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 without traverse of Species 2 in the reply filed on 22 April 2026 is acknowledged.
Specification
The use of the term “pluronic”, which is a trade name or a mark used in commerce, has been noted in this application. See [0068], [0074], [0097], and [0101]. The term should be accompanied by the generic terminology. Furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities:
In [0032], “the initial structure can include a wax, a plastic, or polyvinyl alcohol, polyethylene glycol diacrylate (PEGDA) having 250 - 35,000 Da” should be replaced with “the initial structure can include a wax, a plastic, polyvinyl alcohol, polyethylene glycol diacrylate (PEGDA) having 250 - 35,000 Da”. The conjunction “or” appears in the middle of the recited list of alternatives rather than only before the final alternative.
This same issue is also present in [0072].
In [0103], “the multilayer coating on the final structure comprises at least two different coating materials” should be replaced with “the multilayer coating on the cast structure comprises at least two different coating materials”. [0103] describes the coatings formed at step S218 of the method S200, which [0102] states are formed on the cast structure prior to casting the second material at step S210. Additionally, as written, [0103] does not provide antecedent basis for claim 20, which recites “the multilayer coating on the cast structure”.
In [0216], “The sample structure 1000b as shown in Figure 10A” should be replaced with “The sample structure 1000a as shown in Figure 10A”. See [0217], which identifies the example structure 1000b as the structure shown in Figure 10B, and see Figure 10A, in which the structure is designated 1000a.
Appropriate correction is required.
Claim Objections
Claims 3, 8, 9, 11, and 15 are objected to because of the following informalities:
In claim 3, “a wax, a plastic, or polyvinyl alcohol, polyethylene glycol diacrylate (PEGDA)” should be replaced with “a wax, a plastic, polyvinyl alcohol, polyethylene glycol diacrylate (PEGDA)”, for consistency with the recited list of alternatives, which concludes with “or any combination thereof”.
In claim 3, the abbreviation “MMP” in “MMP-sensitive PEGs (PEG-MMP)” should be spelled out at its first appearance in the claim.
In claim 8, “crystalizing” should be replaced with “crystallizing”.
In claims 9 and 11, “proteinase k” should be replaced with “proteinase K”, for consistency with “cathepsin K” as recited in the same claims.
In claim 15, “ferro fluid” should be replaced with “ferrofluid”.
In claim 15, the options “coating with a layer of collagen” and “coating a portion of the surface with collagen” are redundant. The Examiner suggests deleting one of the two recitations. Alternatively, the recitations should be replaced with “coating at least a portion of the surface with collagen” (or similar), if the intent is to explicitly encompass both partial and full collagen coatings.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 13 is rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement.
The specification, while being enabling for a method of preparing a structure in which a second material is cast using a cast structure and the cast structure is thereafter removed to yield a final structure having a vascular topology formed therein, does not reasonably provide enablement for a method in which the final structure is an artificial tissue or organ. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with claim 13 without undue experimentation. The factors set forth in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988) are addressed below. See MPEP 2164.01(a).
Breadth of the claims. Claim 13 recites that the final structure is an artificial tissue or organ. The claim places no limitation on the type or complexity of the tissue or organ, and therefore encompasses artificial livers, kidneys, hearts, and other complex vascularized organs.
Nature of the invention and state of the prior art. The method of claim 1, from which claim 13 depends, is a fabrication method. Its steps produce a second material having a vascular topology formed therein by casting and by subsequent removal of a sacrificial cast structure. An artificial tissue or organ requires more than a vascular geometry formed in a biomaterial. It further requires living cells that are introduced into the structure, that remain viable, and that organize into functional tissue, as well as endothelialization of the vascular topology and a means of maintaining perfusion. The specification recognizes at [0027] and [0029] that the prepared structure is intended to permit cells to adhere, grow, and migrate and to be maintained under perfusion conditions, but does not describe how these results are obtained by the recited method.
Level of predictability in the art. Tissue engineering is an unpredictable art. Whether a given scaffold geometry and material composition will support cell viability, tissue maturation, and organ-level function cannot be predicted from the fabrication method alone, and must be determined empirically for each tissue type.
Amount of direction provided by the inventor and existence of working examples. The specification identifies artificial tissues and organs as an intended application at [0027] and [0099], and identifies biomaterials suitable for use as the second material at [0097], but provides no guidance regarding cell seeding, cell viability, endothelialization of the vascular topology, tissue maturation, or perfusion of the final structure. The working examples at [0208]-[0224] are directed to structures cast from wax ([0209]-[0211]), polycaprolactone ([0212]-[0213]), gallium ([0216]-[0217] and [0221]-[0222]), and PEG hydrogel ([0218]), and to cast vascular structures coated in silicone with fluorescent beads ([0223]-[0224]). None of the working examples includes living cells, and none produces a tissue or an organ.
