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Massachusetts Institute of Technology v. Shire Pharmaceuticals, Inc.

United States Court of Appeals, Federal Circuit

October 13, 2016


         Appeal from the United States District Court for the District of Massachusetts in No. 1:13-cv-10020-MLW, Chief Judge Mark L. Wolf.

          DAEYL L. WlESEN, Goodwin Procter LLP, Boston, MA, argued for plaintiffs-appellees. Also represented by KEVIN Paul Martin.

          Sandra Kuzmich, Frommer Lawrence & Haug LLP, New York, NY, argued for defendants-appellants. Also represented by Edgar Haug, Laura Ann Fanelli, Russell Alan Garman, Jonathan Herstoff.

          Before O'MALLEY, Chen, and Stoll, Circuit Judges.


          Stoll, Circuit Judge.

         Massachusetts Institute of Technology and Children's Medical Center Corporation (collectively, "MIT") brought suit against Shire Pharmaceuticals, Inc. and Shire Regenerative Medicine, Inc. (collectively, "Shire") for infringement of U.S. Patent Nos. 5, 770, 193 and 5, 759, 830. The '193 and '830 patents are directed to three-dimensional scaffolding for growing cells in vitro to produce organ tissue in vivo. Following the district court's construction of the terms "vascularized organ tissue" and "cells derived from a vascularized tissue" and its determination that the term "three-dimensional scaffold" was not indefinite, the parties stipulated to a final judgment of validity and infringement. For the reasons below, we affirm.



         In the field of organ transplantation, surgeons face the challenge of donor scarcity in addition to the technical complexity of transplanting whole or segmented organs into organ recipients. Given the limited availability of implantable organs, scientists have developed methods of growing artificial organ tissue in vitro[1] by seeding cells onto support structures, known as scaffolds or matrices. These scaffolds are engineered to allow cells to attach and grow, while enabling the diffusion of vital cell nutrients to the cells to contribute to the growth of new functional tissue.

         Before the inventions of the asserted patents, scientists created organ tissue with scaffolds made of either "permanent" synthetic polymers or biodegradable, non-synthetic materials like collagen. Preferably, these scaffolds eventually would be absorbed by the body, leaving behind the newly formed tissue. With the former method, however, the "permanent" synthetic matrix could not be absorbed by the body. Drawbacks of the latter collagen-based matrix included the inability to control the collagen structure's configuration and the variable absorption of the collagen matrix by the surrounding tissue.

         It was also generally understood that in engineering thick organs, like a liver or pancreas, the cells at the center of the artificial structure tended to die as the cell density increased. This was due to the decreased diffusion rate of oxygen and nutrients to the inner cells at the center of the growing structure. These prior art methods of tissue engineering, therefore, were primarily used to make thinner organs such as artificial skin.

         In the face of these challenges, the inventors of the '193 and '830 patents, Drs. Vacanti and Langer, developed biodegradable, synthetic matrices that provide support for cell growth and enhance the formation of blood vessels (i.e., vascularization) of the growing cell mass after implantation. The specifications of the '193 and '830 patents state that "[t]he design and construction of the scaffolding is of primary importance, " and that the scaffolding must be "shaped to maximize surface area to allow adequate diffusion of nutrients and growth factors to the cells." '193 patent col. 6 ll. 25-27; '830 patent col. 10 ll. 12-15. While the prior art methods were generally used to grow only artificial skin, the scaffolding of the claimed invention can support the growth of organs with varying thick- nesses. Indeed, the specifications describe that an object of the invention is to "provid[e] a variety of organs, including skin, liver, kidneys, blood vessels, nerves, and muscles which functionally resemble the naturally occurring organ." '193 patent col. 3 ll. 9-13.


