UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED

Patent Trials and Appeals Board

Mar 15, 2022

2021002018 (P.T.A.B. Mar. 15, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/759,587 03/13/2018 BENJAMIN G. KESELOWSKY T15745 (222108-1500) 2850 154717 7590 03/15/2022 THOMAS|HORSTEMEYER, LLP - UF UNIVERSITY OF FLORIDA (UF) 3200 WINDY HILL ROAD, SE SUITE 1600E ATLANTA, GA 30339 EXAMINER CORDAS, EMILY ANN ART UNIT PAPER NUMBER 1632 NOTIFICATION DATE DELIVERY MODE 03/15/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docketing@thomashorstemeyer.com ozzie.liggins@thomashorstemeyer.com uspatents@thomashorstemeyer.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte BENJAMIN G. KESELOWSKY, THOMAS ETTOR ANGELINI, WALLACE GREGORY SAWYER, and TAPOMOY BHATTACHARJEE __________ Appeal 2021-002018 Application 15/759,587 Technology Center 1600 __________ Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and JOHN E. SCHNEIDER, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a three dimensional apparatus for culturing and interacting with biological cells and/or tissues. The Examiner rejected the claims under 35 U.S.C § 103 as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the Real Party in Interest as the University of Florida Research Foundation (see Appeal Br. 2). We have considered the Specification of Mar. 13, 2018 (“Spec.”); the Final Office Action of Apr., 29, 2020 (“Final Act.”); the Appeal Brief of Oct. 12, 2020 (“Appeal Br.”); the Examiner’s Answer of Dec. 3, 2020 (“Ans.”); and the Reply Brief of Jan. 25, 2021 (“Reply Br.”). Appeal 2021-002018 Application 15/759,587 3 Statement of the Case Background “Conventional cell culture techniques involve growing cells on a two- dimensional (2D) substrate, such as a micro-well plate or a Petri dish” (Spec. ¶ 3). “However, the 2D environment of conventional cell cultures is often a poor substitute for the three-dimensional (3D) environment experienced by cells in vivo. For example, the behavior of a cell is often highly dependent on the microenvironment around the cell” (id. ¶ 3). “Several techniques have been developed for 3D cell culture, including the use of hanging drop plates, magnetic levitation, or biomaterial scaffolds. However, these techniques are typically expensive and/or time consuming, and may be limited in the specific structures or geometries of tissues which may be grown and/or tested” (id. ¶ 4). The Claims Claims 1-15 and 37-39 are on appeal. Claim 1 is the sole independent claim, is representative and reproduced below with bracketed letters added to identify the elements: 1. An apparatus for culturing and interacting with biological cells and/or tissues, the apparatus comprising: [a] a chamber comprising a container holding a three- dimensional (3D) cell growth medium, the 3D cell growth medium being a yield stress material having a yield stress such that the cell growth medium undergoes a phase change from a first solid phase to a second liquid phase upon application of a shear stress greater than the yield stress; [b] equipment to dispense biological cells and/or tissues at particular positions within the 3D cell growth medium in the container; and [c] equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container. Appeal 2021-002018 Application 15/759,587 4 The Issues2 A. The Examiner rejected claims 1, 2, 7-13, 37, and 38 under 35 U.S.C. § 103 as being obvious over Murphy3 and Feinberg4 (Ans. 4-9). B. The Examiner rejected claims 1-13 and 37-39 under 35 U.S.C. § 103 as being obvious over Murphy, Feinberg, and Wang5 (Ans. 9-15). C. The Examiner rejected claims 1, 2, 7-15, 37, and 38 under 35 U.S.C. § 103 as being obvious over Murphy, Feinberg, and Antoni6 (Ans. 15-21). A. 35 U.S.C. § 103 over Murphy and Feinberg The Examiner finds “Murphy teaches a bioprinter for generating tissues (an apparatus for culturing and interacting cells) . . . with a reservoir of bio-ink which includes a gel (three-dimensional cell growth medium) . . . and the gel is thixotropic” (Ans. 4). The Examiner finds as to element [a] of claim 1, that Murphy teaches, “a petri dish to receive the structures generated by the bioprinter (a container holding the 3D growth medium)” (id.). The Examiner finds, as to element [b] of claim 1, that Murphy teaches “the bioprinter has cartridges which are for bio-ink which includes cells and support material (equipment to dispense biological cells and/or tissues at particular positions within the 3D cell growth medium in the container)” (id. at 4-5). The Examiner finds, as to element [c] of claim 1, that Murphy teaches “means for applying a wetting agent to the printed construct 2 The Examiner withdrew the written description rejection (see Ans. 21). 3 Murphy et al., US 2015/0057786 A1, published Feb. 26, 2015. 4 Feinberg et al., US 2016/0167312 A1, published June 16, 2016. 5 Wang et al., US 2015/0217024 A1, published Aug. 6, 2015. 