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 .
Detailed Action
The Examiner for this Application has changed. Please direct all future correspondence to Katriel Kasayan, AU 1634. Additional contact information can be found at the end of this paper.
This action is in response to the papers filed on August 19, 2025. A response to the restriction requirement filed on August 11, 2025 is acknowledged.
Claims 1-16, 18, 20, 23 and 25 are currently pending. Applicants’ election with traverse of Group 1 directed to a 3D cell culture medium, e.g., claims 1-16, 18 and 20 is acknowledged. In addition, Applicants’ election of the species of claim 14 is acknowledged.
Claims 23 and 25 are withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to non-elected invention, there being no allowable generic or linking claim. Claims 5 and 6 are withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to non-elected species, there being no allowable generic or linking claim. Claims 7-12 are withdrawn from further consideration as they are dependent on claim 6. Claim 13 is withdrawn from consideration as it is dependent on claim 5. The restriction requirement is deemed proper, maintained and made FINAL.
Therefore, claims 1-4, 14-16, 18 and 20 are under examination to which the following grounds of rejection are applicable.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/US21/19922 , filed on 02/26/2021 . This application has claims priority to PRO 62/983,056 filed 02/28/2020.
Thus, the earliest possible priority for the instant application is February 28, 2020.
Specification Objection
The use of the term Thermofisher and Sigma Aldreich, which is a trade name or a mark used in commerce, has been noted in this application. 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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 14-16, 18 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention
Claim 1 is indefinite in their recitation of the phrase “substantially spherical” since it is unclear how this term “substantially” is defined, what its metes and bounds are, or to what the term is directed towards. It is not clear in reference to what extent the sphericity of the charge-neutral microgel particles is completed.
Claim 3 and 14 are indefinite in its recitation of “the 3D cell culture gel” in line 1 and 2 respectively. There is not proper antecedent bases for “the 3D cell culture gel”. Claim 1 recites “A three-dimensional (3D) cell culture medium”.
Claim 15 is indefinite in the applicant’s recitation of the term “permeability”, in the context of measuring the permeability of a liquid cell culture medium. The term “permeability” is a property of a solid or porous membrane, not a homogeneous liquid, which are instead characterized by their diffusivity. The claim does not specify whether the permeability refers to the liquid phase itself, microgel particles dispersed herein, or a composite structure formed by the microgels. As a result, it is difficult to understand the scope of the claim with reasonable certainty, rendering the claim indefinite. In the interest of compact prosecution, it will be interpreted that the permeability of the cell culture medium is referring to the permeability of the charge-neutral packed microgels as discussed in the specification.
Claim 16 recites “such that the cell culture medium undergoes a phase change”. As written, claim 16 appears to provide examples and preferences for 3D cell culture medium and a yield stress. It is not clear, however, whether other types of yield stress or which particular forms of yield stress are intended to be within the scope of the claim. Accordingly, claim 16 is indefinite because its metes and bounds are unclear.
Claim 18 is indefinite in its recitation of “microgel particles” in line 2. There is not proper antecedent bases for “microgel particles”. Claim 1 recites “charge-neutral microgel particles”.
Claim Rejections - 35 USC § 112(a): Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 14-16, 18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
M.P.E.P. § 2163 recites, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.” Further, the written description inquiry is limited to that which is contained within the four corners of the specification, not the extent to which the skilled artisan, given his or her knowledge of the art, would have considered it to expand with only routine experimentation. See Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc); see also id. At 1352 (“[I]t is the specification itself that must demonstrate possession. A description that merely renders the invention obvious does not satisfy the requirement.").
Claim 1 recites a generic three-dimensional cell culture medium comprising; a plurality of charge-neutral microgel particles, and a liquid cell culture medium, wherein the charge neutral microgel particles are substantially spherical, and wherein the charge-neutral microgel particles have a radius of 0.5 um to 100um.
