Microfluidic Organs-on-a-Chip

The patent landscape

Robert W Esmond,  Director, Biotechnology/Chemical Group of Sterne, Kessler Goldstein & Fox P.L.L.C., USA

Stephanie L Elmer,  Associate, Biotechnology/Chemical Group of Sterne, Kessler Goldstein & Fox P.L.L.C., USA

Organs-on-a-chip are research tools that offer an alternative to the costly and time consuming use of clinical trials used in drug development. This article will discuss patents covering organs-on-a-chip, in particular those that contain multiple cells or tissue(s), the exceptions to patent infringement for experimental uses, and the prospects for further patenting.

Traditional methods of drug discovery — in particular, the use of animal testing — suffer from many limitations including: (a) the length of time and high costs associated with animal trials;  (b) the loss of animal lives; and (c) the failure of animal tests to accurately predict human responses.  Two-dimensional (2D) cell cultures have shown value in biomedical research;  however, they cannot   adequately simulate the multiple functions of many cell types or accurately predict in vivo tissue functions and drug activities.  Limitations with conventional two-dimensional (2D) cell cultures have led to the development of more complex systems such as three-dimensional (3D) cell cultures and organs-on-a-chip.  These products are often protected by various forms of intellectual property laws. The great potential of using organs-on-a-chip as research tools in the areas of tissue development, organ physiology, and disease etiology is likely to pose many intellectual property rights challenges.

The simplest organs-on-a-chip are microfluidic devices that contain a single, perfused  microfluidic chamber containing a single type of cultured cell that exhibits the functions of a single tissue type. More complex devices contain two or more channels or chambers that are connected by porous membranes which are lined on opposite sides by different types of cells in an attempt to mimic interfaces between different tissue types. These devices can incorporate physical forces such as cellular interactions, liquid flow, and liquid residence parameters, allowing analysis of organ-specific responses.  

The manufacture and use of organs-on-a-chip may infringe intellectual property rights as described in the table below. The limitations on enforcing the rights are also set forth.

Products of commerce may be protected by any one of these IP rights.  Organs-on-a-chip can be used for multiple research purposes, including drug discovery and development, and may find protection under a number of areas of intellectual property. For example, the   software and code used to manufacture organs-on-chips may be protected by copyright.  But it is unlikely that organs-on-a-chip will have a means for expression, ornamental features, or source of origin that can also find protection.

The best way to protect innovation related to organs-on-a-chip is with utility patents. 

In order to determine what patents might dominate the making, using, and selling of organs-on-chips, we carried out a patent landscape search. The landscape search did not attempt to cover all patents filed on potentially large number of manufacturing techniques and uses related to organs-on-a-chip.

The most important patents issued are described below. Pending applications are not included as their issuance as patents is speculative.

The first successful design of a microfluidic device containing two or more channels was termed a "body-on-a-chip" in an article in Newsweek.  This device is described in the following patent: 

US 7288405 "Devices and Methods for Pharmacokinetic-Based Cell Culture System" (Exp. Date: October 29, 2022). What is claimed is:

1. A pharmacokinetic based microscale culture device, comprising: a first microscale chamber containing a first type of cell, wherein the first microscale chamber is dimensioned to maintain the first type of cell under conditions that give rise to at least one pharmacokinetic parameter value comparable to a value for the same at least one pharmacokinetic parameter obtained with respect to the same type of cell in vivo, wherein the at least one pharmacokinetic parameter value is selected from the group consisting of a measurement of liquid residence time, and liquid to cell ratio, wherein the first chamber comprises a first inlet and a first outlet for flow of culture medium; a second microscale chamber containing a second type of cell, wherein the second microscale chamber is dimensioned to maintain the second type of cell under conditions that give rise to at least one pharmacokinetic parameter value comparable to a value for the same at least one pharmacokinetic parameter obtained with respect to the same type of cell in vivo, wherein the second chamber comprises a second inlet and a second outlet for flow of culture medium; and a microfluidic channel interconnecting the first and second microscale chambers wherein the microfluidic channel is dimensioned to transport a culture medium, and wherein the microscale culture device is dimensioned to maintain at least one desired value for shear stress under a condition of flow of the culture medium.