6 Delphine Antoni et al., Three-Dimensional Cell Culture: A Breakthrough in Vivo, 16 Int. J. Mol. Sci. 5517-27 (2015). Appeal 2021-002018 Application 15/759,587 5 (equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container)” (id. at 5). The Examiner acknowledges “Murphy does not explicitly teach the 3D cell growth medium (the thixotropic gel or the support material) is a yield stress material” as recited in claim 1. The Examiner finds Feinberg teaches an “apparatus for the culturing and interacting with biological cells . . . where the container contains a three- dimension[al] cell growth medium that is a support material that is stationary at an applied stress level below a threshold stress level and flows at an applied stress level” (Ans. 7). The Examiner finds Feinberg teaches “the three dimensional printing of soft, biological hydrogel structures that might be too soft to fabricate using other 3D printing techniques” and that these “soft materials have an elastic modulus in the range of 10 GPa to 0.1 kPa” (id.). The Examiner finds it obvious to select the cell growth medium of Feinberg for use in the bioprinting apparatus of Murphy because “Murphy teaches similar thixotropic gels in the apparatus and Feinberg teaches a similar apparatus for the culturing and interacting with biological cells where the container contains a three-dimension cell growth medium” (Ans. 7). The Examiner finds “the elastic modulus of the 3D growth medium and modulus of the modulus of the 3D cell growth medium would be matter of routine optimization depending on the needed characteristics of the 3D cell growth medium for generating or culturing a particular soft tissue as evidenced by Feinberg” (id. at 8). Appeal 2021-002018 Application 15/759,587 6 The issue with respect to this rejection is: Does a preponderance of the evidence of record support the Examiner’s conclusion that Murphy and Feinberg render the claimed composition obvious? Findings of Fact 1. Murphy teaches “devices for fabricating tissues and organs, systems and methods for calibrating and using such devices, and tissues and organs fabricated by the devices, systems, and methods disclosed herein” (Murphy ¶ 19). 2. Murphy teaches, as to the chamber and container of element [a] of claim 1, that a “receiving surface comprises a solid material, a semi-solid material, or a combination thereof. In some embodiments, the receiving surface comprises glass, coated glass, plastic, coated plastic, metal, a metal alloy, or a combination thereof. In some embodiments, the receiving surface comprises a gel” (Murphy ¶ 98). Murphy teaches an exemplary chamber, specifically “a Petri dish for receiving structures generated by the bioprinter. The Petri dish was coated with NovoGel™” (Murphy ¶ 223). Murphy teaches “bioprinting of a three-dimensional construct” (Murphy ¶ 62) using a variety of three-dimensional cell growth media including “hydrogel, NovoGel™, agarose, alginate, gelatin, Matrigel™, hyaluronan, poloxamer, peptide hydrogel, poly (isopropyl n- polyacrylamide), polyethylene glycol diacrylate (PEG-DA), hydroxyethyl methacrylate, polydimethylsiloxane, polyacrylamide, poly(lactic acid), silicon, silk, or combinations thereof” (Murphy ¶ 138). Murphy teaches the “rheology of the compositions or devices disclosed herein is . . . thixotropic” (Murphy ¶ 120) (see Spec. ¶ 27 “a thixotropic or ‘yield stress’ material”). Appeal 2021-002018 Application 15/759,587 7 3. Murphy teaches, as to the dispensing equipment of element [b] of claim 1, that bioprinted cellular constructs, tissues, and organs are made with a method that utilizes a rapid prototyping technology based on three-dimensional, automated, computer-aided deposition of cells, including cell solutions, cell suspensions, cell-comprising gels or pastes, cell concentrations, multicellular bodies (e.g., cylinders, spheroids, ribbons, etc.), and support material onto a biocompatible surface (e.g., composed of hydrogel and/or a porous membrane) by a three-dimensional delivery device (e.g., a bioprinter). (Murphy ¶ 59). Murphy teaches “the bioprinter dispenses bio-ink or support material in a specific pattern and at specific positions in order to form a specific cellular construct, tissue, or organ” (Murphy ¶ 80). 4. Murphy teaches, as to the interaction equipment of element [c] of claim 1, that a “wetting agent is applied after the bio-ink or supporting material is dispensed by the bioprinter. In some embodiments, a wetting agent is applied simultaneously or substantially simultaneously with the bioink or supporting material being dispensed by the bioprinter” (Murphy ¶ 74). Murphy teaches another form of interaction equipment involving “dispensing elongate bodies (e.g., cylinders, ribbons, etc.) of confinement material overlaying the nascent tissue in a pattern” (Murphy ¶ 143). Murphy also teaches interactions where “the cells of the tissue or organ are exposed to nutrients non-uniformly. In non-uniform embodiments, the differential access to nutrients may be exploited to influence one or more properties of the tissue or organ” (Murphy ¶ 144). 