Affirming the district court ruling invalidating Bayer’s patent covering the birth-control drug Yasmin® on the basis of obviousness, a divided panel of the U.S. Court of Appeals for the Federal Circuit held that claims to a “microized” (in terms of particle size) drug formulations was an obvious way to try to increase the exposed surface, notwithstanding prior art that said it couldn’t be done. The dissent argued that what might seem obvious to judges in retrospect, was not obvious to scientists at the time the drug was developed. Bayer Schering Pharma AG v. Barr Laboratories, Inc., Case No. 08-1282 (Fed. Cir., Aug. 5, 2009) (Mayer, J.) (Newman, J., dissenting).
The use of drospirenone as an oral contraceptive was well known. In additional to inhibiting ovulation, it was known to be a diuretic and to have anti-acne qualities. However, drospirenone was also known to be acid-sensitive. Also, because drospirenone has poor water solubility, in order to increase bioavailability pharmaceutical producers commonly employ a technique called “micronization,” whereby the drug’s particle size is reduced, increasing its overall surface area. However, micronizing an acid-sensitive composition has the deleterious effect of increasing its sensitivity to the acid.
One prior art method used to surmount acid-sensitivity was to deliver the drug via an enteric-coated pill, i.e., a pill that releases its drug only after it has passed to the small intestine. However, enteric-coated tablets present an obstacle to absorption, thus further reducing the drug’s already limited bioavailability. Such coatings also introduce a significant and patient-variable delay in the onset of therapeutic response, making a one-size-fits-all dose tablet problematic.
Tack, a Bayer scientist, began work in 1983 to develop drospirenone into an oral contraceptive. At the time, another Bayer scientist, Krause, 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 contraceptive effects resulting from the appearance of drospirenone when it metabolized. Tack considered Krause’s work with drospirenone, including in vivo studies that indicated drospirenone was a metabolite of spirorenone.
Tack’s studies led him to conclude that an enteric coating was needed. For five years, Bayer used this coated pill in its studies, even reconfirming in 1988 that drospirenone needed an enteric coating because of stomach acid issues. However, during later studies, Tack found that the uncoated pill and the enteric-coated pill resulted in the same bioavailability. Following this study, Bayer developed drospirenone in a “normal,” i.e., uncoated pill, which was claimed in the ’531 patent.
During prosecution Bayer relied on Tack’s finding that drospirenone could be absorbed in an uncoated pill form to overcome an obviousness rejection, noting that the prior art taught against micronizing drospirenone without also using an enteric coating. The examiner allowed the claims, giving the specific reason that the prior art suggested that micronizing drospirenone would not work in an acid environment.
After Barr filed an Abbreviated New Drug Application (ANDA) with the U.S. Food and Drug Administration (FDA) seeking approval to market a generic version of Yasmin®, Bayer filed suit. The parties agreed that if the ’531 patent is valid, Barr infringes. Barr alleged that claims were obvious. Based on the Krause studies, the district court found the claims to be invalid as obvious, notwithstanding the prior art teaching that micronizing drospirenone would only increase its sensitivity to stomach acid. The district court reasoned that a person of ordinary skill would be aware of the study’s shortcomings, and would verify, with further tests, whether micronized drospirenone could be absorbed. Thus, the district court held that under KSR, it would have been obvious to a person having ordinary skill in pharmaceutical formulation to try an uncoated pill in formulating micronized drospirenone as an oral contraceptive. Bayer appealed.
In KSR, the Supreme Court stated that an invention may be found obvious if it would have been obvious to a person having ordinary skill to try a course of conduct. The Federal Circuit explained that the “obvious to try” prong of KSR occurs in two settings. An invention would not have been obvious to try when the inventor would have had to try all possibilities in a field unreduced by direction of the prior art. “When what would have been ‘obvious to try’ would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful an invention would not have been obvious.” Rather, an invention is obvious to try only where “the number of options [are] small or easily traversed.”
In addition, the Supreme Court explained that “an invention is not obvious to try where vague prior art does not guide an inventor toward a particular solution. A finding of obviousness would not obtain where what was obvious to try was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance a to the particular form of the claim invention or how to achiever it.” This, the Supreme Court explained, comports with KSR’s “requirement that the identified solutions be ‘predictable.’”
The Federal Circuit reasoned that in this case, a person having ordinary skill in the art would have reached “a crossroads where he must choose between two known options,” i.e., delivery of micronized drospirenone by an uncoated pill or delivery of drospirenone by an enteric-coated pill. Concluding that this is a case of finite number of identified, predictable solutions the majority concluded that the invention would have been obvious.
In dissent, Judge Newman argued that “it would [not] have been obvious to do that which was indisputably unobvious to the experienced formulation scientists whose assignment was to formulate the known product drospirenone.” Judge Newman faulted her colleagues for “employing their own expertise” in concluding “the scientist working in this field turned out to be mistaken” and that “it would have been obvious that it was not necessary to take steps to prevent acid degradation.” Judge Newman further faults the majority for discounting the testimony of the scientists and ignoring the knowledge concerning product instability in acid in order to find that what appeared to be an unlikely to succeed process obviously should have been tried. “That is not the law of obviousness.”
According to Judge Newman, the Supreme Court in KSR explained that the standard for “obvious to try” is whether there was a “reasonable expectation of success” at the time. Here , Judge Newman concludes “it was not reasonably expected that uncoated micronized drospirenone would be 99+% effective as an oral contraceptive when ingested into the acidic stomach, when it was known to degrade rapidly in acid.”
Judge Newman would reverse the district court, noting that its conclusion regarding obviousness under the “obvious to try” standard was based on a finding that micronization was a viable option, although success was uncertain. In Judge Newman’s view, “viability” implies that the experiment may or may not succeed and is not the correct standard. “What the law requires is not guesswork, not dumb luck, but a reasonable degree of predictability of success.”