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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/16/2025 has been entered.
Status of the Claims
Claims 1-2, 12, 26, 30, 39, and 41-42 are pending.
Claim 1, 26, 30, and 39 are newly amended.
Claims 1-2, 12, 26, 30, 39, and 41-42 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of pending claims 1-2, 12, 26, 30, 39, and 41-42 under 35 U.S.C. 103 as being unpatentable over Hasan et al. (Biomed Microdevices, 2015, previously cited) in view of Vulto et al. (WO2014038943, 2014) and Heiden (Genetic Engineering and Biotechnology News 2015, previously cited) as evidenced by Mozafari et al. (Nanotechnol, 2019, previously cited) as discussed in the Office Acton on 08/19/2025, is withdrawn in order to address the claims as newly amended.
Information Disclosure Statement
In regards to the IDS on 12/16/2025, the reference to Zhang et al. (2005) has not been considered because only an unreadable untranslated copy of the reference has been provided.
Claim Interpretation
Claim 1 as amended requires that mesenchymal cells are introduced into a microfluidic channel by an “aqueous medium.”
It is noted that the claim was previously limited introducing the mesenchymal cells with an “aqueous medium” or “gel precursor.”
As acknowledged by Applicant (see Remarks on 12/16/2025, p7), there is no definition given for “aqueous medium”. It is also noted that the specification does not explicitly define “gel precursor” as well.
While Applicant argues that a foundational principle of claim interpretation is that terms are given the meaning and scope with which they are used in the specification (citing In re Suitco Surface, Inc., 603 F.3d 1255, 1260 (Fed. Cir. 2010)), according to MPEP 2111, an examiner must construe claim terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim.
Additionally, the meaning given to a claim term must be consistent with the ordinary and customary meaning of the term (unless the term has been given a special definition in the specification), and must be consistent with the use of the claim term in the specification and drawings. Further, the broadest reasonable interpretation of the claims must be consistent with the interpretation that those skilled in the art would reach. In re Cortright, 165 F.3d 1353, 1359, 49 USPQ2d 1464, 1468 (Fed. Cir. 1999).
Turning to the art, as evidenced by Biology Online (retrieved from internet 03/24/2026), an aqueous solution (medium, it is noted that the terms “medium” and “solution” have been considered synonymous) is a solution wherein water is the dissolving medium or solvent. Thus, as understood in the art, an aqueous medium is simply a medium that comprises water.
In regards to a “gel precursor”, as evidenced by Moeinzadeh et al. (Eur Polym J, 2015), gels form when macromonomers are added to explicitly “aqueous solutions” (Fig. 1). This is agreed upon by Tajima et al. (Regenerative Therapy, 2017, previously cited), who evidences that hydrogels are formed by dissolving gelatin (a macromolecule) in an “aqueous solution” (Preparation of gelatin hydrogel microspheres, p35).
Therefore, as understood in the art, a “gel precursor” is an aqueous medium that comprises a macromolecule and which can form a gel. Thus, as understood in the art, an “aqueous medium” represents a genus, while a “gel precursor” is a species of aqueous media.
Turning to the specification, as discussed above, the specification does not define either these terms specifically.
While Applicant argues that the specification distinguishes between an “aqueous medium” and a “gel precursor” (see Remarks on 12/16/2025, p7), the specification does not explicitly distinguish between an “aqueous medium” and a “gel precursor”. Additionally, while paragraph [0089] states, “the mesenchymal cells are introduced in the microfluidic channel network, either using an aqueous medium, preferably a growth medium, or by using the gel (precursor), this only suggests that an aqueous medium may be an aqueous medium that does not have a gel precursor (e.g., a growth medium that does not comprise an ECM molecule, but does not necessarily suggest that a gel precursor is not a type of aqueous medium or that an aqueous medium may not comprise a macromolecule (such as collagen) that allows the aqueous medium to gel.
Indeed, adopting a contrary definition would contract how the terms are used in the art because as above, the art explicitly states that a cell culture gel (e.g., a hydrogel) is an “aqueous solution” comprising a macromolecule that causes the solution (medium) to gel.