5. Feinberg teaches: The 3D printing techniques described in this disclosure are applicable to gelling polymers and enable true freeform printing Appeal 2021-002018 Application 15/759,587 8 of complex geometries. The techniques can be used to produce anatomically correct, perfusable scaffolds of coronary arteries. The techniques are cross-platform and can easily be adopted for use on many open-source and proprietary 3D printers. (Feinberg ¶ 12). 6. Feinberg teaches, as to the growth medium in element [a] of claim 1, that “the embedded material is initially a fluid or flowable material that transitions to a solid or semi-solid state after deposition” and that “soft materials can include solid materials that have an elastic modulus in the range of approximately 10 GPa to 0.1 kPa” (Feinberg ¶¶ 35, 37). 7. Feinberg further explains that the “support material may exhibit viscoplastic behavior where it acts as a solid below a threshold shear stress and flows like a liquid above the threshold shear stress” (Feinberg ¶ 40). 8. Feinberg teaches, as to element [b] of claim 1, that “a 3D bioprinter can lower a syringe-based extruder into the support material and move around and deposit material in arbitrary 3D geometries. The extruded material stays in place once the tip of the extruder moves away, thus forming the 3D printed object” (Feinberg ¶ 42). Feinberg teaches “cells can be extruded out of the printer nozzle with the hydrogel and maintain viability” (Feinberg ¶ 49). 9. Feinberg teaches, as to element [c] of claim 1, an example where: Once the living muscle fiber threads are generated with FRESH, they can be used to weave muscle tissue constructs that recapitulate the overall shape and cellular architecture of craniofacial muscles. Using custom bioreactors, support posts can be integrated into 35-mm cell culture Petri dishes around which the cell threads can be weaved. Appeal 2021-002018 Application 15/759,587 9 (Feinberg ¶ 81). 10. Feinberg teaches the “support material may include a gel material. The support material may include a hydrogel material. . . . The structure material may include . . . a polysaccharide hydrogel material, synthetic gel material” (Feinberg ¶ 9). Feinberg also recognizes the “structure material may include at least one of a gel material that is different from the support material” (Feinberg ¶ 9). Principles of Law A prima facie case for obviousness “requires a suggestion of all limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Analysis We adopt the Examiner’s findings of fact and conclusion of law (see Ans. 4-9; FF 1-9) and agree that the combination of Murphy and Feinberg renders the claims obvious. We address Appellant’s arguments below. Appellant contends: “[a]dvantages of the features of Appellant's claims over the prior art of record are discussed in Appellant's application as filed” (Appeal Br. 11). Appellant asserts advantages including “a yield stress material having a yield stress such that the cell growth medium undergoes a phase change from a first solid phase to a second liquid phase upon application of a shear stress greater than the yield stress” as recited in claim 1 (id. at 12). Appeal 2021-002018 Application 15/759,587 10 We agree with the Examiner that “the features upon which appellant relies (i.e., the listed advantages by appellant) are not recited in the rejected claims” (Ans. 23-24). That is, advantages listed on pages 11 and 12 of the Appeal Brief such as “facile placement and/or retrieval of a group [of] cells at any desired location”; “the yield stress material may be large enough to prevent yielding due to gravitational and/or diffusional forces exerted by the cells”; and “[s]ince the cells are fixed in place, they may be retrieved from the same location” are not recited in claim 1 and therefore add no limitations to claim 1. See In re Self, 671 F.2d 1344, 1348 (CCPA 1982) (“[A]ppellant’s arguments fail from the outset because . . . they are not based on limitations appearing in the claims.”) Moreover, both Murphy and Feinberg teach the use of “yield stress” or “thixotropic” materials for use in the bioprinting process (FF 2, 6, 7). Also, Feinberg teaches facile placement of cells at locations within the 3D gel that remain in place (see FF 8 “a 3D bioprinter can lower a syringe-based extruder into the support material and move around and deposit material in arbitrary 3D geometries. The extruded material stays in place”). Thus, even the advantages identified by Appellant are disclosed by the prior art. Appellant contends “[w]hile Murphy discloses a petri dish in [0223] that can be printed into, it does not appear to teach a receiving cartridge for the extruded contents that contains a 3D culture medium with the properties recited at least in Appellant’s claim 1” (Appeal Br. 13). We find this argument