The charge-neutral microgel particles are broadly but reasonably interpreted as comprising a genus of monomers, polymers, or a combination thereof resulting in microgel particles have a radius of from 0.5 μm to 100 μm. There is not structure/ function correlation for the claimed genus of charge-neutral microgel particles.
The specification details only microgels composed of poly(ethylene glycol) methyl ether acrylate (PEGa) and poly(ethylene glycol) diacrylate (PEGda) at a ratio of 80:20 (Specification, page 16, lines 11-14, “The polymer can have a PEGa to PEGda ratio of from about 0:100 to about 99:1 or from about 80:20 to about 99:1”; Figure 1). Therefore, there is no possession of the term “microgel” as it encompasses various polymers, and the specification only recites a single working example. The Specification further illustrates in Figure 3B inverse emulsion polymerization of uncharged microgels and estimate average particle size. “These particles were found to be nearly perfect spheres, in contrast to microgels synthesized by precipitation polymerization.” (paragraph [0015] of the published application). Although the specification suggests embodiments of polymers containing acrylamides (Specification, page 6, lines 5-10), there are no working examples within the specification containing molecular weights, ratios, and/or concentrations of acrylamides that result in the creation of charge-neutral microgel particles with a particular radius from 0.5 um to 100 um and have a permeability of 0.1 pm2 to 10000 pm2(claim 15) .
Bhattacharjee et al. (Published: 2018, Soft Matter, 14, 1559-1570) specifies a microgel model that consists of methacrylic acid and acrylamide (pg 1560, col 1, para 1, “The commercially available microgels, known as carbomers, are cross-linked copolymer networks of acrylic acid and neutral alkyl-methacrylate monomers; our custom-made microgels are copolymers of methacrylic acid (MAA) and acrylamide.”). Microgels made of different polymers will obey different scaling laws based on their polymer chain characteristics, and subsequently their charges (pg 1560, col 1, para 1, “For both neutral and charged polymers, the scaling laws that predict hydrogel material properties are well established.28–32 Here, we leverage this understanding of polyelectrolytes to investigate the behavior of jammed anionic microgels as they yield.”) The change of polymers also results in various in different radii than the applicant’s example recited in the specification (page 1565, Figure 7). Given this, the prior art demonstrates that the specification fails to provide the full scope of the claims, and does not provide reasonable possession of all polymers, monomers or combinations thereof.
Xia et al. (Published: 2017, Polym J 49, 695–702), specifies a microgel model that consists of N-Isopropylacrylamide, N,N‘-methylenebisacrylamide through emulsion polymerization. The microgels formed resulted in a materially different microgel system that exhibits different physiochemical behaviors such as thermoreversible gelation (Abstract, pg 2094 “IPN and PNIPAM microgels were characterized and compared by dynamic and static light scattering techniques. The concentrated aqueous solutions of the PNIPAM-PAAc IPN microgels exhibit an inverse thermoreversible gelation. “). This behavior differs from PEG-based hydrogels, which are generally chemically inert and not stimuli-responsive. Furthermore, Xia et al. demonstrates that polymer identity and polymer network directly influences microgel swelling, aggregation, and phase behavior, subsequently affecting permeability of these gel particles (pg 2094, col 1 para 1, under Introduction, “In addition to the improved mechanical properties that usually come from the reinforcement between two interpenetrating networks,2 an IPN hydrogel can have a preferred direction for swelling by prestressing one of the components [poly(N-isopropylacrylamide), PNIPAM] before the gelation of the other one (polyacrylamide, PAAM) takes place.”). Thus, the prior art support the unpredictability of using of N-Isopropylacrylamide, N,N‘-methylenebisacrylamide through emulsion polymerization, for example, in relation to behavior the PEG-based hydrogels.
Therefore, the specification does not describe the claimed subject matter that would reasonably convey to one of skill in the art a three-dimensional cell culture that utilizes all types of monomers, polymers, or a combination thereof to and results in substantially spherical charge-neutral microgels with 0.5um to 100um radii.
