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 status
Applicants reply filed 5/21/2026 is acknowledged.
Claims 4, 6, 14 and 16 is/are cancelled and claims 18-21 is/are newly added. Claims 1-3, 5, 7-10, 11-13, 15, 17, 18-21 is/are currently pending with claims 11-13, 15, 17 is/are withdrawn. Claims 1-3, 5, 7-10, 18-21 is/are under examination.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Claim Objections – New, necessitated by claim amendments
Claim 9 is objected to because of the following informalities: Claim 9 recites “a number of endothelial cells” and “a number of stromal cells”. Appropriate article for this phrase is “the” because “a number” implies other number of cells in the cell structure. However, there cannot be two different numbers of the same cell type in the same structure, therefore use of “the number” in place of “a number” is recommended. Additionally, claim 9 limits “a number of stromal cells” to 1.0% to 50%. However since these are percentages, it is recommended that the claim recite “the amount of stromal cells”. Appropriate correction is required.
Claim 20 is objected to because of the following informalities: Claim 20 recites “a concentration” of various elements. Appropriate article for this phrase is “the” because “a concentration” implies other concentrations of these elements in the cell structure. However, there cannot be two different concentrations of the elements in the same structure, therefore use of “the concentration” in place of “a concentration” is recommended. Additionally, claim 20 repeats “mg” in line 3. Deletion of this excess “mg” is required. Appropriate correction is required.
Claim 21 is objected to because of the following informalities: Claim 21 recites “a concentration” of various elements. Appropriate article for this phrase is “the” because “a concentration” implies other concentrations of these elements in the cell structure. However, there cannot be two different concentrations of the elements in the same structure, therefore use of “the concentration” in place of “a concentration” is recommended. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – New, necessitated by claim amendments
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.
Previous rejection of claims 1-10, 14, 16 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 is withdrawn in light of claim amendments.
Claims 2, 20 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 “selecting the first three-dimensional cell structure sample” however does not identify what property the cell structure is selected for and/or how the selection is made. The specification provides no guidance regarding a selection step. For the purpose of compact prosecution, the claim(s) 2 is/are interpreted as “collecting the first three-dimensional cell structure sample”.
Claim 2 recites “selecting a second three-dimensional cell structure sample”. Considering no second three-dimensional cell structure is made in claim 1, only “one or more first three-dimensional cell structure(s)”, it is unclear how “second three-dimensional cell structure” could be selected. Furthermore, the claim does not identify what property the cell structure is selected for and/or how the selection is made. The specification provides no guidance regarding a selection step. For the purpose of compact prosecution, the claim(s) 2 is/are interpreted as “collecting another first three-dimensional cell structure sample”.
Claim 20 recites concentrations of elements such as heparin and collagen that are “from greater than” the recited range of concentration. It is unclear what concentration range for heparin and collagen are embraced by this claim. For example, it is unclear if the claim embraces the concentration of heparin to be greater than 0 mg/ml but less than 1 mg/ml or if the concentrations of heparin embraced are greater than all the concentrations between 0-1 mg/ml i.e. simply greater than 1 mg/ml. For the purpose of compact prosecution, the claim(s) 20 is/are interpreted as “from
Claim Rejections - 35 USC § 112(d) - Withdrawn
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Rejection of Claim 3 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in light of claim amendment.
IMPROPER MARKUSH - Withdrawn
Rejection of Claim 6 on the basis that it contains an improper Markush grouping of alternatives is moot due to claim cancellation
Claim Rejections - 35 USC § 112(a) – Maintained in part, New for newly added claims
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.
Rejection of Claims 4, 6, 14, 16 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 is moot due to claim cancellation.
Claims 1-3, 5, 7-10 remain rejected and claims 18, 20-21 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 are amended to limit cationic substances and polyelectrolytes to comprise specific molecules however written description issues regarding generic mouse stromal cells remain.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claims are directed to a method for producing a three-dimensional cell structure. The method embraces the following broadly recited genera:
(i) a generic stromal cells from mouse.