Thus, giving the terms “aqueous medium” and “gel precursor” their broadest reasonable interpretation in view of the specification and the art, the term “aqueous medium” has been interpreted as any medium that comprises water, while the term “gel precursor” has been interpreted as an aqueous medium that comprises a macromolecule that allows the aqueous medium to gel.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-2, 12, 26, 30, 39, and 41-42 under 35 U.S.C. 103 as being unpatentable over Hasan et al. (Biomed Microdevices, 2015, previously cited) in view of Vulto et al. (WO2014038943, 2014) and Heiden (Genetic Engineering and Biotechnology News 2015, previously cited) as evidenced by Liu et al. (Applied Materials and Interfaces, 2012), McRae et al. (Tissue Barriers, 2018), and Mozafari et al. (Nanotechnol, 2019, previously cited).
In regards to claims 1 and 26, Hasan teaches a method for making a multilayered blood vessel like structure comprising endothelial cells (HUVECs) in a microfluidic cell channel cell culture system (Title, Abstract, p1; Fig. 1, p4). As noted in the specification, an endothelium can be a simple epithelium (paragraph [0100]), and gives HUVECs as a specific example (Example, 3, paragraph [0211]).
Hasan teaches vascular construct that can be used in numerous applications including drug screening, development of in vitro models for cardiovascular diseases or cancer metastasis, and the study of vascular biology mechanobiology (Abstract, p1), which a person of ordinary skill in the art would have recognized requires culturing and monitoring the epithelial cells as taught by Hasan.
Hasan does not explicitly teach that the system comprises a plurality of microfluidic channel networks.
However, according to MPEP 2144(VI)(B) it is prima facie obvious to duplicate parts. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a "web" which lies in the joint, and a plurality of "ribs" projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced).
Furthermore, Vulto teaches a microfluidic device comprising complex pluralities of microfluidic channel networks (p14, lines 19-22; p16, lines 36-37 to p17, lines 1-3; Figs. 18, 19, 21, 23, and 26).
A person of ordinary skill in the art would have been motivated to use a device with multiple channels because Vulto teaches that these multichannel devices are particularly useful for patterning two gels containing cells that are meant or expected to interact with one another (p12, lines 23-36) and allows for selective filling of lanes (channels) under stable pinning conditions with other lanes (channels) being usable for transporting nutrients, metabolites, or reagents (p17, lines 4-8).
Furthermore, because Vulto teaches that a microfluid device for contacting multiple layers of cells (p14, lines 19-22; p16, lines 36-37 to p17, lines 1-3; Figs. 18, 19, 21, 23, and 26), because Heiden teaches that the commercial products Organoplates (the commercial name for the microfluidic devices as taught by Vulto) can create tubular cellular structures (Fig. 3rd page); and because Hasan and Vulto are in the same technical field of using microfluidic devices for culturing cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to step a), Hasan teaches that fibroblasts or smooth muscle cells (both of which are different types of mesenchymal cells (see instant specification, paragraph [0070])) in GelMA (a water-based medium, and therefore, an “aqueous medium” as defined above) are introduced into a microfluidic channel which comprises an inlet and outlet (Fig. 1, p4; Fabrication of PDMS microfluidic device, p3).
In regards to step b), Hasan teaches that the mesenchymal cells form a tubular structure which formed a tri-layer blood vessel-like structure with fibroblast cells in the outer layer and smooth muscle cells in the middle layer (Fig. 1, p4; p5, Fabrication of blood vessel-like structures with multilayered vessel walls using concentric needles in GelMA hydrogel, p5), and thus a biological surface.
Hasan also teaches that cells proliferate within the construct (p2, right column). Moreover, as evidenced by Liu smooth muscle cells proliferate in GelMA (Figure 4, p1381).
In regards to step c), Hasan teaches that HUVECs (the epithelial cells) are introduced in cell culture media (an aqueous solution) into the microfluidic channel network comprising the mesenchymal cells (Fig. 1, p4; Fabrication of blood vessel-like structures with multilayered vessel walls using concentric needles in GelMA hydrogel, p5).
In regards to step d), Hasan teaches that the epithelial cells formed a tubular structure in the microfluidic channel network such that a tubular structure of epithelial cells formed with inside the tubular structure that is formed by and in cell-to-cell contact with the mesenchymal cells (a biological surface (p2, column 2, top paragraph; Fig. 1, p4).
As discussed above, Hasan also teaches that cells proliferate within the construct (p2, right column). Additionally, it is noted that Hasan uses Endothelial basal medium-2 and endothelial growth bullet supplement (Materials and reagents, p88), both of which are well-known in the art to support endothelial cell proliferation.
Continuing, Hasan teaches that the vascular structure comprises an inner epithelial layer with a hollow channel which allows for perfusion (3.1 Fabrication of Tri-layered vascular structure using GelMA hydrogel in microfluidic device, p88; Fig. 1, p4; Fig. 2, p88), and thus has a perfusable lumen.
In regards to the formation of tight junctions, Applicant should note that this is a property of epithelial cells cultured by the methods as in claim 1, not an active method step. As evidenced by McRae, HUVECs (the epithelial cells) have the property of forming tight junctions in vitro (Introduction, p3). Therefore, the tubular structure of epithelial cells as taught by Hasan would form an epithelial barrier characterized by tight junctions, absent evidence to the contrary.
In regards to claim 2, in regards to a “capillary pressure barrier”, the instant specification states, “The capillary pressure barriers are not to be understood as a wall or a cavity which is filled with the gel precursor, but consists of elements which make sure that the gel precursor due to the surface tension does not spread open. This concept is referred to as meniscus pinning.” (paragraph [0084]). As the pressure barriers as taught by Hasan are created with a series of capillary needles (Fig. 1, p4), they are not capillary pressure barriers as defined in the specification.
However, the multichannel microfluidic device, as taught by Vulto as discussed above, comprises capillary pressure barriers and the gel is patterned by the pressure capillary barrier (claim 1, p11, lines 22-32).
A person of ordinary skill in the art would have been motivated to use a microfluidic channel network comprising microfluidic channels with capillary pressure barriers or pattern gels with a capillary pressure barrier because Vulto teaches that capillary pressure barriers are particularly useful for controlling the flow liquids to in order to establish shapes and patterns in microfluidic chambers (p1, lines 4-15; p4, lines 10-30) and because stable pinning structures (created by capillary pressure barriers) are of utmost important for shaping the boundary of a liquid (p3, lines 26-33).
Furthermore, because Vulto teaches that microfluidic devices can comprise capillary pressure barriers and gel patterned by these pressure capillary barrier (claim 1, p11, lines 22-32); because Vulto teaches that stable capillary pressure barriers arise in the filling and emptying of complex networks of channels and chambers (p14, lines 19-22); because Vulto teaches that microfluidic devices comprising pressure capillary barriers can be used for contacting multiple layers of cells (p14, lines 19-22; p16, lines 36-37 to p17, lines 1-3; Figs. 18, 19, 21, 23, and 26); and because Hasan and Vulto are in the same technical field of using microfluidic devices for culturing cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 12 and 39, Hasan teaches at least a unidirectional flow of growth medium along the epithelial or mesenchymal cells (Fig. 1, p4).
In regards to claims 30, as taught by Hasan, the capillaries where incubated (contacted) with calcein AM (Live-dead staining for cell viability in vessel wall, p5), which is a test compound.
In regards to claim 41, Hasan teaches that endothelial cells form a tunica intima layer while smooth muscle cells form a tunica media (Fig. 1, p4). As evidenced by Mozafari, the intima layer is predominantly populated with endothelial cells, which synthesize proteins, such as collagen IV and laminin, to create a basal lamina (Arterial constituents, p52). Therefore, there is an intermediate basal lamina equivalent between the epithelial cells and mesenchymal cells of Hasan, absent evidence to the contrary.
In regards to claim 42, while Hasan utilizes a rigid structure to initially pattern cells (Fig. 1, p4, glass needles), Hasan teaches that these structures are removed (Fig. 1,p 4). Furthermore, while Hasan teaches that the physical fabrication of the vascular structure takes minutes, Hasan that the formation of a vascular endothelial cell layer inside the vessels takes 3–5 days (Abstract, p1). Indeed, as evidenced by Liu, proliferation takes days (Figure 4, 1381). Taken together, this suggests that proliferation is performed in the absence of a rigid structure.
Therefore, the combined teachings of Hasan, Vulto, and Heiden renders the invention unpatentable as claimed.
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 1-2, 12, 26, 30, 39, and 41-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6-8, 10-11, 13-16, 18-19, 21, and 47 of copending Application No. 18/568,418 in view of Hasan et al. (Biomed Microdevices, 2015, previously cited).
While claims 1-4, 12, 26, 30, 39, 41-45, and 47 are not identical to claims 1-2, 4, 6-8, 10-11, 13-16, 18-19, 21, and 47 of copending Application No. 18/568,418 they are not patentably distinct because the claims of both inventions are drawn to methods for creating lumenized (tubular) structures in pluralities of perusable microfluidic channel networks comprising introducing mesenchymal cells and epithelial cells into the microfluidic channels in aqueous media (hydrogels are a type of aqueous media as discussed above). It is noted that an arrangement of mesenchymal cells and epithelial cells would result in cell-to-cell contact arrangement as demonstrated by Hasan as above (see Fig. 1c, p4).
