Elan Pharm., Inc. v. Mayo Foundation, Med. Educ., 00-1467.

• Decision Date: 30 August 2002
• Docket Number: No. 00-1467.,00-1467.
• Citation: 304 F.3d 1221
• Parties: ELAN PHARMACEUTICALS, INC., and Athena Neurosciences, Inc., Plaintiffs-Appellants, v. MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH, Defendant-Appellee.
• Court: U.S. Court of Appeals — Federal Circuit

304 F.3d 1221

ELAN PHARMACEUTICALS, INC., and Athena Neurosciences, Inc., Plaintiffs-Appellants, v. MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH, Defendant-Appellee.

No. 00-1467.

United States Court of Appeals, Federal Circuit.

DECIDED: August 30, 2002.

COPYRIGHT MATERIAL OMITTED

Lynn H. Pasahow, Fenwick & West LLP, of Palo Alto, California, argued for plaintiffs-appellants. Of counsel on the brief were Beth H. Parker, Mary T. Huser, and S. Christian Platt, McCutchen, Doyle, Brown & Enersen, LLP, of Palo Alto, California. Of counsel was Thomas S. Hixson, McCutchen, Doyle, Brown & Enersen, LLP, of San Francisco, California.

Robert E. Hillman, Fish & Richardson, P.C., of Boston, Massachusetts, argued for defendant-appellee. Of counsel were Shelley K. Wessels, Karen I. Boyd, and Curtis MacFerrin, Fish & Richardson, P.C., of Menlo Park, California. Also of counsel was Chad A. Hanson, Fish & Richardson, P.C., of Minneapolis, Minnesota.

Before NEWMAN, GAJARSA, and DYK, Circuit Judges.

Opinion for the court filed by Circuit Judge PAULINE NEWMAN. Dissenting opinion filed by Circuit Judge DYK.

PAULINE NEWMAN, Circuit Judge.

Elan Pharmaceuticals, Inc. and Athena Neurosciences, Inc. (collectively "Elan") appeal the decision of the United States District Court for the Northern District of California, granting summary judgment in favor of the Mayo Foundation for Medical Education and Research ("Mayo").¹ The district court held that Elan's two patents in suit, United States Patent No. 5,612,486 for "Transgenic Animals Harboring APP Allele Having Swedish Mutation" (the `486 patent) and continuation Patent No. 5,850,003 for "Transgenic Rodents Harboring APP Allele Having Swedish Mutation" (the `003 patent), inventors Lisa McConlogue and Jun Zhao, are invalid on the ground of anticipation by United States Patent No. 5,455,169 for "Nucleic Acids for Diagnosing and Modeling Alzheimer's Disease" (the Mullan patent). We reverse the summary judgment, for the legal requirements of anticipation were not met on the facts of record, and remand for further proceedings.

BACKGROUND

Alzheimer's disease is a progressive neurodegenerative disease that primarily afflicts the elderly. Elan's `486 and `003 patents are directed to transgenic animals whose genetic makeup has been altered so that they are susceptible to Alzheimer's disease. The DNA of these animals has been modified to contain a mutated human gene called the "Swedish mutation," for the gene was isolated from the cells of a Swedish family having an unusually high incidence of early-onset Alzheimer's disease.²

The brains of people with Alzheimer's disease contain abnormal tangles and deposits of plaques. At the time of these Elan inventions it was known that a principal component of these plaques is a protein fragment called beta-amyloid peptide (betaAP, also designated βAP and Aβ). The presence of betaAP in the brain is believed to induce or foster formation of the Alzheimer's plaques. It was known that betaAP may be formed when a protein produced in the brain, called the amyloid precursor protein (APP), is cleaved by enzymes in the brain. The Elan patents summarize scientific research in this field, including various reported mutations. Elan explains that an enzyme called beta-secretase cuts the APP molecule between amino acids 596 and 597, releasing a larger protein fragment called the amino terminal fragment (ATF-betaAPP); and an enzyme called gamma-secretase releases the smaller betaAP fragment from the remaining portion of the APP. This mechanism is illustrated in the Elan brief as follows:

NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

Humans who do not develop Alzheimer's disease are believed to break down APP in a manner that does not produce significant amounts of betaAP.

The Prior Art

The prior art on which the district court based its summary judgment of anticipation is the Mullan patent. Dr. Mullan had learned of the Swedish family susceptible to Alzheimer's disease, obtained samples of their DNA, isolated the relevant mutated gene, and identified the nature and location of the mutation in the gene as well as in the mutated protein (APP_sw) expressed by the gene. Mullan explained that in the Swedish mutation the DNA nucleotides that encode codons 670 and 671³ replace lysine and methionine, the amino acids normally encoded at these positions, with asparagine and leucine. Mullan states that transgenic animals containing the mutated gene can be used in Alzheimer's disease (AD) research and therapy:

The invention also provides a transgenic non-human animal containing, in a germ or somatic cell, the mutated nucleic acid of the invention, wherein the animal expresses a human amyloid precursor protein or fragment thereof which encodes an amino acid other than lysine at codon 670 and/or an amino acid other than methionine at codon 671.