According to the MPEP § 2163, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., 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, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Regarding stromal cells, the specification does not provide a specific definition and the art teaches highly distinct cell types with varied functions as “stromal cells”. Manetti (Int. J. Mol. Sci. 2021, 22, 13422; ref of record) states “The term “stromal cells” refers to a highly heterogeneous class of connective tissue cells that build the infrastructure of any organ and fulfill a variety of fundamental roles in health and disease. Embedded into the framework of stromal cells are parenchymal cells, which define the specific function of an organ. Distinctive populations of stromal cells with different morphologies and functions include (i) fibroblasts, pericytes, and telocytes that are widely distributed throughout various organ systems; (ii) cells with stemness features, such as bone-marrow-derived mesenchymal stem/stromal cells (MSCs) and adipose tissue-derived stem/stromal cells (ASCs); and (iii) stromal cells specifically restricted to some organs, such as interstitial cells of Cajal in the gastrointestinal tract muscularis and fibroblastic reticular cells in secondary lymphoid organs, among others.” (para 1). Thus, in reciting a generic stromal cell, claims embrace a highly heterogeneous class of connective tissue cells ranging from fibroblasts, telocytes to MSCs to organ-specific stromal cells with organ-specific functions.
The specification states the following on page 7: “stromal cell is a generic name for cells constituting a supportive tissue for epithelial cells. Examples of stromal cells include fibroblasts and smooth muscle cells.” Of note this statement is not a limiting definition. See also, claim 19 that recites “other fibroblasts” and “other smooth muscle cells”. Thus, although the specification envisions only stromal cells present in an epithelial tissue, providing two specific examples: fibroblasts and smooth muscle cells, the claims are not limited to mouse epithelial fibroblasts and mouse epithelial smooth muscle cells. Furthermore, significant heterogeneity exists within stromal cells even in epithelial tissues which are highly diverse in of themselves. For example, a post-filing review of stromal cells in just the intestinal epithelium teaches that “Identifying specific stromal niche populations and the factors they produce has been challenging. This is because stromal markers are expressed in more than 1 cell population, cellular phenotypes are influenced by signals within their microenvironment, and injury and disease states impact stromal cell populations” (page 679, col. 2, para 1 in Abud et al (Cellular and Molecular Gastroenterology and Hepatology Vol. 17, Iss. 5, 2024; ref of record). They identify distinct cells with distinct functions as stromal cells (see Figure 1). Thus, while the specification envisions only stromal cells present in an epithelial tissue and provides only two specific examples which do not represent the actual diversity of stromal cells in various epithelial tissues, the claims embrace any stromal cell. Critically, the examples presented wherein mouse-derived stromal cells are used are restricted to mouse embryonic fibroblasts (MEF, Example 1). Considering the embryonic nature of MEFs, these cannot be considered representative of the varied fibroblasts found in mice, especially the variety of adult fibroblasts. Critically, MEFs are not fibroblasts of the epithelial tissue.
Taken together, the genus of “stromal cells” is highly heterogenous while the specification only envisions two broadly recited species (epithelial fibroblast and epithelial smooth muscle cells) and reduces to practice one specific species i.e. MEFs. The specification does not provide relevant identifying characteristics of the claimed genus such that a skilled artisan could envision the structure and related function of the claimed stromal cell species. Thus, the written description does not provide adequate support for the broadly claimed genus of “stromal cells”.
Claim Rejections - 35 USC § 112(a) – 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 1-4, 5, 7-10, 18-21 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. 37 CFR 1.118 (a) states that “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”.
Claim 1 has been amended to recite an optional limitation which is positively recited in new claim 18: “culturing the first three-dimensional cell structure for a time and under conditions that form a three-dimensional structure whose decrease in thickness is suppressed over a time of five days after production compared to a control not containing mouse derived stromal cells.” Thus, these claims embrace a culturing step that is conducted for a specific time under specific conditions that result in a three-dimensional cell structure with the following characteristic: “a three-dimensional structure whose decrease in thickness is suppressed over a time of five days after production compared to a control not containing mouse derived stromal cells” (emphasis added). However, the originally filed specification does not disclose a three-dimensional cell structure that does not contain stromal cells, including mouse derived stromal cells such as mouse derived embryonic fibroblasts. Thus, there is no disclosure of a three-dimensional structure whose decrease in thickness is suppressed over a time of five days after production in comparison to a structure not containing mouse derived stromal cells.
