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 .
Status of the Claims
Claims 16-20 are pending (claim set as filed on 04/08/2026).
Applicant’s election without traverse of Group III, composition claims, in the reply filed on 11/07/2025 is acknowledged. Withdrawn claims were canceled therewith.
Priority
This application is a 371 of PCT/US2021/021162 filed on 03/05/2021, which has a PRO 62/985,408 filed on 03/05/2020.
Withdrawal of Rejections
The response and amendments filed on 04/08/2026 are acknowledged and deemed persuasive to overcome the previously cited rejections from the last office action. However, a new ground of rejection is set forth herein.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
Regarding the claimed term of “about”, the recitation of said term without definition in the specification of how much variation permits a broad interpretation of the range allowed. Thus, the concentrations of the cited prior art may be interpreted to fall within the variation permitted by the use of “about” in this instance (MPEP 2173.05(b)(II)(A): Relative Terminology).
New Grounds of Rejection
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 16-17, 19-26, 28-30, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis (US 2018/0110901 A1) in view of Shirata (Body heat responsive gelation of methylcellulose formulation containing betaine, 2017) - both references cited in the IDS filed on 03/22/2023.
Lewis’ general disclosure relates to tissue engineering and more particularly to fabricating tubular tissue constructs including embedded vasculature and/or tubules (see abstract & ¶ [0004]-[0005]).
Lewis teaches “To produce thick vascularized tissues, multiple inks were sequentially co-printed within the customized perfusion chips. To form a base layer, a thin film of gelatin fibrin
matrix, containing 0.1% wt TG, was cast onto the base of the perfusion chip and allowed to dry. Next, the fugitive Pluronic F127 and cell-laden inks were printed onto the surface. The fugitive (Pluronic F127) and cell-laden inks were printed using 200 μm straight and tapered nozzles,
respectively” (see ¶ [0339]-[0340], [0359]). Lewis teaches “the extracellular matrix material and/or the extracellular matrix composition may comprise a gel. An ideal gel for bioprinting applications may exhibit a rapid transition from a low viscosity solution to a solid-like gel, which may be seen by an initial increase in shear elastic modulus. Rapid, controllable gelation may enhance printed structure fidelity by minimizing or obviating swelling and dissociation typical of slow gelation processes. The term “gel” may refer to a semi-solid substance that may comprise a gelling agent to provide viscosity or stiffness. The gel may be formed upon use of a gelling agent, such as a thickening agent, crosslinking agent or a polymerization agent, and may comprise a cross-linked structure or a non-cross-linked structure. The gel may be hydrophobic or hydrophilic. Some examples of suitable gels include a hydrogel, thermo-reversible gel, a photo-sensitive gel, a pH sensitive gel, a peptide gel, or a cell type specific gel … Hydrogels include those derived from collagen, hyaluronate, fibrin, alginate, agarose, chitosan, gelatin, matrigel, glycosaminoglycans, and combinations thereof” (see ¶ [0215]). Lewis further teaches “the extracellular matrix composition is produced by dissolving 15 wt. % GelMA in cell culture media. Above approximately 25°C., the composition is a low viscosity fluid with a G' value below 10-1 Pa. Upon cooling below 25° C., the composition undergoes gelation, yielding a clear, viscoelastic extracellular matrix material. The elasticity of the extracellular matrix composition increases with decreasing temperature, with G' values of about 103 Pa and 2x104 Pa observed at 22°C. and 2°C. (FIG. 6D), which correspond to typical conditions for printing and fugitive ink removal, respectively” (see ¶ [0291]).
Regarding claims 19 and 28 pertaining to the transglutaminase, Lewis teaches cross-linking with transglutaminase (see ¶ [0055], [0213], [0216], [0359], [0287]-[0288]).
Regarding claim 21, Lewis teaches “The cell laden inks must simultaneously facilitate printing of self supporting filamentary features under ambient conditions and subsequent infilling of the printed tissue architectures by casting without dissolving or distorting the patterned cell laden and fugitive (vasculature) inks (FIG. 27A). The thermally reversible gelation of the gelatin-fibrinogen network enables its use in both printing and casting, where gel and
fluid states are required, respectively (FIGS. 28A though 28F)” (see ¶ [0359]). Lewis teaches “the differences in thermally reversible gelation observed for the fugitive Pluronic F127, pure GelMA, and cell-laden GelMA inks give rise to three distinct processing windows. Between approximately 4° C. and 25° C., each ink is stiff and exhibits a solid-like response, where G'>G” (see ¶ [0293], [0237]).
Regarding claim 26 pertaining to agarose, Lewis teaches agarose (see ¶ [0215], [0236]).
However, Lewis does not teach: a polymer comprising a temperature regulating agent comprising methylcellulose; wherein the agent comprises betaine.
Shirata discloses that “Methylcellulose (MC), a cellulose derivative, is a designated food additive which is widely used as a thickener and gelling agent. MC has thermally reversible gelling properties: when MC is dissolved in cold water, the solution becomes a viscous liquid; the solution changes to a hydrogel state at 50-55°C, and returns to the sol state when cooled. The gelling temperature of MC solution has been previously lowered to below 37°C, suggesting it could be applied as a gelling agent in response to body heat. The addition of inorganic salts (sodium chloride, potassium chloride, sodium bicarbonate, and sodium hydrogen phosphate), organic acid salts (sodium tartrate and sodium citrate), sugars (sucrose and fructose), sugar alcohols (glycerol and sorbitol) and polyethylene glycol) have all been reported to reduce the gelling temperature of MC solution” (see page 1829, bridging ¶). Claim interpretation: the salts or sugars also read on the claimed phrase of “a temperature regulating agent”, see ¶ [0037] of the instant published application which discloses “temperature regulating agents include salts, such as sodium chloride or sodium bicarbonate, and sugars, such as betaine or sorbitol”.
