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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-10, in the reply filed on 10/28/2025 is acknowledged. The traversal is on the following ground(s):
1. Applicant allege that “The Office has asserted that Groups I - II are not related. However, Groups I-II are related as the product and the method of its production and include the same product elements.” (page 7, para 1)
This is not found persuasive because the office did not assert that Groups I - II are not related. In agreement with the Applicant, the restriction requirement dated 10/2/2026 identified “Inventions I and II are related as process of making and product made.” on page 2.
2. Applicant allege that “the Examiner has not provided indication that the content of the claims interpreted in light of the description was considered in making the assertion of different inventions and therefore has not met the burden necessary to support the assertion” (page 7, para 2).
This is not found persuasive because “lack of indication” does not imply lack of consideration. Applicant do not identify what specific description provided in the specification would result in a different relationship between Groups I and II, which were identified as related as process of making and product made. According to MPEP 803, the necessary burden to support a requirement for restriction are (A) The inventions must be independent (see MPEP § 802.01, § 806.06, § 808.01) or distinct as claimed (see MPEP § 806.05 - § 806.05(j)); and (B) There would be a serious search and/or examination burden on the examiner if restriction is not required (see MPEP § 803.02, § 808, and § 808.02). To show distinction between a product and process of making, the requirement is set forth in MPEP 806.05(f). This was applied to show distinction between Groups I and II (see page 2 of restriction requirement dated 10/2/2026). The rationale for serious search and/or examination burden was provided on page 2-3, bridging para of restriction requirement dated 10/2/2026.
3. Applicant allege that “a search of all the claims would not impose a serious burden on the Office” because “the International Searching Authority searched all of the claims together” (page 7, para 5). Applicant point to MPEP 806.03 that states “Where the claims of an application define the same essential characteristics of a single disclosed embodiment of an invention, restriction there between should never be required. This is because the claims are not directed to distinct inventions; rather they are different definitions of the same disclosed subject matter, varying in breadth or scope of definition”. Applicant conclude that “Applicants respectfully submit that the Office has not considered the relationship of the inventions of Groups I - II with respect to MPEP §806.03. Therefore, the burden necessary to sustain the conclusion that the groups are different has not been met” (page 7, last para).
This is not found persuasive because the instant restriction requirement is based on US practice and not based on Unity of Invention practice under the PCT. The necessary burden to support a requirement for restriction under US practice was met in the restriction requirement dated 10/2/2026. Considering if the International Searching Authority did or did not identify Unity or lack thereof in the claims is not one of the requirement for restriction under US practice.
Regarding MPEP 806.03, it must be noted that this guidance is specific to “single disclosed embodiments” wherein the claims are merely varying in the “breadth or scope” of that embodiment. Instant claims are not alternative or different versions of a same embodiment. Method claims and product claims are separate embodiments and even the specification identifies them as distinct; disclosing the various embodiments for the methods on pages 3-13 and disclosing the various embodiments for the product on pages 14-15.
Taken together, the relationship of the inventions of Groups I - II with respect to MPEP §806.03 and, more relevant to the instant case, with respect to 806.05(f) was considered. Furthermore, as noted above the necessary burden to support a requirement for restriction under US practice was met in the restriction requirement dated 10/2/2026.
The requirement is still deemed proper and is therefore made FINAL.