Claim Rejections - 35 USC § 112(a): Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 14-16, 18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
a three-dimensional (3D) crosslinked cell culture comprising poly(ethylene glycol) methyl ether acrylate (PEGa) and poly(ethylene glycol) diacrylate (PEGda); wherein a ratio of PEGa to PEGda is about 80:20; and wherein the 3D cell culture gel comprises about 10 wt% to about 25 wt% crosslinked polymer network,
does not reasonably provide enablement for a three-dimensional cell culture that is not crosslinked, that contains a genus of polymers and/or monomers outside of PEG-based microgels, wherein the charge-neutral microgel particles have a radius of from 0.5 μm to 100 μm, and is highly permeable when compared to non-spherical microgels. The specification does not enable any person with skill in the art to use the invention to commensurate in scope of these claims.
The criteria for enablement set out In re Wands, MPEP 2162.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed to a three-dimensional culture medium comprising of charge-neutral microgels. Thus, encompassing all 3D cell culture-mediums comprising microgels of any polymer or monomer composition. As such, the breadth of the claims is great.
State of Prior Art
Xia et al. (Polym J 49, 695–702 (2017)), specifies a microgel model that consists of N-Isopropylacrylamide, N,N‘-methylenebisacrylamide through emulsion polymerization. The microgels formed resulted in a materially different microgel system that exhibits different physiochemical behaviors such as thermoreversible gelation (Abstract, pg 2094 “IPN and PNIPAM microgels were characterized and compared by dynamic and static light scattering techniques. The concentrated aqueous solutions of the PNIPAM-PAAc IPN microgels exhibit an inverse thermoreversible gelation. “). . This behavior differs from PEG-based hydrogels, which are generally chemically inert and not stimuli-responsive. Furthermore, Xia et al. demonstrates that polymer identity and polymer network directly influences microgel swelling, aggregation, and phase behavior, subsequently affecting permeability of these gel particles (pg 2094, col 1 para 1, under Introduction, “In addition to the improved mechanical properties that usually come from the reinforcement between two interpenetrating networks,2 an IPN hydrogel can have a preferred direction for swelling by prestressing one of the components [poly(N-isopropylacrylamide), PNIPAM] before the gelation of the other one (polyacrylamide, PAAM) takes place.”).
The Amount of Direction Provided by the Inventor
The specification provides insufficient direction and guidance to enable a person of ordinary skill in the art to practice the full scope of the claimed invention. Although the claims encompass microgels formed by any polymer, monomer or combinations thereof, the specification only provides working examples for microgels utilizing PEGa and PEGda (Specification, paragraph [0095], “the microgels can have from about 7 wt % to about 95 wt % polymer, or from about 10 wt % and about 25 wt % polymer. The polymer can have a PEGa to PEGda ratio of from about 0:100 to about 99:1 or from about 80:20 to about 99:1.”). Although it is noted that in some embodiments, the Specification mentions the polymers may include acrylamides, N-alkylacrylamides, etc., the disclosure does not provide teachings for microgels formed from non-PEG polymers, such as those with different monomer chemistries, charge properties, hydrophobicity, crosslinking mechanisms, or swelling behaviors. Aside from the PEGa and PEGda examples, the specification lacks step-by-step protocols, processing conditions, or ranges that would enable a skilled artisan to adapt the methods to other polymers encompassed by the claims. As a result, the guidance provided is not commensurate with the breadth of the claims, and a skilled artisan would require undue experimentation to practice embodiments outside the PEG-based species actually described.
The Presence or Absence of Working Examples
The specification provides working examples for PEGa and PEGda, and does not include any examples demonstrating the successful preparation or performance of microgels formed from other polymers having a radius of from 0.5 um to 100 um, encompassed by the claims. Although the claims broadly encompass any polymer, the specification contains no experimental data, procedures or functional results for non-PEG polymers, polymers with charges, hydrophobicity, molecular weights, etc. The absence of working examples for all species of polymers is highly significant because the prior art establishes that microgel properties such as swelling behavior, charge, and particle size are influenced by the polymer identity. As such, the limited working examples do not encompass the full scope of the claims and the specification does not fully enable the entire genus of polymers.