The examples are limited to structures comprising 80-100% mouse embryonic fibroblasts wherein the culturing steps occurs for either 24 hours or 96 hours and the reduction thickness is compared to a structure comprising only mouse embryonic fibroblasts (Example 1, Table 1). Even the broadly recited embodiments in the specification, such as on page 14, page 15, do not recite a structure not containing mouse derived stromal cells.
Applicant indicates that at least page 4 and 5 in the specification provide support for this newly added limitation. However, neither on these pages or any other pages in the specification explicitly or implicitly disclose a structure not containing mouse derived stromal cells.
Claims 2-4, 5, 7-10, 19-21 embrace the limitation with the new matter issue and thus also comprise new matter.
Claim 9 is amended to recite “wherein [..] stromal cells in the cell population ranges from 1.0% to 50%.” The originally filed specification does not disclose a three-dimensional cell structure that does contains stromal cells at 1-50%. The examples are limited to structures comprising 80-100% mouse embryonic fibroblasts (Example 1, Table 1). Even the broadly recited embodiments in the specification, such as on page 14, page 15, do not recite stromal cells in the cell population ranges from 1.0% to 50%.
Applicant indicates that at least page 7 in the specification provide support for this newly added limitation. However, neither on this page or any other pages in the specification explicitly or implicitly disclose stromal cells in the cell population ranges from 1.0% to 50%.
New claim 19 recites “wherein the stromal cells are epithelial fibroblasts or other fibroblasts or epithelial smooth muscle cells or other smooth muscle cells.” Thus, the claim embraces non-epithelial fibroblasts and non-epithelial smooth muscle cells.
The originally filed specification does not disclose a three-dimensional cell structure comprising non-epithelial fibroblasts or non-epithelial smooth muscle cells. Furthermore, non-epithelial fibroblasts and non-epithelial smooth muscle cells are not even envisioned as stromal cells that could be included in the claimed three-dimensional cell structure. On the contrary, the specification states the following on page 7: “stromal cell is a generic name for cells constituting a supportive tissue for epithelial cells. Examples of stromal cells include fibroblasts and smooth muscle cells.”
Applicant indicates that at least page 7 in the specification provide support for this newly added limitation. However, neither on this page or any other pages in the specification explicitly or implicitly disclose non-epithelial fibroblasts and non-epithelial smooth muscle cells.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure [or point to case law supporting incorporation of such a limitation as in the instant case]” (emphasis added).
Claim Interpretation – New, to address claim amendments
Claim 1 is amended to recite a three-dimensional cell structure that now comprises “(i) syngeneic mouse-derived stromal cells that are non-endothelial mouse-derived cells, and (ii) syngeneic endothelial cells, which may comprise syngeneic mouse-derived endothelial cells, in an amount of 1.5% to 10% of a total cell population” (emphasis added). Since the cells in (i) and (ii) are required to be syngeneic and cells in (i) are required to be derived from mouse, cells in (ii) are also required to be derived from mouse. Thus, regardless of the optionally recited “may comprise syngeneic mouse-derived endothelial cells” in (ii), these cells are syngeneic mouse-derived endothelial cells. Furthermore, since the optionally recited limitation is within commas, it is interpreted that the limitation recited outside of the commas i.e. “in an amount of 1.5% to 10% of a total cell population” is not optional i.e. is required.