Claims status
Claims 14-17 is/are newly added. Claims 1-17 is/are currently pending with claims 11-13 and new claims that depend from claim 11 i.e. claims 15 and 17 is/are withdrawn. Claims 1-10, 14, 16 is/are under examination.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Japan on 08/21/2020. It is noted, however, that applicant has not filed a certified copy of the JP2020-140134 application as required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Drawings
The drawings are objected to because Figures 1, 3 and 4 are of extremely poor quality such that they cannot be evaluated. Figure 3 is disclosed as showing anti-CD31 staining for endothelial cells but it is not clear what is being shown, a dark CD31 stain seems apparent in cultures with 0% endothelial cells on day 5. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
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 1-10, 14, 16 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 1 recites “a cell population comprising a plurality of endothelial cells and a plurality of mouse-derived stromal cells, which exclude mouse-derived endothelial cells”. The use of the comma between the phrase “a cell population comprising a plurality of endothelial cells and a plurality of mouse-derived stromal cells” and “which exclude mouse-derived endothelial cells” results in an indefiniteness issue with this claim. It is unclear if the mouse-derived endothelial cells are excluded from the entire cell population or if the claim merely requires that the stromal cells used in the instant method are not mouse-derived endothelial cells. This is further unclear because claim 16 requires the cells constituting the three-dimensional (3D) cell structure to be syngeneic i.e. the claim requires the endothelial cells and the mouse-derived stromal cells to be syngeneic. Thus, claim 16 does not appear to exclude mouse-derived endothelial cells from the entire cell population of claim 1. Additionally, the only example in the specification wherein a 3D cell structure comprising endothelial cells and the mouse-derived stromal cells was made, used mouse-derived endothelial cells along with mouse-derived fibroblasts as the mouse-derived stromal cells (Example 1). For the purpose of compact prosecution, claim 1 is interpreted “a cell population comprising a plurality of endothelial cells and a plurality of mouse-derived stromal cells, wherein the mouse-derived stromal cells are not mouse-derived endothelial cells”.
Claim 9 recites “a ratio […] is from 1.0% to 50%”. Claims 14 recites “a ratio […] is from 1.5% to 10%”. Percent is not a unit for ratio. The ratio of endothelial to stromal cells is indefinite because the ratio between these cell types cannot be expressed in %. For the purpose of compact prosecution, claim 9 is interpreted as “wherein of the stromal cells in the cell population
Claim 2-10, 14, 16 is/are rejected due their dependence on claim 1 because they do not clarify the 112b issue noted with claim 1.
Claim Rejections - 35 USC § 112(d)
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.
Claim 3 is rejected 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.
Claim 3 depends from claim 1 which already requires that the preparing, the collecting and the culturing steps be performed thus requiring that each of these steps be performed at least once. Thus, in reciting a limitation that is inherent to claim 1, claim 3 fails to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
IMPROPER MARKUSH
Claim 6 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
The Markush grouping of glycosaminoglycan, dextran sulfate, rhamnan sulfate, fucoidan, carrageenan, polystyrene sulfonic acid, polyacrylamide-2- methylpropanesulfonic acid, and polyacrylic acid is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The alternatives are identified as “polyelectrolytes” that could be used in a method for cell culture. The specification broadly defines “The term “polyelectrolyte” as used in the present specification refers to a polymer with a dissociable functional group in the polymer chain” (page 10). No specific function for polyelectrolytes in the claimed cell culture method is identified. Thus, using the broad definition provided in the specification each of the alternatives recited in claim 6 are polyelectrolytes. Nevertheless, this grouping is improper because “polyelectrolyte” is not a recognized physical or chemical class. Furthermore, “polyelectrolyte” is not a class recognized in the field of cell biology or cell culture such that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. To this end, alternatives recited in claim 6, each a “polyelectrolyte”, are not expected to behave in the same way in the context of the claimed cell culture method. For example, although glycosaminoglycan such as heparin have been used in cell culture methods for a long time due to the specific properties of heparin, the other alternatives listed do not share the same properties or use.