The patent is assigned to the Cornell Research Foundation, Inc.  It was filed in the United States, Australia, Canada, China, European Patent Office, and Japan. This patent appears to cover a microscale culture device comprising a first microscale chamber containing a first type of cell and a second microscale chamber containing a second type of cell.  According to the patent specification, the specific chambers provide cellular interactions, liquid flow, and liquid residence parameters for cells, tissues, and organs in vivo.  The patent specification makes clear that it covers not only cells and tissue, but also organs are contemplated:  ‘the device replicates a re-circulating multi-organ system by segregating living cells into discrete, interconnected ‘organ’ compartments (see e.g., FIG 15).’  Additional patent applications were filed, one resulting in a patent and one currently pending, which claim priority to this application.    

US 7725267 ‘Synthetic Microfluidic Microvascular Network’ (Exp. Date:  July 5, 2028)

Assignee:  CFD Research Corporation.  It was filed in the United States only.  What is claimed is:

1. A microfluidic microvascular chip comprising: one or more fluid inlets, one or more fluid outlets, and a plurality of non-linear flow channels forming a synthetic microvascular network allowing fluid flow between one or more fluid inlets and one or more fluid outlets wherein said non-linear flow channels forming said synthetic microvascular network possess a geometric characteristic selected from the group consisting of a variable cross-sectional shape, a variable cross-sectional area, a turn, a bend, a bifurcation, a junction, a convolution, an anastomosis, and combinations thereof.

This patent appears to cover a microfluidic microvascular chip comprising one or more fluid inlets and outlets and a plurality of non-linear flow channels.  The patent is limited to a synthetic microvascular network.  Additionally, seven patent applications were filed, six resulting in patents and one currently pending, which claim priority to this application.  The following patent in this family contains claims that are not limited to a microvascular network:

US 8355876 ‘Microfluidic Assay for Selection and Optimisation of Drug Delivery Vehicles to Tumors’ (Exp. Date:  February 3, 2027).  What is claimed is:

1. An optically transparent microfluidic chip comprising: a) a network of nonlinear, interconnected flow channels in fluid communication with a network inlet and a network outlet, said flow channels having luminal cross-sectional dimensions of between 10 and 500 µm, the network of non-linear, interconnected flow channels having a geometric characteristic selected from the group consisting of a variable cross-sectional shape, a variable cross-sectional area, a turn, a bend, a bifurcation, a junction, a convolution, an anastomosis, and combinations thereof; and b) a tissue space in fluid communication with a tissue space inlet and a tissue space outlet, said tissue space having cross-sectional luminal dimensions of between 100 µm and 1 cm wherein: the tissue space is separated from a lumen of at least one flow channel by a porous wall containing pores or gaps having cross-sections of between 0.2 and 5 microns and is in liquid communication with said flow channel through said porous wall and the tissue space contain cultured cells. 

This patent appears to cover a microfluidic chip comprising a network of interconnected flow channels in fluid communication with a network inlet and a network outlet and a tissue space in fluid communication with a tissue space inlet and a tissue space outlet.  According to the patent specification, while the invention is directed primarily towards tumour drug delivery, the invention may also be used for drug delivery to other tissues.  

US 7763456 ‘3D Micro-scale Engineered Tissue Model Systems’ (Exp. Date:  March 29, 2028)

Assignee:  University of Washington.  It was filed in the United States, European Patent Office, and Japan. What is claimed is:

1. A polymeric chip, comprising, at least one porous scaffold, wherein the porous scaffold is formed from the polymeric chip and is localized within a portion of the polymeric chip, wherein the porous scaffold includes a first surface and a second surface, and wherein the first surface is opposite from the second surface; a first microfluidic inlet channel, wherein the first microfluidic inlet channel is in fluid connectivity with the first surface of the porous scaffold; and a second microfluidic outlet channel, wherein the second microfluidic outlet channel is in fluid connectivity with the second surface of the porous scaffold.