Claim 1, optionally, and claim 18 recite “culturing the first three-dimensional cell structure for a time and under conditions that form a three-dimensional structure whose decrease in thickness is suppressed over a time of five days after production compared to a control not containing mouse derived stromal cells.” Thus, these claims embrace a culturing step that is conducted for a specific time under specific conditions that result in a three-dimensional cell structure with the following characteristic: “a three-dimensional structure whose decrease in thickness is suppressed over a time of five days after production compared to a control not containing mouse derived stromal cells” (emphasis added). As noted above, “a control not containing mouse derived stromal cells” is new matter. Regarding “specific conditions” and “specific timing”, no “specific conditions” and “specific timing” is recited in the claims. The specification states that “The cell culture in step (C) can be performed under culture conditions suitable for the cells to be cultured. A person skilled in the art can select a suitable medium depending on the cell type and desired function.” and “The time required for culturing of a cell aggregate to obtain a three-dimensional cell structure may be 5 minutes to 168 hours, 12 hours to 144 hours, or 24 hours to 72 hours.” (page 12, para 2, 3). The culture conditions in the examples is DMEM + 10% FBS (page 16, para 1) and duration is 24-96 hours (page 16, para 3). Thus, although the intended characteristics of the produced three-dimensional structure suffer from lack of written description, for the purpose of applying art a three-dimensional structure with the claimed characteristics is inherently produced when the three-dimensional structure is cultured in a suitable medium for 5 minutes to 168 hours.
Claim 2 recites additional method steps for the method of claim 1 that is directed to a method for producing a three-dimensional cell structure. In view of the 112b issues noted above, Claim 2 appears to collect two three-dimensional cell structures and two different time points after culture step of claim 1 and a cut a slice from each of these structures. The first three-dimensional cell structure is collected “immediately after production”. The specification defines on page 5: “Here, “immediately after production” may refer to “when 5 minutes to 72 hours has elapsed since the start of culture of one or more cell aggregates”. Thus, the first three-dimensional cell structure is collected 5 minutes to 72 hours after the start of the culturing step. Another three-dimensional cell structure is collected “fifth day since production”. The specification defines on page 6: “Further, “on the fifth day since production” may refer to “on the fifth day (preferably, when 96 hours has elapsed) since culture of one or more cell aggregates”. Thus, another three-dimensional cell structure is collected 96 hours after the start of the culturing step. Taken together, claim 2 is directed to a method of producing two planar three-dimensional cell structures or two three-dimensional cell structures that are each in the form of a slice, wherein the slices are produced from a three-dimensional cell structure collected 5 minutes to 72 hours after start of culture and a three-dimensional cell structure collected 96 hours after start of culture. The claim further requires that two slices be prepared by cutting the cell structures along a pre-determined line resulting a specifically recited relation between the two slices i.e. maximum width of the second slice is at least 90% or more than the first slice.
Claims 5 and 7 recites the concentration ranges for the extracellular matrix component and polyelectrolyte of claim 1. Although claim 1 recites that the extracellular matrix component comprises collagen and polyelectrolyte comprises heparin, there is no requirement that the extracellular matrix component is collagen and polyelectrolyte is heparin. Thus, claim 5 and 7 do not require that collagen and heparin be the present at the specifically recited concentrations, as long as the extracellular matrix component that comprises collagen and polyelectrolyte that comprises heparin are present at the specifically recited concentrations.
Claim Rejections - 35 USC § 102 – Withdrawn
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.
Rejection of Claim(s) 4, 6 under 35 U.S.C. 102(a)(1) as being anticipated by Matsusaki et al (US 2018/0355308 A1; Dec. 13, 2018; IDS 2/21/2023) is moot due to claim cancellation.
Rejection of Claim(s) 1-3, 5, 7-8, 10 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Matsusaki et al (US 2018/0355308 A1; Dec. 13, 2018; IDS 2/21/2023) are withdrawn because claim 1 is amended to recite endothelial cells in 1-5-10% of total cell population which is not explicitly disclosed by Matsusaki.
Claim Rejections - 35 USC § 103 – New, necessitated by claim amendments
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.
Rejection of Claim(s) 14, 16 under 35 U.S.C. 103 as being unpatentable over Matsusaki as applied to claim 1 above, and further in view of Matsusaki is moot due to claim cancellation.