Ling et al (Gene 576 (2016) 292–303) describes the unique properties of Heparin stating “Heparin, a highly sulfated heparan glycosaminoglycan variant produced and stored primarily by mast cells (Ronnberg and Pejler, 2012), possesses the highest net negative charge density of all known biological molecules (Alter et al., 1987). Its negative charge binds to positively charged, heparin-binding domains (HBDs) present in a large number of extracellular proteins. This group of proteins includes fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), bone morphogenetic proteins (BMPs) and large extracellular structural molecules such as fibronectin and laminin” and “Heparin's high affinity for protein has resulted in its application in cell culture to enhance the desirable activity of critical extracellular biomolecules used as supplements for the expansion of human stem cells. For example, heparin has been reported to promote both Wnt and FGF signaling in human embryonic stem cells (hESCs), thereby increasing their proliferation (Furue et al., 2008; Sasaki et al., 2008). Similarly, heparin has been shown to enhance Wnt-induced differentiation signals in osteogenic cells (Ling et al., 2010a), further highlighting its diverse effects. Tissue culture surfaces coated with glycosaminoglycans such as heparin support greater proliferation of MSCs (Uygun et al., 2009; Ratanavaraporn and Tabata, 2012). Heparin-functionalized hydrogels and heparinized nanoparticles have also been developed to support the viability and differentiation of hMSCs (Na et al., 2007; Benoit et al., 2007).” (Introduction, para 1, 2).
In comparison to heparin, other alternatives listed in claim 6 appear to be primarily used as “macromolecular crowding agents (MMC agents)” in post-filing art. Du et al (International Journal of Biological Macromolecules 251 (2023) 126353) identifies “dextran sulphate [19], seaweed polysaccharides, such as carrageenan (CR), fucoidan, galactofucan and ulvan [20]) and non-sulphated (e.g. hyaluronic acid [21,22]) polysaccharides as well as synthetic macromolecules (e.g. Ficoll™ [23,24], polyvinylpyrrolidone [25], polysodium-4-styrene sulfonate [26]) have been assessed as MMC agents” (Introduction, para 3). Regarding the function of MMC agents, Du teaches that these agents are used for “Steric hindrance and electrostatic repulsion” “to obstruct molecular motion/diffusion and, as a result, significantly modulates biochemical, biophysical and biological equilibria and processes [13–16]. In eukaryotic cell culture, MMC has been shown to accelerate the enzymatic processing of collagen, resulting in enhanced collagen-associated ECM deposition [17,18]. (Introduction, para 2).
Taken together, based on teachings from at least Ling and Du, it can be concluded that the alternatives recited do not have a common function in cell culture.
Furthermore, the alternatives recited in claim 6 do not share a structural similarity such that a common use is expected to flow from such a similarity.
The examples in the specification use heparin in the cell culture methods (Example 1 and 2). The specification does not provide any evidence that the alternatives claimed are functionally equivalent and have a common use.
Thus, the group, as a whole, does not share a substantial structural feature and a common use that flows from the substantial structural feature such that “single structural similarity” could be recognized. Critically, there is an no expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. Thus, the group, as a whole, could not be considered to belong to an art-recognized class that were considered functionally equivalent resulting in a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)
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 1-10, 14, 16 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.
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,
(ii) a generic cationic substance, and
(iii) a generic polyelectrolyte.
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.) 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 provides the following guidance 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.” Thus, the specification envisions only stromal cells present in an epithelial tissue, providing two specific examples: fibroblasts and smooth muscle cells. However, 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). 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.
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”.
Regarding cationic substances, the specification does not provide a specific definition and on page 8, the specification states that “As the cationic substance, any positively charged substance can be used, as long as it does not adversely affect the cell growth and the formation of cell aggregates”. Thus the claim embraces any substance with a positive charge, ranging from positively charged ions to positively charged macromolecules of any type.
As an example of this expansive genus of “cationic substance”, the specification only envisions one broadly recited species of cationic buffers; stating on page 8 “Examples of the cationic substance include, but are not limited to, cationic buffer solutions, such as tris-hydrochloric acid buffer solution, tris-maleic acid buffer solution, bis-tris buffer solution, and HEPES; ethanolamine; diethanolamine; triethanolamine; polyvinylamine; polyallylamine; polylysine, polyhistidine; and polyarginine.” However, neither the specification nor the prior art teach that ethanolamine; diethanolamine; triethanolamine; polyvinylamine; polyallylamine; polylysine, polyhistidine; and polyarginine can function as buffers. Thus, the species provided as examples of cationic buffers are not all buffers. Additionally, buffers perform a specific function in solution and thus cannot represent the expansive genus of “cationic substance” which may or may not act as buffers. The examples are limited to the use tris-hydrochloric acid buffer (Example 1 and 2).