         The '193 and '830 patents claim three-dimensional, synthetic, biodegradable structures for growing tissue for vascularized organs as well as methods for creating those structures. MIT brought suit against Shire in the United States District Court for the District of Massachusetts, alleging that Shire's sale of its Dermagraft® scaffold infringes claims 1-4, 6-9, and 15-16 of the '193 patent and claims 1-4, 6, and 8 of the '830 patent. Claim 1 of the '830 patent is illustrative and recites the following, with emphasis given to the disputed terms:

1. A cell-scaffold composition prepared in vitro for growing cells to produce functional vascularized organ tissue in vivo, comprising:
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.

'830 patent col. 24 ll. 23-46 (emphases added).

         Shire's accused Dermagraft® scaffold uses a synthetic, bioabsorbable scaffold 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." J.A. 1004. Product literature for Dermagraft® describes that "[d]uring the manufacturing process, the human fibroblasts are seeded onto a bioabsorbable polyglactin mesh scaffold." Id. 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. According to MIT, Shire uses a three-dimensional, synthetic, biodegradable scaffold to grow vascularized organ tissue and thus infringes the asserted claims of the '193 and '830 patents.


         The parties dispute whether prosecution history disclaimer applies to the asserted claims. In particular, Shire argues that prosecution disclaimers apply to the terms "vascularized organ tissue" and "cells derived from a vascularized tissue." Prosecution of the asserted patents began with their parent application, U.S. Application Serial No. 06/933, 018, filed in 1986 and abandoned in 1989. The '193 patent, a continuation of the parent, and the '830 patent, a continuation-in-part of the parent, both issued in 1998. During the intervening years, MIT's strategy shifted in response to the examiners' prior art rejections, and the claim language evolved over the course of prosecution.

         As originally filed, the pending claims in the '018 application were directed to:

[P]roviding a matrix formed of a biocompatible material, wherein said matrix is used to support cell growth in a nutrient solution, said matrix being configured to allow adequate diffusion of nutrients from the nutrient solution to all of the cells so as to maintain cell growth and proliferation to form a three dimensional cell-matrix structure.

J.A. 22231-32. An examiner rejected the '018 application's claims based on prior art that, according to the examiner, "shows a tissue culture method on a carrier as claimed." J.A. 22212. In 1988, during an examiner interview in response to the prior art rejection, MIT explained that the prior art was directed to skin substitutes. In particular, MIT described the prior art as "limited to extremely thin pieces of collagen matrix for use in preparing skin substitutes, which could not be used to create organ equivalents." J.A. 22234. This interview summary further explained that "although porous structures for implantation have been made in the past, the pores have not allowed adequate diffusion through the matrix material between the environment and the attached cells to support the growth and proliferation of cells on the interior of the matrix material unless the dimensions of the matrix were very small." J.A. 22238. At the same time, MIT sought to amend the claims to recite a "matrix having adequate surface area to provide surfaces of attachment for a cell suspension and a geometric configuration to uniformly support cell growth in a nutrient solution." J.A. 22231-32.

         Dr. Vacanti, a co-inventor on the asserted patents, submitted a declaration in 1989 in support of allowance of the '018 application, explaining that the prior art methods relied on by the examiner to reject the claims were "limited to a very thin layer of cells, principally serving as skin substitutes." J.A. 22268. He described the "key difference" between the claims and prior art as "the design of a polymer scaffold which provides 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." Id. Dr. Vacanti further emphasized the "general applicability" of the invention, which may be "use[d] with different cell types." Id.

         In response, the examiner maintained his rejections of the '018 application's claims over prior art disclosing skin substitutes, dismissing MIT's argument that "the claimed method is not a method for making very thin structures." J.A. 22313. The examiner explained that the "claims herein are not exclusive to methods involving only thick structures." Id. At that time, the claims did not include a thickness limitation and were directed to:

An artificial matrix for controlled cell growth in a nutrient solution comprising: a biocompatible matrix configured to provide points of attachment for a cell suspension, said matrix being configured to uniformly support cell growth in a nutrient solution, having sufficient area to allow adequate diffusion of nutrients, elimination of waste, and adequate gas exchange from the nutrient solution to all of the cells such that, in the absence of a vascular ...

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