This patent appears to cover a polymeric chip comprising at least one porous scaffold, a first microfluidic inlet channel, and a second microfluidic outlet channel.  According to the patent specification, the porous scaffolds can contain a plurality of living cells.  Thus, this patent appears to cover all polymeric chips comprising a porous scaffold, cells, a microfluidic inlet, and a microfluidic outlet in the United States through its expiration date in 2028.

US 8266791 ‘Method of Fabricating Microfluidic Structures for Biomedical Applications’ (Exp. Date:  September 8, 2030)

Assignees:  The Charles Stark Draper Laboratory and Brigham and Women's Hospital, Inc.  It was filed in the United States and European Patent Office.  What is claimed is:

1. A method for fabricating a microfluidic structure, comprising: (a) providing a patterned wafer comprising at least one exposed electrically conductive region and at least one exposed electrically insulating region; (b) electroplating an inverse channel portion with substantially semicircular cross section onto the wafer, thereby forming a first master mold; (c) employing the first master mold so as to emboss a channel portion in a first polymer sheet; (d) aligning and bonding the first polymer sheet with a second polymer sheet having a corresponding channel portion such as to define a first channel with substantially circular cross section between the polymer sheets.

This patent appears to cover a method of preparing a microfluidic structure by aligning and bonding polymer sheets together.  According to the patent specification, an advantage to the described method is the ‘ability to produce vascular networks having vessels with substantially cylindrical geometries, and to construct smooth transitions at vessel bifurcations and vessel diameter changes in a manner similar to healthy physiologic structures.’     

US 8343740 ‘Micro-Organ Device’ (Exp. Date:  October 31, 2031)

Assignee:  United States of America as Represented by the National Aeronautics and Space Administration.  It was filed in the United States only.  What is claimed is:

1. A method for fabricating a micro-organ device comprising: providing a microscale support comprising at least one microfluidic channel and at least one micro-chamber for housing a micro-

organ; bonding the microscale support to a substrate by covering the contact surfaces of each with titanium tetra (isopropoxide); and printing a micro-organ on the microscale support using a cell suspension in a syringe controlled by a computer-aided tissue engineering system, wherein the cell suspension comprises cells suspended in a solution containing a material that functions as a three-dimensional scaffold, and wherein the printing is performed with the computer-aided tissue engineering system according to a particular pattern.

This patent appears to cover a method of preparing a micro-organ microfluidic device in which the micro-organ is printed on a microscale support using cell suspension in a syringe controlled by a computer-aided tissue engineering system.  According to the specification, the invention may be produced by ‘direct bioprinting of specific cells, human or animal, to form micro-organs in micro-chambers of microchips.’ It is noted that the claim requires that the microscale support is bonded to a substrate using titanium tetra (isopropoxide) — therefore, it may be possible to avoid infringement of this claim by using another binding agent.  A second patent in this family is:

US 8580546 ‘Micro-Organ Device’ (Exp. Date March 28, 2028).  What is claimed is:

1. A micro-organ device, comprising: at least one micro-chamber for housing a micro-organ; and at least one microfluidic channel connected to the micro-chamber, wherein the micro-organ comprises cells arranged in a configuration that includes microscale spacing between portions of the cells to facilitate diffusion exchange between the cells and a medium supplied from the at least one microfluidic channel, wherein the micro-organ device is prepared by process comprising: providing a microscale support comprising the at least one microfluidic channel and the at least one micro-chamber for housing a micro-organ; bonding the microscale support to a substrate by covering the contact surfaces of each with titanium tetra (isopropoxide); and printing the micro-organ on the microscale support using a cell suspension in a syringe controlled by a computer-aided tissue engineering system, wherein the cell suspension comprises the cells suspended in a solution containing a material that functions as a three-dimensional scaffold, and wherein the printing is performed with the computer-aided tissue engineering system according to a particular pattern.

