Take it for Pain. Take it for Life.
~ Bayer aspirin slogan

Drospirenone is a progestin that inhibits ovulation. While known in the art, Bayer patented formulations of drospirenone, one of the active ingredients in Yasmin® a daily oral contraceptive. Now, the U.S. Court of Appeals for the Federal Circuit has ruled that the patent is invalid because the formulations were obvious. Bayer Schering Pharma v. Barr Labs (08-1282).

yasminDrospirenone is acid-sensitive so 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 non-antimineralocorticoidal, meaning it will not act as a diuretic, removing the desirable anti-bloating effect that sets drospirenone apart from other prior art progestins.

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,” where the drug’s particle size is reduced, increasing its overall surface area. All commercially available oral contraceptives use micronized progestins and/or estrogens, so this technique was well known in the art.

One method pharmaceutical companies use to overcome an acid-sensitivity problem is to use an enteric-coated pill. An enteric coating, a pH-sensitive film that protects the drug from stomach acid, also reduces the drug’s bioavailability. 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.

Eventually, Bayer tested an unprotected (normal) drospirenone tablet and compared its bioavailability to that of the enteric-coated formulation — and fully expected to find that the normal pill would produce an even lower bioavailability than the enteric-coated tablet. Unexpectedly, they found that the normal pill and the enteric-coated pill resulted in the same bioavailability.

Being clever, Bayer developed drospirenone in a normal pill, the subject of U.S. Pat. No. 6,787,531. Bayer relied on the finding that drospirenone would absorb with a normal pill to overcome an obviousness rejection in the Patent and Trademark Office.

Barr Laboratories filed an Abbreviated New Drug Application with the Food and Drug Administration seeking approval to market a generic version of Yasmin®. Bayer promptly filed a patent infringement suit against Barr.

The district court ruled that the claims were invalid holding that under KSR International Co. v. Teleflex it would have been obvious to a person having ordinary skill in pharmaceutical formulation to try a normal pill in formulating drospirenone as an oral contraceptive.

The Federal Circuit looked to KSR, where the Supreme Court stated that an invention may be obvious if it would have been obvious to a person having ordinary skill to try a course of conduct:

When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.

Finding the use of uncoated drug was obvious, the court stated:

First, 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. O’Farrell, 853 F.2d at 903.

Second, 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 as to the particular form of the claimed invention or how to achieve it.”

Given the above, you’d have thought the court was heading in the direction of upholding the patent. You’d be wrong.  Even though Bayer — a company with over 10,000 employees and over EUR 10.704 billion in sales in 2008 — could not come up with the final solution through years of research, the court held that the formulations would have been obvious to “a person having ordinary skill in the art ” (a person who apparently does not work at Bayer) due to the limited number choices:

At this point, a person having ordinary skill in the art has reached a crossroads where he must choose between two known options: delivery of micronized drospirenone by a normal pill following the spirorenone analogy in the Krause series, or delivery of drospirenone by an enteric-coated pill following the Nickisch teaching that the drug needs to be protected from the stomach. This is a finite number of identified, predictable solutions. See KSR. 550 U.S. at 421. The prior art would have funneled the formulator toward these two options; he would not have been required to try all possibilities in a field unreduced by the prior art, thus avoiding the first pitfall of O’Farrell, 853 F.2d at 903. Additionally, the prior art was not vague in pointing toward a general approach or area of exploration, but rather guided the formulator precisely to the use of either a normal pill or an enteric-coated pill, thus avoiding the second pitfall of O’Farrell. Id. Because the selection of micronized drospirenone in a normal pill led to the result anticipated by the Krause series, the invention would have been obvious. See KSR, 550 U.S. at 421.

Circuit Judge Newman, dissenting, thought that the decision was a crock:

With all respect to my colleagues, I do not share their view that it would have been obvious to do that which was indisputably unobvious to the experienced formulation scientists whose assignment was to formulate the known product drospirenone. The evidence showed, without contradiction, that it was known that micronized drospirenone rapidly degraded at the acidity of stomach acid. The evidence showed, without contradiction, that the Bayer scientists working in this field believed that the product required an enteric coating in order to prevent degradation in the stomach, upon ingestion as an oral contraceptive. Yet my colleagues, employing their own expertise, hold that since the scientists working in this field turned out to be mistaken, it would have been obvious that it was not necessary to take steps to prevent acid degradation. The court discounts the testimony of the scientists themselves, ignores the knowledge concerning this product and its instability in acid, ignores the textbook teachings, and finds that this unlikely process obviously should have been tried. That is not the law of obviousness.

The statutory criterion is whether the invention would have been obvious to persons of ordinary skill at the time of the invention, not whether it is sufficiently simple to appear obvious to judges after the discovery is finally made, despite the years of contrary belief among the scientists charged with the project.

“Obviousness” requires that the subject matter was obvious to persons of ordinary skill in the field of the invention. The law does not hold it “obvious to try” experiments that contravene conventional knowledge, and that are not deemed reasonably likely to succeed. The evidence in this case is a better measure of obviousness than is the hindsight science of judges, for the scientists who eventually made this discovery testified, without dispute, that they did not believe an uncoated micronized product would meet the demanding criteria of contraceptive effectiveness.

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    we are clearly in an anti-patent environment. a few months ago examiners were allowing applications – no more. nothing but non-sensical 112 rejections and prior art rejections, all citing to the kind of decision from the courts we see in Bayer. it is terrible for our industry and ultimately, the public who will not see new drugs and methods of health care as a result.

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    I find it astounding that the Federal Circuit would hold the claims at issue here obvious, when Bayer worked for five years under the reasonable assumption that the patented formulation would not work. In essence, the Federal Circuit has substituted its scientific judgement for that of the Bayer scientists.

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    awesome article…keep it up.
    Good patent information provided.