Taken together, the genus of “cationic substances” is expansive while the specification only envisions one broadly recited species (cationic buffers) and reduces to practice one specific species i.e. tris-hydrochloric acid buffer. Even for cationic buffers, by listing species that are not buffers, the specification fails to provide relevant identifying characteristics of the claimed genus such that a skilled artisan could envision the structure and related function of the claimed cationic substances or even cationic buffers. Thus, the written description does not provide adequate support for the broadly claimed genus of “cationic substances”.
Regarding polyelectrolyte, the specification defines “The term “polyelectrolyte” as used in the present specification refers to a polymer with a dissociable functional group in the polymer chain” (page 10). A polymer is defined as a material made up of long chains of repeating structural units (see Definition from Science Direct in PTO-892). Thus, the claim embraces any molecules with a repeat of a structural unit and a “dissociable functional group”. The structure or function of the “dissociable functional group” is not limited and the specification does not provide any guidance regarding the structure or function of the “dissociable functional group”.
As an example of this expansive genus of “polyelectrolyte”, the specification provides a list of alternatives that do not share a common structure or a common function in cell culture (see Improper Markush rejection above regarding the alternatives listed). On page 10, the specification states “Examples of the polyelectrolyte include, but are not limited to, glycosaminoglycans such as heparin, chondroitin sulfate (e.g., chondroitin 4-sulfate and chondroitin 6-sulfate), heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid; dextran sulfate, rhamnan sulfate, fucoidan, carrageenan, polystyrene sulfonic acid, polyacrylamide-2-methylpropanesulfonic acid, polyacrylic acid, and derivatives thereof. These polyelectrolytes may be used singly or in combination of two or more.” A common structure or function for the species provided as examples of polyelectrolyte cannot be identified and the specification provides no guidance regarding what the function of “polyelectrolyte” is in the claimed method. The examples are limited to the heparin, a single species with a specific unique structure that lends to its function and use in cell culture (See teachings from Ling in Improper Markush rejection above; Example 1 and 2).
Taken together, the genus of “polyelectrolytes” is expansive while the specification provides a list of “species” that do not share a structure or function and reduces to practice one specific species i.e. heparin which is distinct from the other species listed. A skilled artisan could not envision the structure and related function of the claimed polyelectrolytes. The specification fails to convey to an artisan that the alternatives listed as “polyelectrolytes” could be used in the claimed method. Thus, the written description does not provide adequate support for the broadly claimed genus of “polyelectrolytes”.
Claim Interpretation
Claim 2 does not recite an active method step for producing a three-dimensional cell structure, instead it recites limitations using “wherein” clauses. See MPEP 2111.04 for interpretation of “wherein” clauses. In the instant case, the “wherein” clause recited does not give meaning or purpose to the active method steps, instead it recites features of the three-dimensional cell structure produced – the feature being that the three-dimensional cell structure produced by the claimed method shrinks after a few days in culture. This feature is recited as a relationship between the maximum widths of a first slice and a second slice prepared from three-dimensional cell structures of claim 1 such that the second slice which is prepared from a three-dimensional cell structure cultured for 5 days is ~50% as thick as the first slice prepared from a three-dimensional cell structure which was cultured for 0-3 days (see page 5 of specification for definition “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”). The examples teach that a three-dimensional cell structure comprising 1.5-20% endothelial cells and fibroblast stromal cells produced by the claimed method each shrink such that a slice produced from the three-dimensional cell structure cultured for 5 days is about 50-80% as thick as a slice prepared from a three-dimensional cell structure cultured for 1 day (Table 1). Thus, the wherein clause of claim 2 is directed to an intended result of the claimed method since it recites an inherent feature of the three-dimensional cell structure produced by the claimed method. Such an inherent feature of the product produced by the claimed method necessarily flows from the active method steps of the claimed method. Thus, prior art(s) that anticipates or renders obvious the instant claim 1, also meets the limitation recited in claim 2.
