Bayer Schering Pharma Ag v. Barr Laboratories

• Decision Date: 05 August 2009
• Docket Number: No. 2008-1282.,2008-1282.
• Citation: 575 F.3d 1341
• Parties: BAYER SCHERING PHARMA AG and Bayer Healthcare Pharmaceuticals, Inc., Plaintiffs-Appellants, v. BARR LABORATORIES, INC., Defendant-Appellee.
• Court: U.S. Court of Appeals — Federal Circuit

575 F.3d 1341

BAYER SCHERING PHARMA AG and Bayer Healthcare Pharmaceuticals, Inc., Plaintiffs-Appellants, v. BARR LABORATORIES, INC., Defendant-Appellee.

No. 2008-1282.

United States Court of Appeals, Federal Circuit.

August 5, 2009.

Peter B. Bensinger, Jr., Bartlit Beck Herman Palenchar & Scott LLP, of Chicago,

IL, argued for plaintiffs-appellants. With him on the brief was Lawrence D. Rosenberg, Jones Day, of Washington, DC.

George C. Lombardi, Winston & Strawn LLP, of Chicago, IL, argued for defendant-appellee. With him on the brief were Bradley C. Graveline, Michael K. Nutter, Eric L. Broxterman and William P. Ferranti.

Nancy L. Tompkins, Townsend and Townsend and Crew LLP, of San Francisco, CA, for amicus curiae. With her on the brief was Mark T. Jansen. Of counsel on the brief were Cedric C.Y. Tan and Kristin M. Cooklin, of Washington, DC.

Before NEWMAN, FRIEDMAN, and MAYER, Circuit Judges.

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

MAYER, Circuit Judge.

Bayer Schering Pharma AG ("Bayer") appeals the judgment of the United States District Court for the District of New Jersey, holding U.S. Patent No. 6,787,531 ("'531 Patent") invalid due to obviousness. Bayer Schering Pharma AG v. Barr Labs., Inc., No. 05-CV-2308, 2008 WL 628592 (D.N.J. March 3, 2008). Because we hold that the invention would have been obvious to try, we affirm.

BACKGROUND

Bayer is a large pharmaceutical company that produces the daily oral contraceptive, Yasmin®. One of the active ingredients in Yasmin, drospirenone, is a progestin that inhibits ovulation. Each of the invalidated claims requires drospirenone as the active ingredient. Drospirenone was known in the art at all times relevant. Its contraceptive qualities are particularly well suited for producing an oral contraceptive because, in addition to inhibiting ovulation, it is a diuretic which will diminish excess water retention arising from the estrogen component of oral contraceptives, and has anti-acne qualities to promote clear skin. These desirable qualities have led to Yasmin's success. Drospirenone is also acid-sensitive. When exposed to low-pH (highly acidic) environments such as found in the human stomach, drospirenone "isomerizes" — that is, the acid catalyzes a reaction that rearranges drospirenone's molecular structure while its molecular composition remains constant. The resulting isomer is nonantimineralocorticoidal, meaning it will not act as a diuretic, removing the desirable anti-bloating effect that sets drospirenone apart from other prior art progestins. Therefore, scientists working with drospirenone for use in an oral contraceptive must be aware of and work around the effects that the human stomach will have on the drug to ensure that its "bioavailability" — the amount of the active drug absorbed into the bloodstream and available to act on the body — is high enough to perform its contraceptive function.

Drospirenone is also a poorly water soluble hydrophobic composition. Because it will not easily dissolve into a volume of liquid, its bioavailability is degraded. To combat this, pharmaceutical producers commonly employ a technique called "micronization," whereby the drug's particle size is reduced, increasing its overall surface area. Often (but not always) with a larger surface area, the dissolution rate is also increased, ensuring that all of the poorly water soluble drug that can dissolve will dissolve in a given volume of liquid. With more of the drug dissolved, the drug will exhibit a higher bioavailability. Indeed, Bayer's expert testified at trial that this would be his first choice in attempting to increase the dissolution rate because, among the different ways to increase the dissolution rate, micronization presents the best chance of success. All commercially available oral contraceptives use micronized progestins and/or estrogens, so this technique was well known in the art.

While micronizing a poorly water soluble composition may result in increased bioavailability, micronizing an acid-sensitive composition may also increase its sensitivity to the acid. A drug that isomerizes when exposed to acid thus may isomerize at a faster rate if it is micronized.