This patent appears to cover a micro-organ device comprising a micro-chamber, a microfluidic chamber, and a microscale support in which a micro-organ is printed onto a microscale support using cell suspension in a syringe controlled by a computer-aided tissue engineering system.  It is noted that the claim requires that the microscale support is bonded to a substrate using titanium tetra (isopropoxide) — therefore, it may be possible to avoid infringement of this claim by using another binding agent. 

US 8481303 ‘Microfluidic Device for Cell Culture’ (Exp. Date:  July 10, 2031)

Assignee:  Corning Incorporated.  This patent was also filed in China, European Patent Office, and Japan.  What is claimed is:

1. A cell culture apparatus comprising: a cell retention chamber having a first structured surface, wherein the structured surface includes a major surface from which a plurality of projections extend into the chamber, wherein the plurality of projections are arranged to suspend cells cultured in the chamber above the major surface; and a first perfusion channel (i) configured to carry a cell culture medium and (ii) forming a plurality of openings in communication with the cell retention chamber, the openings configured to prevent cells from the retention chamber from entering the perfusion channel.

This patent appears to cover a cell culture apparatus comprising a cell retention chamber having a first structured surface and a first perfusion channel — a channel through which a cell culture medium may flow — with openings to prevent cells from the retention chamber from entering the perfusion channel.  According to the patent specification, the microfluidic devices of the invention may mimic the architecture, perfusion, and flow of tissue in vivo, allowing for cultured cells to adopt in vivo-like morphology and functionality.  Thus, this patent appears to cover microfluidic devices comprising a plurality of cells suspended above a surface in the United States through its expiration date in 2031. 

US 8647861 ‘Organ Mimic Device with Microchannels and Methods of Use and Manufacturing Thereof’ (Exp. Date:  July 16, 2029)

Assignee:  Children's Medical Center Corporation.  This patent was filed in United States, Australia, Canada, China, European Patent Office, Japan, and Korea.  What is claimed is:

1. An organomimetic device comprising: a body having a central microchannel therein; and an at least partially porous membrane positioned within the central microchannel and along a plane, the membrane configured to separate the central microchannel to form a first central microchannel and a second central microchannel, wherein a first fluid is applied through the first central microchannel and a second fluid is applied through the second central microchannel, the membrane coated with at least one attachment molecule that supports adhesion of a plurality of living cells wherein the porous membrane is at least partially flexible, the device further comprising: a first operating channel separated the first and second central microchannels by a first microchannel wall, wherein the membrane is fixed to the first chamber microchannel wall; and wherein applying a pressure to the first operating channel causes the membrane to flex in a first desired direction to expand or contract along the plane within the first and second central microchannels.

This patent appears to cover a microfluidic device comprising a central microchannel and a partially porous membrane positioned to separate the central microchannel into a first and second microchannel in which the porous membrane supports living cells adhered to it.  A very important feature of the claimed organomimetic device is that is provides for expanding or contracting the living cells along a plane thereby providing mechanical forcing regimens similar to those found in vivo.  Such mechanical forcing regimens reportedly improve tissue- and organ-specific functions of cells.1  Thus, this patent appears to cover microfluidic devices with multiple channels containing flexing living cells in the United States through its expiration in 2029.  Additional patent applications were filed, three of which are currently pending, which claim priority to this application.  

US 8748180 ‘Microfluidic Device for Pharmacokinetic-Pharmacodynamic Study of Drugs and Uses’ (Exp. date:  July 29, 2030)

Assignee:  Cornell Research Foundation, Inc.  This application was only filed in the United States.  What is claimed is:

1. A microfluidic device for culturing cells and/or tissue comprising: a base layer; a cell culture chamber layer comprising one or more cell culture chambers; a fluidic channel layer comprising a plurality of fluid channels; a bottom frame; a gasket; and a top frame, wherein: the cell culture chamber layer is positioned between the fluidic channel layer and the base layer so that the one or more cell culture chambers are fluidically connected to one or more fluid channels of the plurality, the fluid channels have defined geometries that produce one or more desired flow rates through the fluid channels that simulate one or more physiological environments or conditions of interest, the bottom frame has an inlet hole and an outlet hole, the base layer has an inlet hole and an outlet hole, and the cell culture chamber layer has an inlet hole and an outlet hole, and wherein the inlet holes of the bottom frame, the base layer and the cell culture chamber layer and the outlet holes of the bottom frame, the base layer and the cell culture chamber layer align with one another, thereby allowing circulation of fluid through the cell culture chamber layer and the fluidic channel layer.