Quantity of experimentation necessary. In view of the breadth of the claim, the unpredictability of the art, the absence of direction in the specification, and the absence of any working example directed to a tissue or organ, one of ordinary skill in the art would be required to undertake an extensive research program, of uncertain outcome, in order to arrive at an artificial tissue or organ using the recited method. Such an undertaking constitutes undue experimentation.
The Examiner notes that this rejection may be overcome by amending claim 13 to recite subject matter commensurate in scope with the enablement provided by the specification, for example by reciting that the final structure comprises a vascular topology, or that the final structure is a tissue model, phantom, stent, or vascular cast. See [0029] and [0066].
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 6 and 9-11 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 6 and 9-11 each recite the term “including” within a recited list of alternatives. The term renders these claims indefinite because it is unclear whether the limitations following the term are part of the claimed invention or are merely exemplary of the broader category that precedes the term. See MPEP § 2173.05(d).
Claim 6 recites “metal or liquid metal including gallium, alloys including Field’s metal, gallium-indium, gallium-tin, and gallium-indium-tin”. It is unclear whether gallium is a required member of the recited group or is instead an example of a metal or liquid metal, and likewise whether Field’s metal, gallium-indium, gallium-tin, and gallium-indium-tin are required members of the recited group or are examples of alloys. Claim 10 recites “metal, including gallium or indium, or alloys, including Field’s metal, gallium-indium, gallium-tin, and gallium-indium-tin”, and presents the same ambiguity.
Claims 9 and 11 each recite “collagenase incubation with a protease or peptidase, including trypsin, collagenase, proteinase k, cathepsin K, or any combination thereof”. It is unclear whether trypsin, collagenase, proteinase K, and cathepsin K are required members of the recited group or are examples of a protease or peptidase.
For purposes of examination, the items following each recitation of “including” in claims 6 and 9-11 are being interpreted as exemplary and not required, such that the broader category preceding the term defines the scope of the corresponding limitation.
Claims 6 and 10 each contain the trade name “pluronic”. Where a trade name or a mark used in commerce is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b). See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. The product identified by a given trade name or mark may change over time while the trade name or mark remains the same. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify a poloxamer, that is, a block copolymer comprising a central polypropylene oxide block flanked by polyethylene oxide blocks, and, accordingly, the identification is indefinite.
The term “low molecular weight PEG” in claim 6 is a relative term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, [0074] recites “low molecular weight PEG” without quantifying the molecular weight, notwithstanding that the specification recites a specific molecular weight range of 250-35,000 Da for PEGDA elsewhere. See [0032] and [0072]. It therefore cannot be determined what molecular weight is sufficiently low to fall within the scope of the claim. For purposes of examination, claim 6 is being interpreted as reciting “PEG” instead of “low molecular weight PEG”.
Claims 9 and 11 are indefinite because the recitation “collagenase incubation with a protease or peptidase, including trypsin, collagenase, proteinase k, cathepsin K, or any combination thereof” is internally inconsistent. The recitation requires an incubation with collagenase that is performed with a protease or peptidase, and then recites collagenase as a member of the group of proteases and peptidases. It is unclear whether collagenase is the agent with which the incubation is performed, a member of the recited group of proteases and peptidases, or both. For purposes of examination, claims 9 and 11 are being interpreted as reciting incubation with a protease or peptidase.
Claim 11 recites that the cast structure is removed by, among other alternatives, “a light process due to presence of photolabile linkers in the initial structure”. Claim 11 depends from claim 1, which requires removing the initial structure from the first material, obtaining a cast structure comprising the first material, casting a second material using the cast structure, and removing the cast structure from the second material. It is unclear how photolabile linkers present in the initial structure, which has already been removed, can be used for removal of the cast structure from the second material. The specification does not resolve the ambiguity, in that [0098] recites the same limitation. For purposes of examination, claim 11 is being interpreted as reciting “photolabile linkers in the cast structure”.
Claim Interpretation
In claim 1, the recited steps are given a sequential meaning to the extent that the steps are interdependent. For example, the first material must be cast in the one or more void volumes of the initial structure before the initial structure can be removed from the first material, and the cast structure must be obtained before the second material can be cast using the cast structure. Although [0347] states that the labels “first,” “second,” and “third” are not necessarily meant to indicate an ordering, that statement does not displace the ordering that follows from the interdependence of the steps as recited in claim 1.