unpersuasive as the broadest reasonable interpretation of the limitation “equipment to dispense biological cells and/or tissues at particular positions within the 3D cell growth medium in the container” in claim 1 reasonably encompasses equipment that dispenses the Appeal 2021-002018 Application 15/759,587 11 biological cells at particular locations. Murphy teaches “computer-aided deposition of cells . . . onto a biocompatible surface (e.g., composed of hydrogel and/or a porous membrane) by a three-dimensional delivery device” (FF 3). Murphy specifically teaches “the bioprinter dispenses bio- ink or support material in a specific pattern and at specific positions in order to form a specific cellular construct, tissue, or organ” (FF 3). Thus, Murphy is reasonably interpreted as teaching that the bioprinter has the capacity to dispense biological cells at particular positions within the three dimensional growth medium. Appellant has provided no evidence or persuasive argument otherwise. Appellant contends the “culture medium recited in Appellant's claim 1 is printed into by the extrusion nozzle and is not a part of the ink or biomaterials printed with the printer” (Appeal Br. 13). We find this argument unpersuasive as there is no claim limitation requiring printing using an extrusion nozzle in claim 1, or that the culture medium cannot be part of the ink or biomaterials. “[L]imitations are not to be read into the claims from the specification.” In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993). We also find this argument unpersuasive as the rejection is not based on Murphy alone, but also relies upon Feinberg, who teaches “cells can be extruded out of the printer nozzle with the hydrogel and maintain viability” (FF 8). Thus, Feinberg teaches extrusion using a nozzle that includes a hydrogel culture medium. Feinberg further teaches “a 3D bioprinter can lower a syringe-based extruder into the support material and move around and deposit material in arbitrary 3D geometries” (FF 8). This is an express teaching of printing biomaterials into a culture material. Appeal 2021-002018 Application 15/759,587 12 Appellant contends the support materials of Feinberg and Murphy are different support materials for different purposes - one is meant for ink and extrusion (Murphy) while the other is meant to receive the printed material (Feinberg) - and it would not be expected that the materials of Feinberg would be suitable for the extrusion cartridge of Murphy, or vice versa. The skilled artisan would therefore not combine the teachings of the cited prior art references with a reasonable expectation of success. (Appeal Br. 14). Appellant contends “the Office has not properly ascertained the scope and content of the prior art and has not properly applied the teachings of the prior art to Appellant’s claims” (id. at 15). We find this argument unpersuasive as both Feinberg and Murphy are in the same field of endeavor, bioprinting cells and support materials into tissues and organs (FF 3) including coronary arteries (FF 5). Appellant provides no evidence that the bioprinting teachings of Feinberg and Murphy would not function together, and provides no evidence showing a lack of a reasonable expectation of success. “[A]ttorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). And both Feinberg and Murphy provide detailed guidance, providing reasonably support for the Examiner’s finding of a reasonable expectation of success. “Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). Appellant contends “Wang does not relate to 3D printing, or more specifically, the printing of biomaterial into a support material” and that “there is no indication, in the reference itself or the obviousness analysis Appeal 2021-002018 Application 15/759,587 13 provided by the Office, that the apparati disclosed in Antoni . . . would be useful for a cartridge with the 3D cell culture medium” (Appeal Br. 15). We find this argument unpersuasive because neither Wang nor Antoni was relied upon for the rejection of claim 1. Instead, Wang was relied upon for particular processes of making hydrogels as required by claims 3-6 and demonstrates that these are known hydrogels and “have shown great promise as a scaffold for tissue engineering due to their tissue-like water content, good biocompatibility, and injectable accessibility” (Wang ¶ 7). Similarly, Antoni was relied upon for a tissue culture apparatus that includes removal of metabolic waste as required by claim 15 (see Antoni 5522 “Bioreactors enable the precise and reproducible control over many environmental conditions required for cell culture, including temperature, pH, medium flow rate, oxygen, nutrient supply, and waste metabolite removal”). Appellant does not provide any persuasive reasons why it would not have been obvious to modify the bioprinting apparatus rendered obvious by Murphy and Feinberg by selecting the known hydrogels of Wang and the known