This patent appears to cover a microfluidic device contain one or more cell culture chamber layers and a fluidic channel layer in which the fluid channels simulate one or more physiological environments.  The specification discloses that the microfluidic device is used for conducting pharmacokinetic and/or pharmacodynamics analysis of the effect of an agent (e.g., drug, chemical composition, toxin) on cultured cells. 

There is room for additional patentable innovations

While it may seem that it is too late to start filing patent applications on organs-on-a-chip research tools, there remains room for further patentable improvements. As stated in an article by Michael Schuler at Cornell University, ‘an in vitro system will probably never be able to capture the complexity of the human body in its entirety.’  Innovation is needed to develop new techniques for patterning cells in a three-dimensional manner, for developing new materials to mimic organs in the human body, and for developing new methods to simulate the environment in the body.  For example, researchers at the Wyss Institute at Harvard University have built human lung-on-a-chip and human gut-on-a-chip devices and are currently working to build ten different human organs-on-a-chip and link them together on an automated system to mimic the physiology of the whole body.

Existing patent filings may require a license to commercialisation of Organs-on-a-chip research tools

While many patents are being granted worldwide claiming organs-on-a-chip, some countries have an exception to patent infringement under what is called the experimental use exception.  Under this exception, if one just tests a patented invention without commercial purposes, there is no infringement of the patent.  However, if one makes and sells a patented organs-on-a-chip as a research tool, they may be held liable for patent infringement.

The United States has a very narrow experimental use exception to patent infringement which focuses on whether the use is solely for amusement, to satisfy idle curiosity, or for strictly philosophical inquiry.  In a 2002 decision, a court held that Duke University's use of a patented invention for research purposes was not exempt from infringement because the use involved objectives that were commercial in nature.  The United States does have an exception to patent infringement so long as the patented invention is used solely for the purpose of generating data for submission to the U.S. FDA.   However, this exception does not extend to the use of a patented research tool to test a drug and submission of the resulting data to the FDA.

In conclusion, the use of organs-on-a-chip to model organ responses to drugs has a very bright future. And, the patenting activity will continue.

References

o Bhatia, S.N. and Ingber, D.E., Nature Biotechnology 32:760-772 (2014).
o For the complete search results, including pending applications, please contact the author at resmond@skgf.com.
o Freedman, David H.  "Your body on a chip," Newsweek 146:59 (October 10, 2005).  
o Shuler, M.L. and Esch, M.B., Pure Appl. Chem. 82:1635-1645 (2010).
o http://wyss.harvard.edu/viewpage/461/.
o Madey v. Duke University, 307 F.3d 1351 (Fed. Cir. 2002).
o 35 U.S.C. § 271(e)(1).
o Proveris Scientific Corp. v. Innovasystems, Inc., 536 F.3d 1256 (Fed. Cir. 2008).

AuthorBio

Robert W Esmond is a Director in the Biotechnology/Chemical Group of Sterne, Kessler, Goldstein & Fox P.L.L.C., Washington, DC, USA. His intellectual property law experience has principally been in the biotechnology and chemical areas. His legal experience includes counseling clients in various intellectual property matters such as patentability investigations, validity and infringement analyses, freedom to operate and FDA/ANDA practice.

Stephanie L Elmer is an Associate in the Biotechnology/Chemical Group of Sterne, Kessler, Goldstein & Fox P.L.L.C., Washington, DC, USA.  Her intellectually property law experience has been concentrated in the biochemical and chemical arts.  Her legal experience includes preparation and prosecution of US and foreign patent applications and providing support in various intellectual property areas such as validity and infringement analyses and patentability opinions.

-- Issue 22 --

Author Bio

Robert W Esmond
Stephanie L Elmer
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