Rejection of Claim(s) 9, under 35 U.S.C. 103 as being unpatentable over Matsusaki as applied to claim 1 above, and further in view of Matsusaki is withdrawn due to withdrawal of rejection it depended from.
Claim(s) 1-3, 5, 7-10, 18-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsusaki et al (US 2018/0355308 A1; Dec. 13, 2018; IDS 2/21/2023).
Regarding claims 1 and 18, in view of claim interpretation noted above, Matsusaki teaches a method for producing a three-dimensional cell structure comprising a step of mixing cells with a cationic , an extracellular matrix component, a polymeric electrolyte [0023-0025, 0064-0069], collecting a cell aggregate from the mixture and culturing the cell aggregate to obtain a three-dimensional cell structure [0024, 0066-0069]. Regarding cationic substances, Matsusaki teaches tris-hydrochloric acid buffer solution as a cationic substance [0033, 0099, 101, 108, 113, 120, 123], collagen as extracellular matrix component [0032, 0079, 0098, 0099, 123] and heparin as a polyelectrolyte [0031, 0077, 0099, 101, 108, 113, 120, 123]. Regarding the cells used in their method, Matsusaki teaches embodiments wherein the cells are a plurality of kinds of cells such as one selected from vascular endothelial cells and fibroblasts (=stromal cells; [0037-0038, 0082) and are derived from cells of species including mouse [0082]. Furthermore, Matsusaki teaches culturing the three-dimensional cell structure in suitable culture conditions and for a duration based in the cell type and desired functions [0090]. In their examples, they teach DMEM +10% FBS as culture conditions and a culture duration of at least 24 hours, up to 8 days; thus meeting the optional limitation of claim 1 and limitation of claim 18 [0099, 123, 125]. Of note, Matsusaki also teaches that their method reduces collapse i.e. suppresses decrease in thickness overtime ([0068], Example 10).
Thus, Matsusaki teaches a method for producing a three-dimensional cell structure comprising a step of preparing a mixture of cationic substance comprising tris-hydrochloric acid buffer solution, an extracellular matrix component comprising collagen, a polymeric electrolyte comprising heparin, endothelial cells from mouse and fibroblast stromal cells from mouse.
Matsusaki does not explicitly teach that the fibroblasts and endothelial cells must be syngeneic and including the endothelial cells at 1.5-10% of total cell population.
However, in examples 7 and 8, Matsusaki teaches syngeneic vascular endothelial cells (HUVEC) and fibroblasts cells (NHDF) derived from human wherein they teach three-dimensional cell structures comprising 1.5% endothelial cells to fibroblast in example 7 and 10% endothelial cells to fibroblast in example 8.
Thus, Matsusaki provides teachings regarding the % of endothelial cells to fibroblasts that could be used in their method for producing three-dimensional cell structures and also teaches that cells derived from mouse could be used in their method. Additionally, Matsusaki provides teachings regarding use of syngeneic cells in their method for producing three-dimensional cell structures.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention when using the method of Matsusaki to use the guidance provided by Matsusaki regarding the % of endothelial cells to fibroblasts that could be used in their method for producing three-dimensional cell structures and the guidance provided by Matsusaki regarding use of syngeneic cells in their method. Using this guidance provided by Matsusaki would result in a three-dimensional cell structure which comprises 1.5-10% endothelial cells. Furthermore, based on the teachings of Matsusaki , it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that Matsusaki’s method is applicable to cells from different species, including mice, such that when using Matsusaki’s method to make a mouse three-dimensional cell structure, an ordinary artisan would use mouse-derived endothelial cells and mouse-derived fibroblasts i.e. syngeneic. An ordinary artisan would be motivated to use Matsusaki’s method to make a mouse three-dimensional cell structure because mouse-derived cells are easier to acquire and routinely used in cell culture. An ordinary artisan would reasonably expect to use desired cells, such as mouse-derived endothelial cells and mouse-derived fibroblasts in Matsusaki’s method by simply substituting desired cells, such as mouse-derived endothelial cells and mouse-derived fibroblasts in Matsusaki’s method. Such a substitution would be expected to produce a three-dimensional cell structure made of syngeneic cells, wherein the three-dimensional cell structures comprises 1.5% or 10% endothelial cells.