In claim 2, the recitation “generated by additive or subtractive manufacturing” describes the initial structure based on how it was created, but it is not an affirmative step, and claim 2 depends from claim 1, which only recites “providing”, using, and “removing” the initial structure, not any creation of it. Under MPEP 2113, such a limitation is given weight only to the extent that the recited process (the additive or subtractive manufacturing) imparts distinguishing structural characteristics to the resulting product (the initial structure/hydrogel matrix structure). The specification does not describe any structural characteristic imparted by additive or subtractive manufacturing that distinguishes the resulting hydrogel matrix structure from a hydrogel matrix structure produced by other means. Accordingly, claim 2 is interpreted as requiring that the initial structure be a hydrogel matrix structure, without limitation as to the manner in which that structure was created.
In contrast to claim 2, the recitation in claim 19 that “the multilayer coating is obtained by forming a coating at least two times” is given patentable weight. Claim 19 depends from claim 16, which recites the affirmative step of forming one or more coatings on the cast structure prior to casting the second material. Claim 19 is therefore interpreted as requiring that the coating step of claim 16 be performed such that at least two coatings are formed on the cast structure.
In claim 3, the recited molecular weight range of 250-35,000 Da is interpreted as modifying only polyethylene glycol diacrylate (PEGDA), and not the polyvinyl alcohol, PEG-norbornene, MMP-sensitive PEGs, or gelatin methacrylate that are also recited. See [0032] and [0072], which recite the same range in the same position within the corresponding list.
In claim 12, the recitation “the initial structure comprises a vascular topology within a tissue or organ” is interpreted as requiring that the vascular topology of the initial structure be modeled on, or correspond to, vasculature found within a tissue or organ. The recitation is not interpreted as requiring that a tissue or organ be present, or that the initial structure be disposed within a tissue or organ. See [0029], which describes a vascular topology as a bounded void volume topology comprising a vessel or one or more networks of vessels.
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.
Claims 1, 12, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2018/0214614 (“Yoo”).
Regarding claim 1, Yoo discloses a method of preparing a structure (a method of creating a three-dimensional, hollow vascular scaffold; see [0006]-[0007], [0049], and Figures 1A-1D), comprising:
providing an initial structure (the vascularized tissue 14, obtained from an autologous, allogenic, or xenogenic source; see [0028], [0049], and Figure 1A);
casting a first material in one or more void volumes of the initial structure (perfusing the sacrificial internal casting material 10 via the syringe 12 into the vasculature of the vascularized tissue 14, the perfused material taking the three-dimensional shape of the tissue and thereafter solidifying; see [0007], [0024], [0049], and Figure 1A);
removing the initial structure from the first material (digesting the native tissue 14; see [0007], [0049], and Figure 1B; see also [0058], which describes placing the perfused kidney in 20% w/v sodium hydroxide for 48 hours to digest the tissue);
obtaining a cast structure comprising the first material (the vascular internal corrosion cast 16; see [0007], [0049], and Figure 1B);
casting a second material using the cast structure (coating the internal cast 16 with the durable external scaffold material 18, which surrounds the internal cast and is thereafter allowed to set; see [0007], [0029], [0049], [0057], and Figure 1C);
removing the cast structure from the second material (removal of the internal casting material by dissolving and/or melting; see [0007], [0008], [0025], [0049], [0057], and Figure 1C); and
obtaining a final structure comprising the second material (the hollow vascular scaffold 20, comprising a branching three-dimensional network of hollow vessel-like tubes that substantially mimics the original vasculature; see [0007], [0049], [0057], and Figure 1D).
Yoo describes the step of forming the second material around the cast structure as a “coating” step rather than a “casting” step. This difference in terminology does not distinguish claim 1 over Yoo. Yoo’s durable external scaffold material 18 is applied to the internal cast 16 in a flowable state, conforms to the exterior geometry of the internal cast, and is then set in place, such that removal of the internal cast leaves a hollow shell having the shape of the original vascular cast (see [0029], [0049], and [0057], the last of which describes coating the PCL casts with collagen, crosslinking the collagen, and dissolving the sacrificial PCL cast to yield a hollow shell of collagen in the shape of the original vascular cast). Forming a material into a desired shape by conforming it to a pattern and then solidifying it is casting, and Yoo therefore discloses casting a second material using the cast structure as recited in claim 1.
Regarding claim 12, Yoo discloses that the initial structure comprises a vascular topology within a tissue or organ (the vasculature of the vascularized tissue 14, which can comprise a renal, gastrointestinal, nervous system, pulmonary, cardiac, hepatic, splenic, pancreatic, and/or musculoskeletal vasculature; see [0028] and [0049]).
Regarding claim 13, Yoo discloses that the final structure is an artificial tissue or organ (the hollow vascular scaffold 20, seeded on its internal surface with endothelial cells 22 and surrounded by a culture of muscle cells or parenchymal cells chosen to regenerate a particular organ, so as to form a tissue construct around the scaffold; see [0008]-[0010], [0049], and Figures 1E-1G).
Claims 1, 2, 4-7, 9-11, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Justin et al., “Multi-casting approach for vascular networks in cellularized hydrogels,” Journal of the Royal Society Interface, vol. 13, no. 125, article 20160768 (December 2016) (“Justin”).
Regarding claim 1, Justin discloses a method of preparing a structure (a method for producing a hierarchical, three-dimensional, perfusable vasculature in a large, cellularized fibrin hydrogel; see the Abstract, section 3, and Figure 1), comprising:
providing an initial structure (the calcium alginate hydrogel, cast within the silicone chamber so as to fully encapsulate the thermoplastic model, and from which the model material is thereafter evacuated using near-boiling water and acetone to leave the channel structure; see sections 2.4 and 2.5 and Figures 1e-1g);
casting a first material in one or more void volumes of the initial structure (infiltrating liquid gelatin, 15% w/v porcine skin, into the channel structure of the alginate via suction; see section 2.5 and Figure 1g);
removing the initial structure from the first material (placing the chamber in a bath containing 200 mM sodium citrate and 200 mM glycine to chelate the calcium cross-linking ions, whereupon the alginate is fully dissolved into solution, followed by a calcium-free PBS bath and a PBS purge to remove residual alginate; see section 2.5);
obtaining a cast structure comprising the first material (the gelatin network template; see the Abstract, section 2.5, section 3, and Figure 1g);
casting a second material using the cast structure (injecting a collagen solution at 7.5 mg/ml, or a fibrin precursor solution of fibrinogen and thrombin, into the chamber so as to displace the PBS supporting the gelatin template, and gelling the injected solution; see section 2.6 and Figure 1h; see also section 3, which describes that the template is then cast in a collagen or fibrin gel);
removing the cast structure from the second material (placing the chamber in a sterile 37°C bath to melt the gelatin, and removing the gelatin from the channel network by gentle suction of PBS at 37°C through the inlets; see sections 2.6 and 2.7); and
obtaining a final structure comprising the second material (the collagen or fibrin hydrogel construct containing the perfusable bifurcating channel network; see the Abstract, section 3, and Figure 1h).
Regarding claim 2, and consistent with the interpretation of this claim set forth above, Justin discloses that the initial structure is a hydrogel matrix structure (the calcium alginate hydrogel, prepared by an internal setting method using CaHPO4 and gluconolactone with 7.5% w/v sodium alginate to yield a uniformly cross-linked hydrogel; see section 2.4).
Regarding claim 4, Justin discloses that the one or more void volumes forms a vascular topology (the channel structure within the alginate, replicating a design consisting of a 1 mm inlet which symmetrically bifurcates into a series of sixteen 200-250 μm channels which then converge into a single 1 mm outlet; see section 2.2, section 3, and Figures 1a and 1g).
Regarding claim 5, Justin discloses that the initial structure is post-processed via washing in a solvent (cleaning the channel structure of the alginate by injecting 2 ml of acetone into the channels to purge any remaining model material; see section 2.5).
Regarding claim 6, Justin discloses that the first material comprises a thermoreversible material (the gelatin, which is infiltrated in a liquid state and which is thereafter liquefied at 37°C to be removed; see sections 2.5, 2.6, and 3), and further comprises gelatin (15% w/v porcine skin gelatin; see section 2.5).
Regarding claim 7, Justin discloses filling the first material in the one or more void volumes of the initial structure at a first temperature (infiltrating the gelatin into the channel structure in a liquid state; see section 2.5) and solidifying the first material at a second temperature (holding the chamber for 24 hours at 4°C; see section 2.5), wherein the first material at the first temperature and the first material at the second temperature have different physical states (the gelatin is expressly described as liquid when infiltrated, and is thereafter melted or liquefied at 37°C in order to be removed, and so is necessarily in a solidified, gelled state prior to that melting step; see sections 2.5, 2.6, 2.7, and 3).
Regarding claim 9, Justin discloses that the initial structure is removed by dissolution (chelation of the calcium cross-linking ions in a bath of 200 mM sodium citrate and 200 mM glycine, whereupon the alginate is fully dissolved into solution; see sections 2.5 and 3).
Regarding claim 10, Justin discloses that the second material comprises a biomaterial comprising collagen or fibrin (the collagen hydrogel at 7.5 mg/ml prepared from rat-tail tendon, or the fibrin hydrogel prepared from 10-20 mg/ml bovine fibrinogen and 2 U/ml human plasma thrombin; see section 2.6).
Regarding claim 11, Justin discloses that the cast structure is removed by heating the cast structure to liquify the first material (placing the chamber in a sterile 37°C bath, which melts the gelatin, and liquefying the gelatin at 37°C; see sections 2.6, 2.7, and 3).
Regarding claim 13, Justin discloses that the final structure is an artificial tissue or organ (the cellularized collagen or fibrin hydrogel construct, in which human dermal fibroblasts are mixed into the precursor solution at 1 × 106 cells/ml immediately prior to casting, and in which human umbilical vein endothelial cells are injected into the channel network at 2 × 107 cells/ml and perfused with endothelial growth medium for 7 days, after which tight cell-cell junctions between the channel endothelial cells are demonstrated by CD31 immunocytochemistry; see the Abstract and sections 2.6, 2.7, and 2.8).
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.
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 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Justin, as applied to claim 1 above, and further in view of Grigoryan et al., “Multivascular networks and functional intravascular topologies within biocompatible hydrogels,” Science, vol. 364, no. 6439, pp. 458-464 (May 3, 2019) (“Grigoryan”).
Justin discloses the initial structure as a calcium alginate hydrogel prepared by an internal setting method and cast within a silicone chamber so as to encapsulate a thermoplastic model, the model thereafter being evacuated to leave the channel structure (see sections 2.4 and 2.5). Justin does not disclose that the initial structure is generated by additive or subtractive manufacturing, and does not disclose that the initial structure comprises any of the materials recited in claim 3.
Grigoryan discloses the production of hydrogels containing intricate and functional vascular architectures by projection stereolithography, using biocompatible food-dye photoabsorbers to prevent inadvertent polymerization within the narrow void spaces designed to be hollow perfusable vasculature (see page 458). Grigoryan discloses that these hydrogels are composed primarily of water and poly(ethylene glycol) diacrylate, specifically PEGDA of 6 kDa at 20 weight percent (see page 458). Grigoryan further discloses the use of a custom stereolithography apparatus for tissue engineering (SLATE), and fabrication using mixtures of PEGDA and gelatin methacrylate (see page 463).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted a stereolithographically printed PEGDA hydrogel, as taught by Grigoryan, for the cast calcium alginate hydrogel of Justin as the initial structure. Justin arrives at a hydrogel containing the channel network only indirectly, by first printing a thermoplastic model, mounting that model within a silicone chamber, casting alginate around it, and then evacuating the model with near-boiling water and acetone (see sections 2.2, 2.3, and 2.5). Grigoryan demonstrates that a hydrogel containing an equivalent perfusable vascular void network can be produced directly in a single stereolithographic operation. Substituting Grigoryan’s directly printed hydrogel for Justin’s cast alginate would therefore eliminate the printing, mounting, encapsulation, and model-evacuation steps of Justin’s process, and would do so while retaining the hydrogel initial structure that Justin’s subsequent gelatin infiltration and casting steps require. This is a simple substitution of one known element for another to obtain predictable results. See MPEP 2143(B).
Regarding claim 2, Grigoryan discloses that the initial structure is a hydrogel matrix structure generated by additive manufacturing (hydrogels containing vascular architectures produced by projection stereolithography using a custom stereolithography apparatus for tissue engineering; see pages 458 and 463).
Regarding claim 3, Grigoryan discloses that the initial structure comprises polyethylene glycol diacrylate (PEGDA) having 250-35,000 Da (PEGDA of 6 kDa at 20 weight percent; see page 458), and gelatin methacrylate (mixtures of PEGDA and gelatin methacrylate; see page 463).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Yoo, as applied to claim 1 above, and further in view of Fassler et al., “3D structures of liquid-phase GaIn alloy embedded in PDMS with freeze casting,” Lab on a Chip, vol. 13, no. 22, pp. 4442-4450 (2013) (“Fassler”), as evidenced by Briggs, “Gallium: Thermal Conductivity; Supercooling; Negative Pressure,” Journal of Chemical Physics, vol. 26, no. 4, pp. 784-786 (1957) (“Briggs”).
Regarding claim 8, Yoo discloses that casting the first material in the one or more void volumes of the initial structure comprises injecting the first material in the one or more void volumes of the initial structure at a first temperature (perfusing melted gallium via the syringe 12 into the vasculature of the tissue 14, gallium having been selected as a sacrificial casting material because it has an extremely low melting temperature; see [0027], [0049], [0054], and Figure 1A), and thereafter solidifying the injected first material within the initial structure (solidifying the sacrificial internal casting composition within the native vasculature; see [0007]).
