The doctrine of equivalents was upheld for AstraZenaca’s patent on Propofol, used to induce and maintain general anaesthesia and sedation in patients. After the district court found Mayne had infringed AstraZeneca’s U.S. Pat. Nos. 5,714,520, 5,731,355 and 5,731,356, literally and under the doctrine of equivalents, the CAFC found that the district court erred in its construction of “edetate” and reversed the finding of literal infringement but affirmed since the district court did not err in determining that the accused product infringes under the doctrine of equivalents. Abraxis Bioscience (f/k/a Astrazeneca) v. Mayne Pharma (f/k/a Faulding Pharmaceutical) (06-1118).

AstraZeneca sold DIPRIVAN® for treatment in humans and RAPINOVET® for veterinary use. The composition consists of an injectible oil-in-water emulsion containing propofol, or 2,6-diisopropylphenol, as its active ingredient. DIPRIVAN® is administered to patients by infusion, which involves the use of a “giving set.” A giving set involves connecting a reservoir containing the propofol emulsion with the patient’s vein via the appropriate tubing.

AstraZeneca researchers began developing an improved formulation using preservatives and discovered that one preservative in particular, disodium edetate, was unexpectedly effective in retarding microbial growth in the propofol formulation without disrupting the oil-in-water emulsion for at least twenty-four hours. In March 1995, the inventors applied for a patent on their improved DIPRIVAN® formulation. In December 1995, AstraZeneca also filed a supplemental New Drug Application (“NDA”) on the new formulation.

In 1995, scientists at ESI Lederle (later part of Baxter) learned of the reports of infection relating to original DIPRIVAN®. ESI decided to develop a similar generic formulation and screened antimicrobial agents in an effort to replace the edetate in the improved DIPRIVAN® formulation with a different agent. They found that the calcium trisodium salt of diethylenetriaminepentaacetic acid (pentetate), which is also referred to as DTPA, was a promising candidate as an antimicrobial agent.

In selecting that compound, they noted that since calcium trisodium DTPA is “structurally similar to edetate, product stability is predicted to be unaffected.” ESI filed a patent application on its pharmaceutical composition and was later granted U.S. Patent 6,028,108. ESI filed an ANDA with a Paragraph IV Certification asserting that the patents in suit were invalid, unenforceable, or would not be infringed by its generic propofol formulation, which led to this suit.

The district court issued a Markman ruling construing the term, “edetate” as “EDTA as well as compounds structurally related to EDTA regardless of how they are synthesized.” Based on the district court’s construction of edetate as encompassing structural analogs of EDTA, the court found that Mayne’s generic propofol formulation literally infringed claims 1 and 3-14 of the asserted patents, and claim 38 of the ’520 patent and claims 38 and 39 of the ’520 patent under the doctrine of equivalents.

Claim construction is an issue of law reviewed de novo while the district court’s determination of infringement is a question of fact that we review for clear error. In construing edetate, the court noted that the patentees defined edetate in the specification as EDTA and derivatives thereof. The court proceeded to define the term derivatives by adopting a broad definition, specifically one that encompasses structural analogs of EDTA as well as synthetic derivatives.

The CAFC disagreed with the district court’s definition of derivatives as unsupported by the intrinsic evidence. The part of the specification describing “edetate” reads:

By the term “edetate” we mean ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, for example the disodium derivative is known as disodium edetate. In general suitable edetates of this invention are those salts having lower affinity for EDTA than calcium. Particular derivatives of use in the present invention include trisodium edetate, tetrasodium edetate and disodium calcium edetate.

The CAFC concluded that

[T]he listing of EDTA salts as “[p]articular derivatives of use in the present invention,” coupled with the statements regarding the uniqueness of edetate as the only successful antimicrobial agent, and the patentees’ description of EDTA salts as advantageous, preferable, and “exceptional,” limit the term “derivatives” to EDTA salts or compounds that maintain the EDTA free acid structure. Those statements are inconsistent with a definition of “derivatives” that includes structural analogs that can encompass a large number of non-derivative compounds. That definition fails to recognize that the patentees’ discovery focused on the unexpected effectiveness of edetate and its salts as antimicrobial agents.

Under the DOE, Mayne argued (1) that the court clearly erred in its analysis with regard to the “way” prong of the function-way-result test by improperly defining the “way” in which edetate works (that it should have been one that incorporates the specific metal ions that are chelated, the strength of the bonds that are formed during chelation, and the stability constants); (2) that it was impermissible as a matter of law for the meaning of edetate to extend to calcium trisodium DTPA by equivalence because the patentees chose to narrowly claim their invention (i.e., using the narrower term “edetate rather than broader terms such as “polyaminocarboxylates” or “metal ion chelators”); and (3) that the lack of known interchangeability between calcium trisodium DTPA and edetate as an antimicrobial agent indicates that the substitution of calcium trisodium DTPA is a “substantial” change weighing against a finding of equivalence.

The district court concluded that calcium trisodium DTPA and edetate were equivalent after finding that the differences existing between the two were insubstantial. In reaching this conclusion, the court performed a function-way-result analysis. The court identified the “function” of edetate as “retard[ing] microbial growth in propofol oil-in-water emulsions.” The court then defined the “way” that edetate worked as by metal ion chelation and found that the result achieved was “retard[ing] microbial growth to the extent required by the microbiological test set forth in the claims.”

In reaching a conclusion that the compounds are equivalent, the CAFC held that:

Contrary to Mayne’s assertion, the inventors did not clearly disavow other polyaminocarboxylates, including DTPA, by claiming edetate. There is no evidence that the patentees made a clear and unmistakable surrender of other polyaminocarboxylates, or calcium trisodium DTPA in particular, during prosecution. See Cordis Corp. v. Medtronic AVE, Inc., 339 F.3d 1352, 1363 (Fed. Cir. 2003) (noting that a “clear and unmistakable surrender of subject matter” is required to find estoppel by argument). Indeed, the district court found that “the antimicrobial activity of calcium trisodium DTPA was unforeseeable during prosecution.” Nov. 2, 2005 Opinion, slip op. at 37-38. Mayne itself acknowledged the unforeseeability of DTPA while prosecuting its own patent. Id. at 38. Thus, a person of ordinary skill in the art reading the patent would not conclude that by claiming “edetate,” the patentees surrendered or waived coverage of all polyaminocarboxylates, including DTPA, as an equivalent, particularly in light of the unforeseeability of calcium trisodium DTPA as an equivalent.

The CAFC also rejected the conclusion that the accused product does not infringe under the doctrine of equivalents based on the fact that Mayne was able to receive a patent on its generic propofol formulation stating:

As stated in Warner-Jenkinson, known interchangeability is only one factor to consider in a doctrine of equivalents analysis. It aids the fact-finder in assessing the similarities and differences between a claimed and an accused element. … As discussed above, the court made factual findings that insubstantial differences exist between calcium trisodium DTPA and edetate, and further found that the separate patentability of Mayne’s generic formula did “not outweigh the substantial evidence of equivalence between Mayne’s calcium trisodium DTPA and the claimed edetate.” Nov. 2, 2005 Opinion, slip op. at 39. We see no clear error in that finding.


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