Regarding claim 3, as noted in the U.S.C. 112d rejection above, the limitation recited in claim 3 is inherent to the method of claim 1. Thus, prior art(s) that anticipates or renders obvious the instant claim 1, also meets the limitation recited in claim 3.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-8, 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).
Regarding claims 1, 2 and 3, in view of 112b issue and claim interpretation noted above, Matsusaki teaches a method for producing a three-dimensional cell structure comprising a step of mixing cells with a cationic substance, an extracellular matrix component, a polymeric electrolyte [0023-0025, 0064-0067, 0068], 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]. Thus, Matsusaki teaches a method for producing a three-dimensional cell structure comprising a step of preparing a mixture of cationic substance, an extracellular matrix component, a polymeric electrolyte, endothelial cells and mouse-derived fibroblast stromal cells. Matsusaki also teaches steps of collecting a cell aggregate from the mixture and culturing the cell aggregate to obtain a three-dimensional cell structure [0024, 0066, 0067].
Regarding claim 4, Matsusaki teaches “the extracellular matrix component is selected from the group consisting of collagen, laminin, fibronectin, vitronectin, elastin, tenascin, entactin, fibrillin, proteoglycan, and a combination thereof.” [0032, 0079]
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 6, Matsusaki teaches “the polymeric electrolyte is selected from the group consisting of glycosaminoglycan, dextran sulfate, rharnnan sulfate, fucoidan, carrageenan, polystyrene sulfonic acid, polyacrylamide-2-methylpropanesulfonic acid, polyacrylic acid, and a combination thereof.” [0031, 0077].
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, 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.
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.
Therefore, Matsusaki anticipates the claimed invention.
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) 9, 14, 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsusaki as applied to claim 1 above, and further in view of Matsusaki.
The teachings of Matsusaki as detailed in the U.S.C. 102 rejection above are relied upon for the instant rejection.
Matsusaki teaches the method of claim 1 wherein Matsusaki teaches that the cells in the method 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].
In examples 7 and 8, Matsusaki teach 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 1-50% endothelial cells, as required in claim 9, or 1.5-10%, as required in claim 14,. 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, as required by claim 16. 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, as required by claim 16, wherein the three-dimensional cell structures comprises 1.5% or 10% endothelial cells, as required in claim 9 and 14.
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
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.
Claims 1-10, 14, 16 are 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.
Claims 1 and 5 of `971 are directed to methods for producing a three-dimensional cellular tissue each comprising a step of mixing stromal cells with a cationic substance, an extracellular matrix component and a polyelectrolyte followed by step wherein a cell aggregate is obtained from the mixture (=claimed collecting step) which is followed by a step of culturing the cell aggregate to obtain a three-dimensional cellular tissue. Claims 1 and 5 of `971 also recite removal of liquid from the mixture, thus inherently reciting a cell mixture in liquid form, as required by instant claim 10.
Claims 2, 7, 9 of `971 each recite a list of extracellular matrix component identical to instant claim 4.
Claims 3, 4, 8, 10 and 11 of `971 each recite a list of polyelectrolytes identical to instant claim 6.
Claims in `971 do not teach mixing the stromal cells with endothelial cells or using mouse-derived cells in their methods for producing a three-dimensional cellular tissue, as required by instant claim 1 and inherent to instant claims 2 and 3. Claims in `971 do not teach the concentration of extracellular matrix component and a polyelectrolyte, as required by instant claims 5 and 7. Claims in `971 do not teach syngeneic cells or vascular endothelial cells or mouse fibroblasts wherein the cell mixture comprises 1-50% or 1.5-10% endothelial cells, as required by instant claims 8, 9, 14, 16.