Yoo does not expressly disclose supercooling the first material, or crystalizing the first material at a second temperature. Yoo’s disclosure of perfusing gallium in a melted state and thereafter solidifying it within the native vasculature necessarily implies that the gallium is brought from the elevated temperature at which it is perfused to a lower temperature at which it is solid, but Yoo does not describe the cooling conditions employed or the manner in which solidification proceeds.
Fassler discloses a freeze casting technique for gallium-indium alloys in which a PDMS mold having patterned channels is filled with liquid gallium-indium alloy at room temperature, the filled mold is placed in a freezer so that the alloy solidifies within the channels, and the solidified alloy is thereafter removed from the mold while still in its solid state (see the Abstract and page 4444). Fassler discloses that the alloy may be introduced into the mold either by injection through a needle or by vacuum perturbation (see page 4444 and Figures 5 and 6 at page 4445). Fassler further discloses that eutectic gallium-indium was selected for this process because of its melting point of 15°C, as compared with a melting point of -19°C for Galinstan, and that the same methods are expected to work with other gallium-indium based alloys (see page 4444). Fassler reports that no fracture or cracking was observed during freezing, and that the frozen components are self-supporting and can be handled and manipulated using tools such as tweezers and pliers (see pages 4442 and 4444).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have solidified Yoo’s perfused gallium by cooling it below its melting point in the manner taught by Fassler. Yoo requires that the perfused casting material solidify within the native vasculature and thereafter withstand digestion of the surrounding tissue, handling, and coating with the durable external scaffold material 18, and Fassler demonstrates that a gallium-based alloy cast into the channels of a mold and cooled below its melting point yields a solid structure of the same geometry that is self-supporting and can be handled and manipulated without loss of shape. One of ordinary skill would further have been motivated to look to the gallium casting art for improved process conditions because Yoo reports at [0056] that the gallium casts of Example 2 formed incomplete microvascular structures.
In the resulting method, the step of supercooling the first material is necessarily present. As evidenced by Briggs, gallium exhibits pronounced supercooling and remains in the liquid state at temperatures substantially below its melting point in the absence of a nucleation event, small drops of liquid gallium having been supercooled to -28°C, or 58°C below the melting point of gallium, before freezing occurred (see page 786; see also the abstract at page 784). Cooling Yoo’s perfused molten gallium below its melting point, as taught by Fassler, therefore necessarily carries the gallium through a supercooled liquid state before nucleation occurs, whereupon the gallium crystalizes at the reduced temperature to form the solid cast, thereby crystalizing the first material at a second temperature. A limitation is met where it is necessarily present in the prior art method, whether or not it was recognized as such by those of ordinary skill. See MPEP 2112.
Claims 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Justin, as applied to claim 1 above, and further in view of US 2012/0058174 (“West”).
Justin does not disclose modifying a surface of the cast structure prior to casting the second material, or forming one or more coatings on the cast structure prior to casting the second material.
West discloses methods of fabricating substantially interconnected vascular networks within biomaterials, in which the void space of a sacrificial fiber network is backfilled with a biomaterial, the biomaterial is allowed to harden, cure, and/or solidify, and the fibers are thereafter removed by wet etching, dissolution, or degradation so as to leave a substantially interconnected vascular network (see [0052] and [0053]). West further discloses that a fiber network, or a portion of a fiber network, may be surface coated, and that it may be desirable to do so in order to inhibit wet etching or dissolution of the fiber network, or for stabilization of the fiber network (see [0045]). West identifies suitable surface coatings as including poly(lactic acid) (PLA), a solution of PLA in dichloromethane, poly(lactic co-glycolic acid) (PLGA), a solution of PLGA in chloroform, collagens, gelatins, zein, shellac, starches, and petroleum jelly, some of which are known to be directly biocompatible with in vivo blood flow (see [0045]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have surface coated the gelatin template of Justin prior to casting the collagen or fibrin hydrogel, as taught by West, in order to stabilize the template and to inhibit its premature dissolution. Justin expressly recognizes both concerns: Justin states that the choice of gelatin is essential to the process because a low bloom gelatin must be used that can withstand alginate removal and the subsequent casting step, and that because the 7.5% w/v collagen solution is highly viscous it must be injected slowly using a syringe pump at 15 ml/h on ice so as not to displace the gelatin template (see sections 2.6 and 3). Surface coating the template as taught by West would predictably increase the mechanical robustness of the template against displacement during casting and reduce its susceptibility to dissolution during the preceding alginate chelation and PBS washing steps, and would do so using coating materials that West identifies as biocompatible and suitable for use in vascular networks intended to support cells.