Shirata teaches “We examined a methylcellulose (MC) formulation that gels at body temperature for enteral alimentation. Betaine was found to have a lowering effect on the gelation temperature of the MC solution. The thermal gelation temperature of a body heat-responsive (BHR) gelling MC formulation, consisting of 2% MC, 15% glucose, 1.2% sodium citrate, and
3.5% betaine mixture, was approximately 32°C, indicating that it could gel in response to body heat” (see abstract & page 1831: Results).
Regarding claims 20 and 29 pertaining to the amount of polymer and temperature regulating agent, Shirata teaches “the thermal gelation temperature of 2% methylcellulose solution containing 5, 10, 15, and 20% betaine” (see page 1830, left col.: Measurement of the thermal gelation temperature of MC solution).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use or employ a temperature regulating agent comprising, e.g. betaine, such as taught by Shirata in the composition of Lewis. The ordinary artisan would have been motivated to do so is because Shirata provides a teaching-suggestion-motivation (TSM) to use betaine as it was found to have a lowering effect on the gelation temperature in composition comprising methylcellulose. Thus, the use of betaine allows for control of gelation which would be beneficial in Lewis’s disclosure directed to hydrogels that can be used in bioprinting tissue engineering applications.
Claims 18 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis in view of Shirata as applied to the claims above, and in further view of Ma (US 2010/0084328 A1).
The combined disclosures of Lewis and Shirata is discussed above as it pertains to a support medium composition comprising a polymer (e.g., collagen or methylcellulose), temperature regulating agent (e.g., inorganic salts, sugars, or betaine), and a media (e.g., a cell culture media).
However, modified-Lewis-Shirata does not teach: agarose microparticles has an average maximum particle size of about 40-70 µm.
Ma’s general disclosure relates to the preparation of polysaccharide particles, such as agarose beads in general in the field of biological engineering (see abstract & ¶ [0002]). Ma discloses “known drawbacks of such emulsion methods are that the particle size of the liquid droplets cannot be controlled, the prepared emulsion has uneven particle size, the cured agarose gel beads have uneven particle size … When gel beads are used to the embed cells, each bead embeds a different number of cells and different proliferation rates occur during cell growth due to their uneven particle size. In addition, agarose gel beads with uniform particle size are very
important to research gel properties” (see ¶ [0008]). Ma teaches beads with particle sizes in the range of 3-60 μm (see ¶ [0009]-[0014]).
It would have been obvious to one of ordinary skill in the art to use agarose micro-particle sizes in the range of 3-60 μm such as taught by Ma in the composition of modified-Lewis-Shirata. The ordinary artisan would have been motivated to do so is because Ma discloses the importance of particle size for agarose bead gel properties, its effect on cells, and further discloses a particle size range of 3-60 µm which overlaps with the claimed range (In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists, MPEP 2144.05(I)). The ordinary artisan would have had a reasonable expectation of success because the disclosures are directed to agarose and tissue engineering.
Claims 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis in view of Shirata as applied to the claims above, and in further view of Ruel (WO 2018/201260 A1 - cited in the IDS filed on 03/22/2023).
The combined disclosures of Lewis and Shirata is discussed above as it pertains to a support medium composition comprising a polymer (e.g., collagen or methylcellulose), temperature regulating agent (e.g., inorganic salts, sugars, or betaine), and a media (e.g., a cell culture media).
However, modified-Lewis-Shirata does not teach: a gel state viscosity of no more than 10,000 centipoise; or a solid state viscosity of at least than 50,000 centipoise.
Ruel’s general disclosure relates to hydrogel compositions (see page 1: Field of Invention).
Ruel teaches “hydrogel compositions described herein may typically be prepared in a mixing system for injection to a subject in need thereof via syringe or other such administration
route. Where administration is via syringe injection, the hydrogel composition prepared in the mixing system may be configured to have a suitable viscosity so as to facilitate substantially
homogenous or even flow through the syringe. By way of example, viscosity of lower than about
0.10 Pa*s, or lower than about 0.05 Pa*s, may facilitate syringe injection. Where delivery via
syringe injection is desired, for example, cross-linking of the hydrogel composition may be
initiated or pre-configured in the mixing system, and injection via the syringe may be performed
while the hydrogel composition is in substantially liquid form having a suitable viscosity.
Following injection, the cross-linking may progress, with the hydrogel composition solidifying
or gelling after administration. By way of example, the mixing system may be maintained at low
temperature (i.e. on ice) before injection so as to limit cross-linking/solidification, and upon injection into a subject the increased temperature in vivo may accelerate crosslinking/ solidification of the hydrogel, thereby forming a hydrogel matrix in vivo” (see page 23, lines 6-19).
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Lewis-Shirata to include wherein the support medium, when in the gel state, has a viscosity of no more than 10,000 centipoise, and, when in the solid state, has a viscosity of at least 50,000 centipoise as taught by Ruel. The motivation would have been to provide a hydrogel composition for regeneration or repair of tissue and improvement of tissue functions (see Ruel at page 6, lines 16-19).
Conclusion
No claims were allowed.
Correspondence Information
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653
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