Regarding claim 2, in view of 112b issues and claim interpretation above, Matsusaki teaches collecting the three-dimensional cell structures and preparation of slices from the structures, wherein the three-dimensional cell structures are collected 24 hours after culture initiation [0099, 0117-118] or 3 days [0125] or 8 days after culture initiation [0123].
Matsusaki does not explicitly teach collecting the three-dimensional cell structures at 96 hours after culture initiation. However, in teaching a range of collection days from 1-8 days, Matsusaki renders obvious collection at 5 days which lies within the range of days taught. According to MPEP 2144.05(I), “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”, “In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range)”. In the instant case, there is no evidence that collecting at 96 hours is critical. Furthermore, an ordinary artisan would use routine optimization to identify day of collection that produces a cell construct of the desired size and maturation. In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See MPEP 2144.05(II). In the instant case, an ordinary artisan would use the same routine collection method for any day of collection based on desired results. Furthermore, an ordinary artisan could predetermine the line of slicing to arrive at thicker or thinner sections, such that the maximum width of the second slice is at least 90% or more than the first slice. Therefore, Matsusaki renders instant claim 2 prima facie obvious.
Regrading claim 3, Matsusaki teaches repeating the mixing and collecting step and culturing the collected aggregates ([0091], Example 4)
Regarding claim 5, Matsusaki teaches “The concentration of the extracellular matrix component used in the present embodiment is preferably more than 0 mg/mL and less than 1.0 mg/mL. The concentration of the extracellular matrix component used in the present embodiment is more preferably 0.025 mg/mL or more to 0.1 mg/mL or less. For example, the concentration of the extracellular matrix component used in the present embodiment is 0.025, 0.05, 0.075, or 0.1 mg/mL. The concentration of the extracellular matrix component used in the present embodiment is further more preferably 0.05mg/mL or more to 0.1 mg/mL or less.” [0080].
Regarding claim 7, Matsusaki teaches “The concentration of the polymeric electrolyte used in the present embodiment is preferably more than 0 mg/mL and less than 1.0 mg/mL. The concentration of the polymeric electrolyte used in the present embodiment is more preferably 0.025 mg/mL or more to 0.1 mg/mL or less. For example, the concentration of the polymeric electrolyte used in the present embodiment is 0.025, 0.05, 0.075, or 0.1mg/mL. The concentration of the polymeric electrolyte used in the present embodiment is further more preferably 0.05 mg/mL or more to 0.1 mg/mL or less.” [0078].
Regarding claim 8 and 19, Matsusaki teaches that the cells are a plurality of kinds of cells such as one selected from vascular endothelial cells and fibroblasts (=stromal cells; [0037-0038, 0082) and are derived from cells of species including mouse [0082]. Thus, Matsusaki teaches vascular endothelial cells and mouse fibroblasts. Since Matsusaki does not explicitly recite that the fibroblasts are epithelial-origin, thus Matsusaki teaches at least “other” fibroblasts.
Regarding claim 9, in Matsusaki’s examples the number of endothelial cells are 1.5-10% and thus do not excess the number of fibroblasts. However, Matsusaki does not teach fibroblasts at 1-50%. In Matsusaki’s examples, fibroblasts range from 90-98.5%. However, inclusion of cells at desired concentration, such as claimed, would be a matter of routine optimization. An ordinary artisan would optimize the amount of cell types in the three-dimensional cell structure based on the cell structure desired, i.e. the tissue intended for modeling by the cell structure, and such an optimization would only require routine methods such that cells in different ratios would be mixed in the mixing steps. According to MPEP 2144.5 (II), “In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). Thus, Matsusaki renders the instant claim prima facie obvious.
Regarding claim 10, Matsusaki teaches that the mixture is in a liquid medium. See reference to “removing a liquid portion from the obtained mixture” in [0026, 0070], thus teaching that the mixture was in a liquid medium prior to its removal in this step.