Regarding claim 14, West discloses modifying a surface of the cast structure prior to casting the second material (surface coating the fiber network, and repeating a combination of surface coating and wet etching or dissolution processes, before backfilling a biomaterial into the fiber network; see [0045] and [0054]; see also [0046], which discloses substantially roughening a fiber network and/or a coating on a fiber network).
Regarding claim 15, West discloses that modifying the surface of the cast structure further comprises roughening of the surface (substantially roughening a fiber network and/or a coating on a fiber network to increase the surface area, optionally by direct etching with argon plasma under high vacuum; see [0046]), and coating with a layer of collagen (surface coating the fiber network with collagens; see [0045]).
Regarding claim 16, West discloses forming one or more coatings on the cast structure prior to casting the second material (surface coating the fiber network before backfilling a biomaterial into the fiber network; see [0045] and [0054]).
Regarding claim 17, West discloses that the one or more coatings comprises a biocompatible material, a hemocompatible material, collagen, and gelatin (surface coatings including PLA, PLGA, collagens, gelatins, zein, shellac, starches, and petroleum jelly, some of which are known to be directly biocompatible with in vivo blood flow; see [0045]).
Regarding claim 18, West discloses that the one or more coatings has a thickness between 10 nm and 1000 μm (a thin uniform layer of polylactic acid approximately 1 μm thick; see [0045]).
Regarding claim 19, West discloses that the one or more coatings comprises a multilayer coating, wherein the multilayer coating is obtained by forming a coating at least two times (repeating a combination of surface coating and wet etching or dissolution processes before backfilling a biomaterial into a fiber network, so as to optionally create multi-layer structures; see [0054]).
Regarding claim 20, West discloses that a surface coating may be applied to a fiber network for either of two distinct purposes, namely to inhibit wet etching or dissolution of the fiber network, or to stabilize the fiber network, and further discloses that a surface coating may be designed either to be removed during wet etching or dissolution of the fiber network, or alternatively to remain for a short or long period as a basement membrane lining all vessels, much as collagen type IV lines human blood vessels as a native basement membrane (see [0045]). West additionally discloses that the roughening of a fiber network and/or of a coating on a fiber network may be accomplished by buildup of additional material, and specifically by chilling the network to approximately 4°C and suspending it above a heated solution of the fiber material or of another material, such as an aqueous solution of sugars at 60°C, whereupon the vaporized solute crystallizes on and grows uniformly off the chilled network (see [0046]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have formed the multilayer coating of claim 19 from at least two different coating materials. A coating designed to be removed during dissolution of the template and a coating designed to remain in place as a basement membrane serve different and mutually incompatible functions, and one of ordinary skill seeking both functions would have selected different materials for the two layers. Moreover, West’s roughening process expressly contemplates depositing another material onto an existing coating on a fiber network, such that applying that process to a network already bearing a first surface coating yields a multilayer coating of two different materials. The selection of two or more coating materials from West’s disclosed group is further supported by West’s own claims 22, 29, and 45, each of which recites surface coating with at least one material selected from a group consisting of poly(lactic acid), poly(lactic co-glycolic acid), collagen, gelatin, zein, shellac, a starch, and petroleum jelly.
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.
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Claims 1, 2, 4, 7, 9, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-11, 13-17, and 19 of copending Application No. 19/386,988 (reference application) (published as US 2026/0131512).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application recite each step of the rejected claims in narrower terms, as set forth below.
Claim 17 of the reference application (by virtue of its dependency from claims 1, 13, and 16) recites a method of forming a three-dimensional article comprising providing a first mold comprising an interior volume, the first mold being formed from a hydrogel; injecting a first fluid material into the interior volume of the first mold; solidifying the injected first fluid material within the interior volume of the first mold to form a solidified object; removing the first mold from the solidified object; applying a second fluid material to the exterior surface of the solidified object; solidifying the second fluid material on the exterior surface of the solidified object to form a second mold of the solidified object; and removing the solidified object from the second fluid material to provide a second mold of the solidified object comprising an interior volume.
Claim 1 of the instant application recites the same sequence of steps in broader terms. The first mold of claim 17 of the reference application is an initial structure, its interior volume is a void volume of that initial structure, injecting the first fluid material into that interior volume is casting a first material in the void volume, the solidified object is a cast structure comprising the first material, applying and solidifying the second fluid material on the exterior surface of the solidified object is casting a second material using the cast structure, removing the solidified object from the second fluid material is removing the cast structure from the second material, and the resulting second mold comprising an interior volume is a final structure comprising the second material.
Regarding claim 2, claim 1 of the reference application requires that the first mold be formed from a hydrogel, and claim 9 of the reference application recites forming the first mold by additive manufacturing.