While copending Application No. 18/568,418 is silent on whether the microfluid device comprises an inlet and outlet, a person of ordinary skill in the art would have recognized that since Application No. 18/568,418 is drawn to a microfluidic device that utilizes the flow of solutions through the microfluidic networks that it would suggest an inlet and outlet.
In regards to the formation of tight junctions, as evidenced by McRae, HUVECs (a type of epithelial cell as defined above (see also claim 15 of copending Application No. 18/568,418) form tight junctions (Introduction, p3), and therefore, the tubular structure of epithelial cells of copending Application No. 18/568,418 would be expected to have this property.
In regards to claims 2, 12, 26, 30, 39, and 41-42, as taught by Hasan in depth above, these are all known embodiments for perfusable lumenized models as discussed in depth above.
This is a provisional non-statutory double patenting rejection.
Response to Arguments
Applicant argues that the claimed method is a mold-free process unlike Hasan (Remarks, p6).
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a mold-free process) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The claims as amended only require that the mesenchymal cells form a “biological surface.” However, this this does not suggest that a mold is disallowed. Indeed, a tube of mesenchymal cells, formed with a mold is still a “biological surface.”
Applicant argues that the claims as amended require a non-obvious functional results, specifically that the formation of a tubular structure has a perfusable lumen and forms an epithelial barrier characterized by tight junctions (Remarks, p7).
Applicant argues that the Examiner's combination provides no reasonable expectation of achieving this complex functional outcome and that the prior art does not suggest that the cells would self-organize into a coherent, perfusable monolayer tubule (referring to the epithelial layer) that functions as a barrier (Remarks, p7).
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
In regards to the claimed results, as discussed above, in regards to a perfusable lumen, this feature is explicitly taught by Hasan as discussed above (3.1 Fabrication of Tri-layered vascular structure using GelMA hydrogel in microfluidic device, p88; Fig. 1, p4; Fig. 2, p88).
In regards to a monolayer, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a monolayer) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In regards to epithelial barrier characterized by tight junctions, this is a property of epithelial cells when cultured as discussed above. As above, as evidenced by McRae, HUVECs (the epithelial cells) form tight junctions in vitro (Introduction, p3), and therefore, the tubular structure of epithelial cells as taught by Hasan would form an epithelial barrier characterized by tight junctions, absent evidence to the contrary.
Applicant argues that a person of ordinary skilled in the art would have realize that the devices disclosed in the reference of Vulto et al. (WO2014/038943A1) is not suitable for the introduction of artificial molds using Hasan's molding technique.
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
It is noted that regardless of the suitability of adapting the introduction of artificial molds using Hasan's molding technique, as argued by Applicant, according to MPEP 2144(VI)(B) it is prima facie obvious to duplicate parts. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a "web" which lies in the joint, and a plurality of "ribs" projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced).
In regards to Vulto, as discussed above, a person of ordinary skill in the art would have been motivated to use a device with multiple channels because Vulto teaches that these multichannel devices are particularly useful for patterning two gels containing cells that are meant or expected to interact with one another (p12, lines 23-36) and allows for selective filling of lanes (channels) under stable pinning conditions with other lanes (channels) being usable for transporting nutrients, metabolites, or reagents (p17, lines 4-8).
Furthermore, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In particular, because, as above, Vulto teaches that a microfluid device for contacting multiple layers of cells (p14, lines 19-22; p16, lines 36-37 to p17, lines 1-3; Figs. 18, 19, 21, 23, and 26), because Heiden teaches that the commercial products Organoplates (the commercial name for the microfluidic devices as taught by Vulto) can create tubular cellular structures (Fig. 3rd page); and because Hasan and Vulto are in the same technical field of using microfluidic devices for culturing cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to introduction of artificial molds using Hasan's molding technique specifically, it is noted that this is beyond the scope of the claims as the claims broadly allow for Hasan’s molding technique within its scope. Furthermore, as all of Hasan, Vulto, and Heiden teach the use of microfluidic devices it is unclear how Hasan’s molding techniques would not be suitable in the molds as taught by Vulto and Heiden beyond Applicant’s assertions.
Applicant argues that the claims as amended require direct cell-to-cell contact (Remarks, p7). Applicant argues that this is fundamentally different from Hasan’s concentric, physically separated layers (Remarks, p7). Continuing, Applicant argues that the claimed direct interaction at a planar interface is critical for the biological function and is not taught by the prior art (Remarks, p7).