Matsusaki rectifies each of these deficiencies.
Same as claims in `971, Matsusaki also teaches a methods for producing a three-dimensional cellular tissue using the steps similar to `971 [0023-0025, 0064-0068]. Matsusaki teaches three-dimensional cellular tissue using their method can be produced using 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], as required by claims 1-3, 8. Matsusaki also teaches concentration of extracellular matrix component and a polyelectrolyte, as required by instant claims 5 and 7 [0031, 0032, 0077-0080]. Matsusaki also teaches cell mixture comprises 1-50% or 1.5-10% endothelial cells and wherein cells are syngeneic cells, as required by instant claims 9, 14, 16 (Example 7, 8).
Therefore, based on Matsusaki’s teachings, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of claims of `971 could be modified to comprise endothelial cells in addition to the recited stromal cells and that these cells could be derived from a mouse. Since both `971 and Matsusaki teach a methods for producing a three-dimensional cellular tissue using similar steps, combining the teachings of Matsusaki with `971 would not require inventive ingenuity. Similarly, Since both `971 and Matsusaki teach a methods for producing a three-dimensional cellular tissue using similar steps, an ordinary artisan would reasonably expect that inclusion of endothelial cells and mouse-derived cells in the method of `971 would result in a three-dimensional tissue with endothelial cells and mouse-derived cells.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 8-10, 14, 16 are 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.
Claim 1, 2 of `415 is directed to method for producing a three-dimensional cell structure comprising a step of mixing endothelial cells with a cationic substance, an extracellular matrix component and a polyelectrolyte followed by step collecting a cell aggregate from the mixture which is followed by a step of culturing the cell aggregate. Claim 6 of `415 recites removal of liquid from the mixture, thus inherently reciting a cell mixture in liquid form, as required by instant claim 10.
Claims 3 of `415 recites a list of extracellular matrix component identical to instant claim 4.
Claims 4 of `415 recites a list of polyelectrolytes identical to instant claim 6.
Claims in `415 do not teach mixing the endothelial cells with mouse-derived stromal cells in their methods for producing a three-dimensional cellular tissue, as required by instant claim 1 and inherent to instant claims 2 and 3. Claims in `415 do not teach syngeneic cells or vascular endothelial cells or mouse fibroblasts wherein the cell mixture comprises 1-50% or 1.5-10% endothelial cells, as required by instant claims 8, 9, 14, 16.
Matsusaki rectifies each of these deficiencies.
Same as claims in `415, Matsusaki also teaches a methods for producing a three-dimensional cell structure using the steps similar to `415 [0023-0025, 0064-0068]. Matsusaki teaches three-dimensional cell structure using their method can be produced using 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], as required by claims 1-3, 8. Matsusaki also teaches cell mixture comprises 1-50% or 1.5-10% endothelial cells and wherein cells are syngeneic cells, as required by instant claims 9, 14, 16 (Example 7, 8).
Therefore, based on Matsusaki’s teachings, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of claims of `415 could be modified to comprise mouse-derived stromal fibroblast cells in addition to the recited endothelial cells and that each of these cells could be derived from a mouse such that they are syngeneic. Since both `415 and Matsusaki teach a methods for producing a three-dimensional cellular tissue using similar steps, combining the teachings of Matsusaki with `415 would not require inventive ingenuity. Similarly, Since both `415 and Matsusaki teach a methods for producing a three-dimensional cell structure using similar steps, an ordinary artisan would reasonably expect that inclusion of mouse-derived stromal cells in the method of `415 would result in a three-dimensional cell structure with endothelial cells and mouse-derived stromal cells.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr. 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATASHA DHAR/Examiner, Art Unit 1632