The Quantity of Experimentation Necessary
In view of the material-dependent behavior of specific microgel polymers in the art, a person of ordinary skill in the art would not reasonably expect the PEG-based synthesis methods in the specification to be able to the full scope of the charge-neutral microgels formed in different polymer chemistries to result in charge-neutral microgel particles having a radius of from 0.5 μm to 100 μm encompassed in the claims without undue experimentation.
Conclusion
In light of the unpredictability surrounding the claimed subject matter and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. It is especially noted that applicants provide no data, examples, figures, etc. demonstrating that the plurality of charge-neutral microgel particles are substantially spherical, and have a radius of from 0.5 µm to 100 µm. One wishing to practice the presently claimed invention would have to produce additional data and experimentation to determine whether the claimed charge-neutral microgel particles are capable of achieving the intended results (e.g, a particular radius from 0.5 um to 100 um, a permeability of 0.1 pm2 to 10000 pm2 (claim 15), a surface roughness of from Oto 5 micrometers, claim 2). In the absence of such information, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation.
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.
Claims 1-3 and 18 are unpatentable over 35 U.S.C. 103 as being unpatentable over O’Bryan (Published 26 February 2019, ACS Appl. Bio Mater, IDS filed on 8/28/2022 ).
Regarding claim 1, O'Bryan teaches a three-dimensional (3D) cell culture medium (abstract, "We explore the potential application of these microgels as biomaterials for 3D cell culture") comprising: a plurality of microgel particles (pg 1511 col 2 para 3, "Each microgel system is prepared with a charged species at varying polymer charge density; here, we use ... carboxybetaine methacrylate (CBMA) for zwitterionic microgels"); and a liquid cell culture medium (pg 1511 col 1 para 1-2, "Microgels for cell culturing are swollen in MEGM cell growth media to a final polymer concentration of 4 wt %. After passaging, the cells are pelleted and resuspended at a high density in liquid growth media before subsequently being pipetted into the microgel growth media"), wherein the microgel particles are spherical, and wherein the microgel particles have a radius of from 0.5 um to 100 um (pg 1511 col 2 para 3, ''We measure the average size of each microgel in the dilute state and find the mean particle diameters to be ... 5.21 +/- 2.14 um for the CBMA microgels"). Additionally, it would be obvious to one of ordinary skill in the art to modify and optimize the polymer concentration or composition through routine experimentation such that the radii of the microgels falls within the range of 0.5 micrometers to 100 micrometers.
O'Bryan does not explicitly teach the microgel particles as charge-neutral or substantially spherical or within the same embodiment.
However, O’Bryan further discusses the modification of the hydrogel composition to be charge neutral to reduce deformities within the microgel particles (pg 1512 col 2 para 2, "Neutral hydrogels swell to an equilibrium concentration in which the driving osmotic pressure (pi) generated from the random motion of the polymer chains is balanced"; pg 1514 col 1 para 2, "As the polymer concentration of the microgels increases above the jamming concentration, individual microgel particles will deform without osmotically driven deswelling, resulting in volume fractions in excess of the random close packing limit of hard spheres. However, increasing the concentration of added salts appears to drive the deswelling of the microgel particles, leading to a transition of the system from the jammed to unjammed state";pg 1516 col 1 para 1, "In contrast, simple polyelectrolyte scaling laws do not capture the rheological behavior of zwitterionic microgels. Instead, zwitterionic microgels exhibit a plateau in rheological properties in the high-salt limit. This unique behavior may be advantageous when swelling microgels in salt-rich solvents, such as cell growth media. However, interactions between the zwitterionic microgels and biological zwitterionic molecules, including amino acids and proteins, may result in unforeseen changes in rheological properties beyond the scope of this work. Further development of charge-neutral microgels may circumvent these interactions, providing opportunities for further biomaterial applications using microgels").