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
As discussed above, as demonstrated in Fig. 1(c) of Hasan, the epithelial cells (endothelial cells, tunica intima) are in direct contact with the mesenchymal cells (smooth muscle cells, tunica media). Thus, these cells are in direct cell-to-cell contact.
Applicant argues that the prior art does not teach introducing mesenchymal cells using an aqueous medium (Remarks, p7-8). Applicant argues that while the Examiner has previously concluded that an "aqueous medium" and a "gel or gel precursor" are not necessarily discrete entities, but rather represent a genus/species relationship, Applicant disagrees with this interpretation (Remarks, p7).
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
As discussed above, Hasan teaches that fibroblasts or smooth muscle cells (both of which are different types of mesenchymal cells (see instant specification, paragraph [0070])) in GelMA (a cell culture medium comprising water and therefore an aqueous medium as defined above) are introduced into a microfluidic channel which comprises an inlet and outlet (Fig. 1, p4; Fabrication of PDMS microfluidic device, p3).
Specifically, Applicant argues that this interpretation is inconsistent with the plain language and consistent teachings of the specification (Remarks, p7; citing In re Suitco Surface, Inc., 603 F.3d 1255, 1260 (Fed. Cir. 2010).
Applicant argues that although it is correct that there is no "definition" given for an "aqueous medium", the specification as a whole consistently and unambiguously treats "aqueous medium" and "gel precursor" as two distinct and alternative materials with different physical properties and functions (Remarks, p7).
Specifically, Applicant argues that the method as originally described and claimed presented these as clear alternatives (i.e., "a1) using an aqueous medium; or a2) using a gel precursor and allowing the gel precursor to gelate . . .”, citing paragraph [0051]) (Remarks, p8).
Applicant argues that the use of the disjunctive "or" to separate two distinct, detailed steps demonstrates the Applicant's clear intent that these are alternative, not interchangeable, methods (Remarks, p8). Applicant argues that if they were the same, reciting them as separate alternatives would be redundant and illogical (Remarks, p8).
Continuing, Applicant argues that the Examiner misinterprets paragraph [0089], and that while the Examiner correctly notes this paragraph uses the word "or," the full phrase is "either using an aqueous medium or by using the gel (precursor). Thus, Applicant argues that the "either/or" construction serves to emphasize a choice between two distinct options (Remarks, p8).
Applicant argues that an "aqueous medium" is described in the specification as a fluid carrier like "cell culture medium" (paragraph [0073]), which is intended to remain liquid, while in contrast, a "gel precursor" is defined by its explicit function to gelate (solidify) (paragraph [0075]) and become a "cross-linked system" (paragraph [0122]) (Remarks, p8).
Applicant argues that a person of ordinary skill in the art would immediately recognize the fundamental difference between a fluid medium designed for nutrient transport and a polymer solution designed to form a solid scaffold (Remarks, p8).
Therefore, Applicant argues that the Examiner's conclusion that an aqueous medium is a species of a gel precursor is contradicted by the specification (Remarks, p8).
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
As discussed above, as acknowledged by Applicant (see Remarks on 12/16/2025, p7), there is no definition given for “aqueous medium”. It is also noted that the specification does not explicitly define “gel precursor” as well.
While Applicant argues that a foundational principle of claim interpretation is that terms are given the meaning and scope with which they are used in the specification (citing In re Suitco Surface, Inc., 603 F.3d 1255, 1260 (Fed. Cir. 2010)), according to MPEP 2111, an examiner must construe claim terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim.
Additionally, the meaning given to a claim term must be consistent with the ordinary and customary meaning of the term (unless the term has been given a special definition in the specification), and must be consistent with the use of the claim term in the specification and drawings. Further, the broadest reasonable interpretation of the claims must be consistent with the interpretation that those skilled in the art would reach. In re Cortright, 165 F.3d 1353, 1359, 49 USPQ2d 1464, 1468 (Fed. Cir. 1999).
Turning to the art, as evidenced by Biology Online (retrieved from internet 03/23/2026), an aqueous solution (medium, it is noted that the terms “medium” and “solution” have been considered synonymous) is a solution wherein water is the dissolving medium or solvent. Thus, as understood in the art, an aqueous medium is simply a medium that comprises water.