One method pharmaceutical companies use to surmount an acid-sensitivity problem with a drug to be taken orally is to deliver the drug via an enteric-coated pill, as opposed to an immediate release pill, also called a "normal pill." An enteric coating is a pH-sensitive film that protects the drug from stomach acid, and only releases the drug when it has passed into the less acidic duodenum and small intestine. However, enteric coatings are not without drawbacks themselves. Coated tablets including enteric coated tablets present an obstacle to absorption, and thus reduce the drug's exhibited bioavailability. Additionally, as was known in the art at the time, they introduce a significant delay in the onset of therapeutic response while creating a considerable patient-to-patient variation of that onset. In fact, even for an individual taking the drug at different times, the response time may vary considerably from dose to dose. Bayer scientists noticed these intra- and inter-individual bioavailability differences in practice in their studies on beagles and women. This presented a further complication because Bayer required the drug to be 99% effective, and work on all women at a single dose — "one dose must fit all." A normal pill may not present such variations, but will expose its contents to the stomach's highly acidic environment.

Dr. Johannes Tack, a Bayer scientist, began work in 1983 to develop drospirenone into an oral contraceptive. At the time, Bayer had been working with a related compound, spirorenone, as a diuretic. When consumed, spirorenone metabolizes into drospirenone, which is still a diuretic, but was found to have progestogenic (contraceptive) effects. Spirorenone itself had some contraceptive effects that Bayer concluded were the result of the appearance of drospirenone when it metabolized. Bayer decided to harness the diuretic effect of isolated drospirenone to create the new contraceptive. Tack consulted prior Bayer work with drospirenone including in vitro isomerization studies performed by a fellow Bayer scientist, Dr. Werner Krause. Krause had also performed in vivo studies with spirorenone, about which he published three articles. These studies, Krause I, II, and III, included the knowledge that drospirenone was a metabolite of spirorenone. Tack decided, however, that these in vivo studies garnered little information on the practice of drospirenone in vivo.

Tack tested the stability of drospirenone in acid at pH 1 to simulate the conditions of the stomach. He found that after 10 minutes, 21% of the drospirenone had isomerized in the acid, and after 45 minutes, half had isomerized. He came to a critical conclusion:

If the results obtained in vitro are applied to in vivo conditions, it can be presumed that, with an assumed gastric juice volume of 100ml, the majority of the dose (solubility of drospirenone 5-10 mg/l) passes into solution during passage through the stomach and consequently undergoes rapid isomerization. A clear reduction in the bioavailability of the unchanged active substance is to be expected as a result.

The planned studies on the progestogenic efficacy of [drospirenone] should therefore be performed with an enteric-coated formulation.

Tack then moved into clinical studies with an enteric-coated formulation of drospirenone. For five years, Bayer used this coated pill in its studies, even reconfirming in 1988 that drospirenone needed an enteric coating because it isomerized quickly in a pH 1 acidic solution.

In 1988, Bayer also planned a study to determine how effectively its enteric-coated tablet delivered a formulation as compared to an intravenous injection of the same formulation. This study would thus measure the "absolute bioavailability" of the drug. Bayer added what it terms a "non-routine" element to the study, by which it added an unprotected (normal) drospirenone tablet and compared its bioavailability to that of the enteric-coated formulation and the intravenous delivery. Tack expected to find that the enteric-coated tablet would produce a lower bioavailability than an intravenous injection, while the normal pill would produce an even lower bioavailability than the enteric-coated tablet. However, he found that despite his observations that drospirenone would quickly isomerize in a highly acidic environment and his belief therefore that an enteric coating would be necessary to preserve bioavailability, the normal pill and the enteric-coated pill resulted in the same bioavailability. Following this study, Bayer developed drospirenone in a normal pill, for which it would eventually receive the `531 patent.

Bayer relied on the finding that drospirenone would absorb with a normal pill to overcome an obviousness rejection in the Patent and Trademark Office. During prosecution, the examiner rejected the claims as obvious in view of a De Castro reference, which the examiner said taught to micronize poorly soluble drugs to increase their bioavailability. Bayer responded that another piece of prior art, the Nickisch reference, taught that micronizing drospirenone would increase its exposure to the highly acidic environment in the stomach, which would result in increased isomerization. The examiner allowed the claims, giving the specific reason that the prior art suggested that micronizing drospirenone would not work: "The micronized drospirenone will be degraded even more rapidly because the micronization of drospirenone expose [sic] the drug particles in the stomach (acidic). Therefore, to formulate an oral dosage forms [sic] containing the drospirenone particles, which exposed to the gastric environment upon dissolution, would be un[o]bvious in view of the data...