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The invention also provides a method of screening for an agent capable of treating AD. The method comprises contacting these transgenic animals or host cell lines with the agent and monitoring the expression, processing or deposition of amyloid precursor protein or fragments thereof.

Mullan, col. 4, lines 36-64. Mullan states that the mutated human gene can be used to create transgenic animals in various ways; for example:

In yet a further use of the present invention, the mutated gene (i.e., a variant APP codon 670/1 gene) can be excised for use in the creation of transgenic animals containing the mutated gene. For example, an entire human variant APP codon 670/1 allele can be cloned and isolated, either in parts or as a whole, in a suitable cloning vector (e.g., 1Charon35, cosmid, retrovirus or yeast artificial chromosome). The vector is selected based on the size of the desired insert and the ability to produce stable chromosome integration.

Col. 11, lines 23-31. Mullan also states that the mutated gene can be transferred to a mouse that preferably will express the variant human APP:

The human variant APP codon 670/1 gene, either in parts or in whole, can be transferred to a host non-human animal, such as a mouse. As a result of the transfer, the resultant transgenic non-human animal will express one or more variant APP codon 670/1 polypeptides. Preferably, a transgenic non-human animal of the invention will express one or more variant APP codon 670/1 polypeptides in a neuron-specific manner (Wirak et al. (1991) EMBO 10:289). This may be accomplished by transferring substantially the entire human APP gene (encoding a codon 670/1 mutant) including the 4.5 kilobase sequence that is adjacent to and upstream of the first major APP transcriptional start site.

Col. 11, lines 32-43. Mullan discusses the various known procedures of gene transfer, citing scientific articles as to each "approach" used to create transgenic animals:

One approach to creating transgenic animals is to target a mutation to the desired gene by homologous recombination in an embryonic stem (ES) cell line in vitro followed by microinjection of the modified ES cell line into a host blastocyst and subsequent incubation in a foster mother (see Frohman and Martin, Cell (1989) 56:145). Alternatively, the technique of microinjection of the mutated gene, or a portion thereof, into a one-cell embryo followed by incubation in a foster mother can be used. Certain possibilities for the general use of transgenic animals, particularly transgenic animals that express a wild-type APP fragment, are disclosed in Wirak et al., the EMBO Journal, 10(2) 289-296 (1991); Schilling et al., Gene 98(2) 225-230 (1991); Quon, et al. (1991) Nature 352:239; Wirak, et al. (1991) Science 253:323; and Kawabata, et al. (1991) Nature 354:476. Alternatively, viral vectors, e.g., Adeno-associated virus, can be used to deliver the mutated gene to the stem cell. In addition, such viral vectors can be used to deliver the mutated gene to a developed animal and then used to screen (Mendelson et al. Virology 166:154-165; Wondisford et al. (1988) Molec. Endocrinol. 2:32-39 (1988)).

Col. 11, line 58 to col. 12, line 11. Mullan also states that the mouse gene allele can be mutated to produce a mutation corresponding to the Swedish mutation:

Site-directed mutagenesis and/or gene conversion can also be used to mutate a murine APP gene allele, either endogenous or transfected, such that the mutated allele does not encode lysine/methionine at the codon position in the mouse APP gene that corresponds to codon 670/1 (of APP770) of the human APP gene (such position is readily identified by homology matching of the murine APP gene or APP protein to the human APP gene or APP770 protein). Preferably, such a mutated murine allele would encode asparagine or leucine at the corresponding codon position.

Col. 12, lines 12-21.

It is undisputed that Mullan did not produce a transgenic animal with the Swedish mutation, or determine which of the known procedures would be effective for this purpose, or suggest conditions or details of any method for successful production of the desired animal. Expert witnesses for both sides testified as to the difficulty, uncertainty, unpredictability, and low success rate of each method that has been used to create transgenic animals.

The Elan Patents

The Elan patents describe the production and characteristics of transgenic rodents, specifically mice, whose DNA contains a gene harboring the Swedish mutation, which gene expresses human APP having the Swedish mutation. This APP_sw in turn produces human betaAP by action of the mouse enzymes. Expert witnesses for both sides testified as to the unpredictability of the process and the various steps thereof, for not all of the known methods may work, very few attempted gene transfers are successful, and of the relatively few mice that may accept the Swedish gene, not all will express the mutated human APP in a way that is subject to enzymatic cleavage to produce betaAP.

Elan explains that the...