In regards to a “gel precursor”, as evidenced by Moeinzadeh et al. (Eur Polym J, 2015), gels form when macromonomers are added to explicitly “aqueous solutions” (Fig. 1). This is agreed upon by Tajima et al. (Regenerative Therapy, 2017, previously cited), who evidences that hydrogels are formed by dissolving gelatin (a macromolecule) in an “aqueous solution” (Preparation of gelatin hydrogel microspheres, p35).
Therefore, as understood in the art, a “gel precursor” is an aqueous medium that comprises a macromolecule and which can form a gel. Thus, as understood in the art, an “aqueous medium” represents a genus, while a “gel precursor” is a species of aqueous media.
Turning to the specification, as discussed above, the specification does not define either these terms specifically.
While Applicant argues that the specification distinguishes between an “aqueous medium” and a “gel precursor” (see Remarks on 12/16/2025, p7), the specification does not explicitly distinguish between an “aqueous medium” and a “gel precursor”. Additionally, while paragraph [0089] states, “the mesenchymal cells are introduced in the microfluidic channel network, either using an aqueous medium, preferably a growth medium, or by using the gel (precursor), this only suggests that an aqueous medium may be an aqueous medium that does not have a gel precursor (e.g., a growth medium that does not comprise an ECM molecule, but does not necessarily suggest that a gel precursor is not a type of aqueous medium or that an aqueous medium may not comprise a macromolecule (such as collagen) that allows the aqueous medium to gel.
Indeed, adopting a contrary definition would contract how the terms are used in the art because as above, the art explicitly states that a cell culture gel (e.g., a hydrogel) is an “aqueous solution” comprising a macromolecule that causes the solution (medium) to gel.
Thus, giving the terms “aqueous medium” and “gel precursor” their broadest reasonable interpretation in view of the specification and the art, the term “aqueous medium” has been interpreted as any medium that comprises water, while the term “gel precursor” has been interpreted as an aqueous medium that comprises a macromolecule that allows the aqueous medium to gel.
In regards to Applicant’s argument that the disjunctive "or" to separate two distinct options, again as above, a person of ordinary skill in the art would have recognized that the phrase can refer to either the genus (aqueous medium) or a specific species (a gel precursor).
Moreover, a person of ordinary skill in the art would have recognized that the phrase could also refer to combining multiple aqueous media – for example, aqueous media with different gel precursors or aqueous media without a gel precursor and a different aqueous media with a gel precursor.
Furthermore, in regards to Applicant’s references to gelation, cross-linking, a fluid medium designed for nutrient transport, and a polymer solution designed to form a solid scaffold, as discussed above, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, these are not definitions, and as freely admitted by Applicant, as discussed above, the specification does not define the terms “aqueous medium” or “gel precursor”.
Finally, it is not stated that an “aqueous medium is a species of a gel precursor” as argued by Applicant, but rather that a gel precursor is a species of aqueous medium.
Applicant argues that the claims as amended are patentably distinct from 1-2, 4, 6-8, 10-11, 13-16, 18-19, 21, and 47 of copending Application No. 18/568,418 (Remarks, p9).
Applicant’s arguments filed 12/16/2025 have been fully considered but are not found persuasive.
As discussed above, while claims 1-4, 12, 26, 30, 39, 41-45, and 47 are not identical to claims 1-2, 4, 6-8, 10-11, 13-16, 18-19, 21, and 47 of copending Application No. 18/568,418 they are not patentably distinct because the claims of both inventions are drawn to method for creating lumenized (tubular) structures in pluralities of perusable microfluidic channel networks comprising introducing mesenchymal cells and epithelial cells into the microfluidic channels in aqueous media (hydrogels are a type of aqueous media). It is noted that an arrangement of mesenchymal cells and epithelial cells would result in a cell-to-cell contact arrangement.
While copending Application No. 18/568,418 does not explicitly teach that microfluid device comprise an inlet and outlet, a person of ordinary skill in the art would have recognized that since Application No. 18/568,418 is drawn to a microfluidic device that utilizes the flow of solutions through the microfluidic networks that it would suggest an inlet and outlet.
Additionally, as evidenced by McRae, HUVECs (a type of epithelial cell as defined above (see also claim 15 of copending Application No. 18/568,418) form tight junctions (Introduction, p3), and therefore, the tubular structure of epithelial cells of copending Application No. 18/568,418 would be expected to have this property.
In regards to claims 2, 12, 26, 30, 39, and 41-42, as taught by Hasan in depth above, these are all known embodiments for perfusable lumenized models as discussed above.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631