Regarding claims 20 and 21, Matsusaki teaches Tri-HCl as a cationic substance wherein cationic substances are at a concentration of 10-100mM, specifically using Tris-HCl at 50mM ([0074, 0075], Example 1, 8). Matsusaki teaches heparin as a polyelectrolyte wherein polyelectrolytes are at a concentration of 0-1mg/ml, specifically 0.025-0.1mg/ml, specifically using heparin at 0, 0.1, 1, 2 mg/ml in Example 1 and 0.2mg/ml in Example 7, 0.1 mg/ml in Example 8 ([0077-0078], Figure 1, 3). Matsusaki teaches collagen as an extracellular matrix component wherein extracellular matrix component is at a concentration of 0-1mg/ml, 0.025-0.1mg/ml, specifically using collagen at 0, 0.1, 1, 2 mg/ml in Example 1, 0.2mg/ml in Example 7, and 0.1mg/ml in Example 8 ([0079-0080], Figure 1 and 3).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Double Patenting - Withdrawn
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Rejection of Claims 1-10, 14, 16 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-5, 7-11 of copending Application No. 18/774,971 in view of Matsusaki is withdrawn in light of claim amendments.
Rejection of Claims 1-4, 6, 8-10, 14, 16 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 6 of copending Application No. 18/171,415 in view of Matsusaki is withdrawn in light of claim amendments.
Declaration under 37 C.F.R. 1.132
The Declaration of Morimura under 37 CFR 1.132 filed 5/21/2026 is acknowledged. The rejection it addresses are now withdrawn however, the declaration is considered and is found to be insufficient to overcome the new U.S.C. 103 rejection of claims based upon Matsusaki as set forth in the last Office action.
First, Morimura presents a comparison of a specific embodiment embraced by the claim with a specific embodiment of Matsusaki (page 2, Table). This comparison appears to compare example 8 from Matsusaki with a specific condition presented in instant example 1 wherein endothelial cells are at 10% of total cells. Morimura allege that “increasing cell concentration alone does not lead to the drastic thickness increase (73 μm) observed in the present invention” (page 2, last para)
In response, at first it must be noted that the claimed comparison is directed to significantly narrower scope than is embraced by the claims. The claims are not limited to mouse embryonic fibroblasts and mouse endothelial cells, wherein the endothelial cells are 10% of total cells. In fact, none of the claims recite mouse embryonic fibroblasts. Furthermore, comparison of example 8 from Matsusaki with instant Example 1 is not reasonable since in this example 8, Matsusaki presents an exemplary embodiment with human cells cultured for 3 days while example 1 from the instant specification uses mouse cells cultured for 5 days, i.e. nearly twice as long. Matsusaki teaches a method of three-dimensional cell construct and teaches embodiments wherein mouse cells are used. An ordinary artisan using Matsusaki’s method to make mouse construct would not use human cells. Furthermore, no assertion was made that “simply increasing the initial cell concentration will proportionally increase the final tissue thickness” (page 2, para 2). A ordinary artisan would recognize that a construct comprising only one cell type, such as NHDFs or MEFs, would not have the same properties, including properties of compression, when compared to cells comprising other cells types especially endothelial cells that tend to form a vasculature with lumens inside the construct. The alleged “drastic thickness increase” in a construct comprising MEFs with 10% endothelial cells is not comparable to a construct comprising only MEFs or NHDFs. Furthermore, an ordinary artisan using Matsusaki’s method to make mouse construct using mouse cells would arrive at this property since this is a latent property that arises in a mouse construct rendered obvious by Matsusaki.
Next, Morimura present that results presented in the specification are “entirely unexpected and contrary to the general behavior of 3D cell structures” (page 3, para 3) because “3D tissue tends to gradually shrink and thin over time” (page 3, para1) however in their example using mouse cells (MEFs and endothelial cells) the shrinkage was less than 10% (90% maintenance while human constructs have more shrinkage (page 3, para 3).