Therefore, it would be obvious for one skilled in the art to incorporate charge-neutral microgels to prevent unwarranted changes in rheological properties as contemplated by O’Bryan with a reasonable expectation of success .
Regarding claim 2, O'Bryan renders obvious the 3D cell culture medium according to claim 1, but does not explicitly teach wherein the charge-neutral microgel particles have a surface roughness of from 0 to 5 micrometers, relative to a perfect spherical surface.
However, it would have been obvious to one of ordinary skill in the art to modify polymer concentration by routine experimentation wherein the particles have a surface roughness of from 0 to 5 micrometers, relative to a perfect spherical surface to optimize cell culture viability (abstract, "We find that the short-term viability of cells cultured in polyelectrolytes is highly dependent on the chemical composition of the system"; pg 1514 col 1 para 2, "As the polymer concentration of the microgels increases above the jamming concentration, individual microgel particles will deform without osmotically driven deswelling, resulting in volume fractions in excess of the random close packing limit of hard spheres.).
Regarding claim 3, O'Bryan renders obvious the 3D cell culture medium according to claim 1, wherein the 3D cell culture gel comprises from 0.1 % to 10% polymer (pg 1511 col 1 para 1-2, "Microgels for cell culturing are swollen in MEGM cell growth media to a final polymer concentration of 4 wt% ... ").
Regarding claim 18, O’Bryan renders obvious the 3D cell culture medium according to claim 1, wherein the concentration of the microgel particles is from 0.05% to 1.0% by weight (Results and Discussion, pg 1511 col 2 para 7 bridging into pg 1512 col 1 para 1, “We find the jamming concentrations of the microgels to be 0.3, 0.45, and 0.9 wt % for microgel particles containing 17 mol % of MAA, qDMAEMA, and CBMA, respectively"), falling within the scope of concentration of microgel particles is from 0.05% to 1.0% by weight.
Claims 4, 16 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of O’Bryan et al., ( Published 26 February 2019, ACS Appl. Bio Mater, IDS filed on 8/26/2022) and Weaver et al. (US 20190321797 A1, IDS filed on 08/26/2022).
With regard to instant claim 1, the teachings the 3D cell culture medium in O’Bryan render obvious the claimed product, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety. However, O’Bryan fails to teach teaches a pore space formed between adjacent charge-neutral microgel particles is from 50 nm to 10 um as recited in claim 4.
However, Weaver teaches a pore space formed between adjacent charge-neutral microgel particles is from 50 nm to 10 um (Claim 10, “ the stabilized scaffold comprising pores having a median diameter of about 10 μm to about 35 μm).
It would have been obvious to combine the teachings of O’Bryan et al., on charge-neutral microgel particles with the teachings of Weaver on charge-neutral microgel particles a pore space formed from 50 nm to 10 um with a reasonable expectation of success.
Regarding claim 16, O’Bryan renders obvious teaches the 3D cell culture medium according to claim 1. Moreover, Weaver teaches a yield stress of 0.1 to 100 Pa (para 0065, “The gel before annealing may have a compressive modulus (mechanical stiffness) of about 200-1000 Pa. The gel before annealing may have a compressive modulus (mechanical stiffness) of about 200-500 Pa. The gel before annealing may have a compressive modulus (mechanical stiffness) of about 500-1000 Pa.”).
It would have been obvious to combine the teachings of O’Bryan et al., on charge-neutral microgel particles with the teachings of Weaver on charge-neutral microgel particles having a compressive modulus (mechanical stiffness) of about 200-1000 Pa with a reasonable expectation of success. Undergoing a phase change from a first solid phase to a second liquid phase upon application of about 200-1000 Pa would be an expected property of said application.
In relation to claims 4 and 16, the prior art differs from the claimed invention only with respect the pore diameter of the microgel scaffold and the yield stress of the 3D culture medium. However, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount.
