughton et al., modified by Skardal et al., render obvious the production of ECM by cells on microcarrier coated with attachment proteins. Naughton et al. teach the use of dextran beads as microcarriers (See ¶0087 and 0158), and Skardal et al. teach the lyophilization and sterilization of ECM-coated beads by autoclaving prior to use (See page 8427, col. 2, full ¶4). Neither Naughton et al. nor Skardal et al. expressly teach the attachment proteins as being modified and crosslinked hyaluronic acid and collagen.
Votanopoulos et al. teach the fabrication of tumor organoids using an ECM-mimicking hydrogel comprising a thiolated hyaluronic acid component and a methacrylated collagen component (See Abstract and page 1958, col. 1, ¶1). Thiol-methacrylate and methacrylate-methacrylate crosslinking was initiated with UV light (See page 1958, col. 1, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method rendered obvious by Naughton et al. and Skardal et al. to comprise cell inoculation of microcarriers in the hydrogel matrix or onto the hydrogel matrix taught by Votanopoulos et al. One would have been motivated to make these modifications because Votanopoulos et al. demonstrate that it is a suitable substrate for supporting the growth of cells within organoids (See fig. 1). There would be a reasonable expectation of success in doing so because Naughton et al. teach that the culture supports can comprise hydrogels and can be coated with proteins such as collagen and hyaluronic acid to enhance cell attachment (See ¶0058, 0069, 0076, and 0132). While Votanopoulos et al. teach culture of cells directly in the hydrated gel, one of ordinary skill in the art would have also found it obvious to coat the microcarriers in the hydrogel, followed by lyophilization, as done by Skardal et al. with using a crosslinked thiolated hyaluronic acid derivative and thiolated gelatin (See fig. 1).
Claims 1, 3-4, 7-8, and 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Naughton et al. (US 20130344161 A1) in view of Skardal et al. (Biomaterials, 2010), further in view of Zhau et al. (In Vitro Cellular and Developmental Biology—Animal, 1997) and da Cunha et al. (Journal of Cancer, 2019).
The teachings of Naughton et al. and Skardal et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 8: Following the discussion of claims 1, 3-4, 7, and 10-16, Naughton et al., modified by Skardal et al. render obvious the production of ECM by cells of an organoid on microcarriers but do not teach the organoid as comprising tumor cells.
Zhau et al. teach the co-culture of prostate fibroblasts and LNCaP prostate cancer cells (which reads on “established tumor cell line”) on dextran microcarrier beads in a 110 ml RWV (See Abstract and page 376, col. 1, full ¶1).
Da Cunha et al. teach that expression of ECM components is increased during the neoplastic process and that the collagen-rich tumor microenvironment is associated with induction of survival and proliferation (See page 4576, col. 1, full ¶3 and page 4578, col. 1, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method rendered obvious by Naughton et al., modified by Skardal et al., to seed the microcarriers with fibroblasts and a prostate cancer cell line, as taught by Zhau et al. One would have been motivated to make this modification because the teachings of da Cunha et al. suggest that tumor-derived ECM may promote cell growth (See page 4576, col. 1, full ¶3 and page 4578, col. 1, ¶1). There would be a reasonable expectation of success in doing so because Zhau et al. demonstrate that the co-cultured cells can be grown on microcarriers in an RWV (See Abstract and page 376, col. 1, full ¶1).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
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