In response, as above, at first it must be noted that the claimed comparison is directed to significantly narrower scope than is embraced by the claims. The claims are not limited to mouse embryonic fibroblasts and mouse endothelial cells, wherein the endothelial cells are 10% of total cells. In fact, none of the claims recite mouse embryonic fibroblasts. Critically, the greater than 90% maintenance was observed for only 10% endothelial cell group and no other group (Table 1).
Furthermore, an ordinary artisan would recognize that a construct comprising cells from one species, would not have the same properties, including properties of compression, when compared to cells from other species. Critically, an ordinary artisan using Matsusaki’s method to make mouse construct using mouse cells would arrive at this property of reduced shrinkage in comparison to a human construct since this is a latent property that arises in a mouse construct rendered obvious by Matsusaki.
See MPEP 2145 (II) “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention” “"The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.).
Finally, Morimura present concluding remarks that summarize the positions mentioned previously and these have been addressed above (page 3-4).
Response to Arguments
Applicant's arguments filed 5/21/2026 regarding the U.S.C. 112a rejection of the claims 1-10, 14 and 16 have been fully considered but are only persuasive in part.
Rejection pertaining to broad recitation of mouse-derived stromal cells is maintained.
Applicant argue that “The specification need not disclose what is well-known to those skilled in the art and preferably omits that which is well-known to those skilled and already available to the public” and point to page 7 of the specification that states that stromal cells are supportive tissue for epithelial cells, such as fibroblasts and smooth muscle cells, which maybe identified by morphology, markers. (page 11).
In response, as noted in the rejection, based on teachings from Manetti and Abud, the generic stromal cell embraces a highly heterogeneous class of connective tissue cells ranging from fibroblasts, telocytes to MSCs to organ-specific stromal cells with organ-specific functions. The two prophetic examples provided in the specification of epithelial fibroblasts and epithelial smooth muscle cells do not provide sufficient support from the broadly claimed stromal cell. The examples provided do not use epithelial fibroblasts. Thus, a skilled artisan cannot envision the various stromal cells, that are highly heterogenous, that result in the claimed construct with the claimed features.
Applicant’s arguments with respect to the U.S.C. 102 rejection of claim(s) 1-8, 10 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 9 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to instant U.S.C. 103 rejection are addressed below.
Applicant allege “unexpected results” (page 12, para 3) stating that “The invention's advantage as described in more detail below is to maintain thickness better than the 32 μm human control “(page 12, para 4). Applicant compare date presented in Table 1 with Example 8 of Matsusaki and state that “While Matsusaki et al. likely experienced significant thickness reduction due to "contraction" (compaction), which is common in general 3D tissue engineering, our invention demonstrates that the thickness is almost entirely maintained from the start of culture up to day. Therefore, even if one were motivated to replace the cells with MEFs and mouse endothelial cells based on the disclosure of Matsusaki et al., the effect of maintaining tissue thickness to this degree is entirely unexpected and could not have been predicted by a person skilled in the art.” (page 13, para 2). Applicant point to declaration of Morimura that also identifies the same comparison as above. Applicant allege that the results presented are surprising because “the prior art does not reach the specific problem of mouse cell contraction, nor the critical content ratio required to overcome it.” (page 13-14 bridge para).
In response, to applicant's argument that claimed invention maintains thickness, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). See MPEP 2145 (II)
Contrary to Applicant argument, if one were motivated to replace the cells with MEFs and mouse endothelial cells based on the disclosure of Matsusaki et al., the effect of maintaining tissue thickness to this degree would naturally arise. As noted in the rejection, an ordinary artisan would be motivated to use Matsusaki’s method to make a mouse three-dimensional cell structure because mouse-derived cells are easier to acquire and routinely used in cell culture.
Critically, as noted in the response to the declaration, an ordinary artisan would recognize that a construct comprising cells from one species or one cell type, would not have the same properties, including properties of compression, when compared to cells from other species or comprising other cell types.
Finally, although, it is obvious to include specific cells types in a tissue constructs, especially cell types already taught by Matsusaki, there is no evidence that the reduced compression is applicable to all mouse stromal cells.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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