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 1-20 are pending (claim set as filed on 09/01/2022).
Election/Restrictions
Applicant’s election without traverse of Group III, composition claims 16-20, in the reply filed on 11/07/2025 is acknowledged.
Claims 1-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Therefore, only composition claims 16-20 are presented for examination.
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.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 03/22/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Claim Rejections - 35 USC §103, Obviousness
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 non-obviousness.
Claims 16-17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US 2019/0328930 A1) in view of Shirata (Body heat responsive gelation of methylcellulose formulation containing betaine, 2017 - citation #9 in the IDS filed on 03/22/2023).
Liu’s general disclosure relates to a hydrogel-based bioink for use in 3D bioprinting, hydrogel matrices comprising the bioink, 3D bio-printed scaffolds, and methods of preparing and using the same (see abstract & ¶ [0002]). Liu teaches “live cells can be mixed with the bioink solution and printed as part of the bioink” (see ¶ [0062]).
Liu teaches hydrogel-based bioink materials compatible with bioprinting wherein the bioink comprising a mixture comprising a collagen and a polysaccharide, and a polyhedral oligomeric silsesquioxane (see ¶ [0007], [0021]-[0022]). Liu teaches “In addition to, or as an alternative to, the collagen, the bioink can comprise other thermal-induced gelation materials, for example, methylcellulose … Advantageously, collagen demonstrates heat-up induced gelation, e.g., as the temperature increases from 0 to 37°C., which allows gelation at temperatures at which live cells can survive. In contrast, cool-down induced gelation may require temperatures below 0° C., at which live cells cannot survive” (see ¶ [0023]) Claim interpretation: collagen and methylcellulose reads on the claimed term of a polymer, e.g., as seen in claim 17 in part, wherein methylcellulose has thermal reversible gelling properties (see Shirata reference cited below) which reads on the claim 16’s functional limitation of being configured to change between a gel state to a solid state. Liu teaches the collagen type I was mixed with alginate stock solution and cell culture medium (claim 17 in part) (see ¶ [0069]).
However, Liu does not teach: a temperature regulating agent (claim 16’s 1st limitation); wherein the agent comprises betaine (claim 17).
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 claim 20 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 Liu. 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 Liu’s disclosure directed to improving gelling kinetics and mechanical stability that can be used in bioprinting tissue engineering applications. The ordinary artisan would have had a reasonable expectation of success is because both disclosures are directed to the widely used methylcellulose as a gelling agent and examining the temperature characteristics or effects of gelation.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Shirata as applied to claims 16-17 and 20 above, and in further view of Ma (US 2010/0084328 A1).
The combined disclosures of Liu 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), a polysaccharide, and a media (e.g., a cell culture media).
Note that Liu does teach that the polysaccharide for use in bioinks may include agarose and may be cross-linked to form a stable hydrogel matrix (see Liu at ¶ [0026]).
However, modified-Liu-Shirata does not teach: agarose microparticles has an average maximum particle size of about 40-70 µm (claim 18).
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-Liu-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.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Shirata as applied to claims 16-17 and 20 above, and in further view of Sun (US 2016/0024461 A1).
The combined disclosures of Liu 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), a polysaccharide, and a media (e.g., a cell culture media).
Liu does teach that the polysaccharide for use in bioinks may include agarose and may be cross-linked to form a stable hydrogel matrix (see Liu at ¶ [0026]).
However, modified-Liu-Shirata does not teach: a cross-linking agent comprising transglutaminase (claim 19).
Sun discloses that “hydrogels are formed by crosslinking polymer chains-through physical, ionic or covalent interactions and are well known for their ability to absorb water. Hydrogels possess a good biocompatibility in general. Their three-dimensional (3D) structure is excellent to mimic extracellular environments and, consequently, they are frequently used to encapsulate cells in a 3D-microenvironment” (see ¶ [0008]-[0009]). Sun teaches that “There are several advantageous characteristics of enzymatic crosslinking of the biomaterials making it one of the preferable methods for in situ gelation to encapsulate viable cells. Most of the enzymes are involved in biological functions in nature and catalyze the reactions at body temperature, neutral pH, and aqueous environment. With the formation of covalent bonds, the enzymatically crosslinked hydrogels are stable and can resist subsequent changes of in vitro and in vivo environment. Due to the site specificity of enzyme, unwanted side reactions or toxicity that can occur with photo-initiator or organic solvents could be avoided, and functional groups in the biomaterials are mostly uncompromised” (see ¶ [0010]). Sun teaches the use of transglutaminase to crosslink hydrogels (see ¶ [0023]-[0026]).
It would have been obvious to one of ordinary skill in the art to employ or use a cross-linking agent of transglutaminase such as taught by Sun in the composition of modified-Liu-Shirata. The ordinary artisan would have been motivated to do so is because Sun teaches that there are several advantages to using an enzymatic crosslinking agent because it is stable, specific, and can resist subsequent changes of in vitro and in vivo environment (see Sun at ¶ [0010]). The ordinary artisan would have had a reasonable expectation of success is because Liu discloses that polysaccharides can be cross-linked to form a stable hydrogel matrix (see Liu at ¶ [0025]) and also indicates that “chemical crosslinking, which provides uniform, rigid structures with excellent mechanical properties” (see ¶ [0005]).
Conclusion
No claims were allowed.
Correspondence Information
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653