This case involves three dimensional scaffolds for growing cells in vitro for in vivo organ culture holding patent numbers 5,770,193 and 5,759,830. The prior art states that in vitro cell growth for in vivo organ culture was performed using either permanent synthetic polymer scaffolds or biodegradable scaffolds and also limitations exist like variability in degradation of the collagen scaffold also these are unsuitable for solid organs (liver, pancreas) due to limited diffusion into inner organ cells and resulting cell death.

The prior art has drawbacks such as problems in diffusion of nutrients though out the medium, reciting that the scaffolding requires maximized surface area which allows adequate diffusion of nutrients and growth factors to the cells. The drawback included foe various organs including skin, liver, kidneys, blood vessels, nerves, and muscles which functionally resemble the naturally occurring organ” to be produced.

The scaffolds mentioned in patents ‘193 and ‘830 promoted vascularization that overcame the diffusion problem in the prior arts.

It claims that, “a cell-scaffold composition prepared in vitro for growing cells to produce functional vascularized organ tissue in vivo, comprising of a fibrous three-dimensional scaffold composed of fibers of a biocompatible, biodegradable, synthetic polymer; and cells derived from a vascularized tissue attached in vitro to the surface of the fibers of the scaffold uniformly throughout the scaffold;
wherein the fibers of the scaffold provide sufficient surface area to permit attachment in vitro of an amount of the cells effective to produce the functional vascularized organ tissue in vivo; wherein the fibers of the scaffold are spaced apart such that the maximum distance over which diffusion of nutrients and gases must occur through a mass of cells attached to the fibers is between 100 and 300 microns; and
wherein the diffusion provides free exchange of nutrients, gases and waste to and from the cells uniformly attached to the fibers of the scaffold and proliferating throughout the scaffold in an amount effective to maintain cell viability throughout the scaffold in the absence of vascularization.

It was undisputed that Shire’s accused infringing product, Dermagraft®, were “seeded with connective tissue cells called fibroblasts to grow the dermis (or inner) layer of skin for “the treatment of full-thickness diabetic foot ulcers.”  And:

After seeding onto the Dermagraft® scaffold, “

[t]he fibroblasts proliferate to fill the interstices of this scaffold and secrete human dermal collagen, matrix proteins, growth factors and cytokines, to create a three-dimensional human dermal substitute containing metabolically active, living cells.”  Id.  The fibroblasts attach to the top, bottom, and sides of the fibers of the mesh scaffolding that, after implantation, is gradually absorbed by the surrounding tissue”.

The argument put forward by Shire was the disclaimer applied to the claim terms “vascularized organ tissue” and “cells derived from a vascularized tissue.” In detail, Shire pointed to language changes in claim necessitated by prior art rejections and declarations by the named inventors, including assertions stated that “the polymer is designed in such a way that scaffold will provide adequate sites for attachment and growth of enough cells to survive and function in vivo yet does not limit survival and growth of cells adjacent to the matrix surface as cells increase in number in vitro.”  The claims were granted after further extensive amendment and argument to recite the allowed claims.

The District Court’s comments:

  • It rejected Shire’s assertions of stating the term “three-dimensional scaffold” which was indefinite.
  • It also rejected Shire’s contention that, during a prosecution of distinguishing the prior art on the grounds saying that the art was limited to skin grafts (based on the thickness limitations in the art)
  • It also commented MIT’s claims should be limited to non-skin organs with regard to both the terms at issue (both the terms here are vascularized organ tissue” and “cells derived from a vascularized tissue”).
  • The District Court found the asserted claims of the ‘193 and ‘830 patents were not invalid and were infringed on stipulated final judgment.
  • The District Court construed the term to include skin on the basis that the ordinary meaning of the word “organ” would include skin and that there was no clear and unmistakable disclaimer of this scope in the prosecution history.

The Federal Circuit affirmed that the standard for prosecution of this disclaimer was a stringent one, and it requires such disclaimer to be “clear and unmistakable,” citing Trivascular, Inc. With regard to the claim term “vascularized organ tissue,”

The District Court also found, and the Federal Circuit agreed, that this use of the term was consistent with how the term was used in the ‘193 and ‘830 patent specifications.  Elaborately, the District Court found that this interpretation of the term was consistent with the parties’ Joint Technology Tutorial, which was provided to the District Court as “background” during claim construction.

From an interview summary of the priority patent that ultimately resulted in the ‘193 and ‘830 patents, regarding claims that did not recite the “vascularized organ tissue” language, neither the District Court nor the Federal Circuit was convinced by Shire’s arguments to the contrary, which the panel opinion characterized as relying on “a single sentence”.

According to the panel opinion, the claim terms then at issue reveals that MIT emphasized the structure of the invention’s scaffold, not the type of organ it can be used to grow.  Also declaration made Shire’s citation was unavailing in the statements of an inventor, which the District Court found were not made to distinguish the claimed invention from prior art skin grafts but rather to emphasize the diffusion-related advantages of the claimed invention.

The context does not meet high standards of prosecution to attach the disclaimer according to the courts.

Both the District Court and the Federal Circuit were further convinced that the claims did not disclaim skin as an artificial organ falling within the scope of the claims because MIT attempted during prosecution to include this limitation but the Examiner rejected the amendment as being new matter.

The argument also proceeded that the claims at issue at that time contained an express organ thickness limitation and that the statements cited by Shire were used in relation to those limitations which were not in the claims that issued in either the ‘193 or ‘830 patents.

According to District Court the claims themselves did not distinguish between parenchymal and non-parenchymal cells. Even Shire’s expert admitted that bone-forming cells which are a type of parenchymal cells fell within the scope of the ‘193 and ‘830 patent claims.

In addition to this “plain meaning” interpretation, the Court found that the specification(s) of these patents were consistent with the District Court’s construction.  As with Shire’s earlier arguments (regarding the “”vascularized organ tissue” term), the Court found the arguments related to parenchymal versus non-parenchymal cells were not supported by Shire’s citation to portions of the prosecution history, and that a skilled worker “would not read MIT’s statement made during prosecution of [a related] patent—and directed to very different claim language—as limiting the term ‘cells derived from a vascularized tissue’ to parenchymal cells.”

Shire’s own expert explained the meaning of “plain meaning” and the three the term “three-dimensional scaffold” was definite Citing Nautilus, Inc. v. Biosig Instruments, Inc.,

Judge O’Malley concurred to address the question of whether the District Court’s judgment was “final” without a determination of damages and the question of willful infringement.

The Federal Circuit recently affirmed a district court’s claim construction and determination that claim terms were not indefinite in Massachusetts Institute of Technology Vs Shire Pharmaceuticals, Inc.

Keywords: Massachusetts Institute of Technology, Shire Pharmaceuticals, Inc., cell culture, infringement.