Regarding claim 20, O’Bryan renders obvious teaches the 3D cell culture medium according to claim 1. Moreover Weaver et al., teaches a similar microgel 3D culture medium that further comprises antibiotics (Abstract, “The microgel scaffolds are fluidic during application and annealed or crosslinked after application to the implant site in the subject. The microgel scaffolds may contain various therapeutic agents, including antibiotics and analgesics, throughout the gel.”). Therefore, it would have been obvious to one of ordinary skill in the art to incorporate antibiotics into the 3D cell culture as routine experimentation to prevent unwanted microbial growth in O’Bryan’s 3D cell culture.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of O’Bryan et al., (Published 26 February 2019, ACS Appl. Bio Mater, under Cite no 1 and 2 in IDS filed on 08/26/2022) and Canning et al. (Published on March 9 2016, Macromolecules 2016, 49, 6, 1985–2001).
With regard to instant claim 1, the teaching the 3D cell culture medium in O’Bryan render obvious the claimed product, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety. Moreover, O’Bryan teaches a weight percentage of a crosslinked polymer network, as recited in claim 14, line 6 (page 1511 col 1 para 1 “Microgels for cell culturing are swollen in MEGM cell growth media to a final polymer concentration of 4 wt %”).
However, O’Bryan does not teach the charge-neutral microgel particles comprise a crosslinked polymer network; wherein the crosslinked polymer network comprises poly(ethylene glycol) methyl ether acrylate (PEGa) and poly(ethylene glycol) diacrylate (PEGda) wherein a ratio of PEGa to PEGda is about 80:20;.
Canning et al. teaches non-ionic microgels particles comprise a crosslinked polymer network of poly(ethylene glycol) methyl ether acrylate and poly(ethylene glycol) diacrylate, (page 1989, col 2 para 3 bridging into page 1990 col 1 para 1, “Chain extension of a poly(ethylene glycol) (PEG)-based macro-CTA with 2-methoxyethyl acrylate (MEA), PEG methyl ether acrylate, and a small amount of PEG diacrylate (PEGDA) cross-linker produced spherical nanogels, whose dimensions decreased almost linearly as the solution temperature was increased from 20 to 60 °C.”, page 1993 col 2 para 2, “…such covalent cross-linking also eliminates the desirable stimulus-responsive behavior…”).
It would be obvious to substitute the charged-microgels of O’Bryan with the charge-neutral microgels of Canning, because PEG-based acrylates are well known in the art to be neutral and hydrophilic monomers. The incorporation of PEGa and PEGda would result in a chemically inert gel that would not respond to any charged stimuli, representing a predictable design choice that a skilled artisan would to produce a neutral microgel. Furthermore, O’Bryan mentions the use of charge-neutral microgels to overcome the unforeseen changes in rheological properties (pg 1516 col 1 para 1,”Further development of charge-neutral microgels may circumvent these interactions, providing opportunities for further biomaterial applications using microgels.”). So, a skilled artisan in the art would have been motivated to utilize PEGa and PEGda as they are known to produce charge neutral microgels and prevent any change in rheological characteristics of the gel.
Though neither O’Bryan or Canning explicitly teach the ratio of PEGa to PEGda to be about 80:20 and the 3D cell culture gel comprises about 10 wt% to 25 wt% crosslinked polymer network, as recited in claim 14, and that the charge-neutral microgels have a permeability of 0.1 um2 to 10000 um2 recited in claim 15, it would be obvious to modify and optimize the polymer composition (e.g. polymer block ratio, crosslinker content within liquid medium, and permeability of microgels) as it would involve routine experimentation within the ordinary skill in the art absent any evidence of unexpected results. Standard microgel synthesis parameters such as the block ratio of polymers, permeability can be adjusted by a skilled artisan by simple iterative trials and well-known procedures in the art. Routine characterization techniques would also have guided such optimization and trends to achieve the claimed parameters. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount.
Conclusion
Claims 1-4, 14-16, 18 and 20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 7:30a-5p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634