Regarding claim 4, claims 10 and 11 of the reference application recite that the interior volume of the first mold has a vascular topology formed from one or more tubular structures.
Regarding claim 7, claim 1 of the reference application recites injecting a first fluid material and solidifying it to form a solidified object, and claim 19 of the reference application recites that solidifying the injected first fluid material comprises cooling the first fluid material within the interior volume of the first mold, such that the first material is introduced in a fluid state at a first temperature and is thereafter solidified at a lower second temperature.
Regarding claim 9, claim 14 of the reference application recites that removing the first mold from the solidified object comprises dissolving or dispersing the first mold, and claim 15 of the reference application recites that the first mold is dissolved or dispersed using aqueous sodium hydroxide.
Regarding claim 12, claims 10 and 11 of the reference application recite that the interior volume of the first mold has a vascular topology formed from one or more tubular structures, the tubular structures having an average diameter of 1-20 mm or 50-300 µm.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Applicant’s attention is directed in particular to US 5,989,476 (“Lockard”), which is assigned to 3D Systems, Inc., the applicant of the present application. At Figure 1 and lines 18-57 in column 1, Lockard describes a process that Lockard identifies as a typical process then currently in use for producing tooling for plastic injection molding. In that process, RTV silicone rubber 200 is poured around a master pattern 202 held in a frame 204 and is cured to form an interim mold pattern 206, the master pattern typically being formed using stereolithography. The master pattern is separated from the interim RTV mold, and an intermediate mold 208 is formed by pouring a second RTV material in and around the interim RTV mold 206, curing that second material, and removing the interim RTV 206 so as to leave a cavity 210 in the mold 208. A mixture of refractory metal particles and a heat fugitive organic binder 212 is poured into the intermediate RTV mold 208 and is cured or solidified, and the resulting green article is removed from the RTV mold. The green article is heated to remove the binder and to sinter the refractory particles, and the sintered article is infiltrated with a metallic infiltrant such as copper to produce a metal composite refractory article (MCRA) 213. A polymeric structure 214 duplicating the master pattern is thereafter formed by injection molding within the MCRA 213.
This process corresponds to the method of claim 1. The intermediate RTV mold 208 is an initial structure, the cavity 210 is a void volume of that initial structure, the mixture of refractory particles and binder 212 poured into the cavity 210 is a first material cast in that void volume, separation of the green article from the RTV mold is removal of the initial structure from the first material, the green article and the MCRA 213 derived from it are a cast structure comprising the first material, injection molding of the polymeric structure 214 within the MCRA 213 is casting a second material using the cast structure, ejection of the molded polymeric structure from the MCRA 213 is removal of the cast structure from the second material, and the polymeric structure 214 is a final structure comprising the second material. Lockard accordingly indicates that the sequence recited in claim 1, in which an article produced by a first casting operation is itself used as the mold for a second casting operation, was already well established in the art at the time of the present invention.
Applicant’s attention is further directed to Golden and Tien, “Fabrication of microfluidic hydrogels using molded gelatin as a sacrificial element,” Lab on a Chip, vol. 7, pp. 720-725 (2007) (“Golden”). Golden discloses introducing liquid gelatin at 45°C into the channels of a patterned PDMS stamp sealed against a flat substrate, gelling the gelatin by cooling to 4°C, releasing the gelatin from the stamp as a free-standing mesh, gelling collagen, fibrin, or Matrigel around the mesh, and melting the gelatin at 37°C to leave a perfusable microfluidic network within the surrounding gel. See the abstract and Figure 1.
Applicant’s attention is further directed to US 2018/0179680 (“Gruba”), which discloses at Figure 3 and [0064]-[0071] forming a mold by stereolithography, applying a degradable material within the interior of the mold to form a scaffold, removing the scaffold from the mold, electrospinning a polymer onto the scaffold, and thereafter dissolving the scaffold to leave the electrospun structure. See in particular [0066], which identifies the degradable material as including polyethylene glycol, polycaprolactone, and poly(lactic-co-glycolic acid).
Applicant’s attention is further directed to US 2020/0047401 (“Yu”), which discloses at [0021]-[0022] applying a thin layer of poly(D-lactide-co-glycolide) to sacrificial polyester wax filaments before casting a hydrogel solution around them and removing the wax filaments by warming under light vacuum to leave perfusable channels.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to John DeRusso whose telephone number is (571)270-1287. The examiner can normally be reached Monday-Friday, 10:00 AM-6:00 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sam Zhao, can be reached at (571) 270-5343. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/John J DeRusso/Primary Examiner, Art Unit 1744