bioreactors of Antoni for their known benefits. “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 550 U.S. at 417. Appellant contends “only instance of the Office addressing the differences between at least Murphy and Feinberg appears to be the conclusory statement [that the support material] ‘may be the same’ that is not supported with any reasoning or rationale that is required for an obviousness analysis” (Appeal Br. 16). We are not persuaded because the issue is obviousness, not anticipation. The Examiner provided a very detailed and thorough Appeal 2021-002018 Application 15/759,587 14 obviousness analysis that fully addressed all of the claims (see, e.g., Final Act. 5-22). Appellant is essentially incorrectly asserting that the ordinary artisan, aware of hydrogels, tissue engineering, and bioprinting from Murphy and Feinberg, would have been unable to recognize that the hydrogels used in a bioprinting process that deposited multiple layers of biogel could not be either the same or different, as desired by the ordinary artisan. Appellant’s argument is particularly inaccurate given that Murphy teaches that the device may print cell-comprising gels and that the support material may be a hydrogel in a single paragraph (FF 3). Moreover, Feinberg teaches that gel materials may be used in both the structure and support materials and may be different (FF 10). In contrast, Appellant provides no evidence or persuasive argument explaining why the ordinary artisan would have been unable to select the same or different hydrogels for use in the bioprinting processes given the extensive disclosures in the prior art. Appellant contends the “Office concludes that elastic modulus and modulus of Appellant's claim 1 are result effective variables without making any serious attempt to explain how or why one would optimize these values for what purpose” (Appeal Br. 16). We agree with the Examiner that, because Feinberg teaches a range of elastic modulus values from 10 GPa to 0.1 kPa (FF 6), the ordinary artisan would have had reason to optimize within that known range (Ans. 29) that overlaps with the elastic modulus range “between approximately 1 Pas and 10,000 Pa” recited in the Specification (see Spec. ¶ 48). “Such overlap itself provides sufficient motivation to optimize the ranges.” In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012). Also see In re Appeal 2021-002018 Application 15/759,587 15 Peterson, 315 F.3d 1325, 1330 (Fed.Cir.2003) (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of . . . ranges is the optimum combination.”). Appellant argues “[a]ny motivation to optimize would be therefore be for a different purpose than Appellant’s medium, and there would be no reasonable expectation of success by optimizing Murphy in view of Feinberg” (Appeal Br. 17). We find this argument unpersuasive for the reasons already given, particularly as the prior art has a resoundingly likely expectation of success, unrebutted by Appellant. As to the different reason for optimizing, “the motivation in the prior art to combine the references does not have to be identical to that of the applicant to establish obviousness.” In re Kemps, 97 F.3d 1427, 1430 (Fed. Cir. 1996). Indeed, “[i]n determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls. What matters is the objective reach of the claim. If the claim extends to what is obvious, it is invalid under § 103.” KSR, 550 U.S. at 420. In this case, we agree with the Examiner that the claims extend to what is obvious. Appellant contends that the Examiner’s “analysis is over-simplistic and reduces teachings of the cited prior art merely to the gist without recognizing critical functionality of Murphy relating to 3D printing and extrusion by the print head” (Appeal Br. 18). We are not persuaded. We have reviewed the Examiner’s extensive obviousness analysis (see Final Act. 5-22) and find that the Examiner provides specific citations to evidence of record along with reasonable Appeal 2021-002018 Application 15/759,587 16 analysis that properly determines that the claims at issue would have been obvious. Conclusion of Law A preponderance of the evidence of record supports the Examiner’s conclusion that Murphy and Feinberg render the claimed composition obvious. B. and C. 35 U.S.C. § 103 over Murphy, Feinberg, and Wang or Antoni Having affirmed the obviousness rejection of claim 1 over Murphy and Feinberg for the reasons given above, we also find that the further combinations with Wang or Antoni render the rejected claims obvious for the reasons given by the Examiner (see Ans. 9-21). Appeal 2021-002018 Application 15/759,587 17 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 2, 7-13, 37, 38 103 Murphy, Feinberg 1, 2, 7-13, 37, 38 1-13, 37- 39 103 Murphy, Feinberg, Wang 1-13, 37- 39 1, 2, 7-15, 37, 38 103 Murphy, Feinberg, Antoni 1, 2, 7-15, 37, 38 Overall Outcome 1-15, 37- 39 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED