The Medicine Chest:
Experts and Obviousness

IP Today Columnist Steven Ludwig is a U.S. patent attorney at the law firm of Venable LLP in Washington, D.C.  Dr. Ludwig’s legal practice includes litigating and prosecuting pharmaceutical / biotech cases for his clients.  He can be reached at 202-344-4690 or via email at sludwig@venable.com.

Two recent District Court cases (1) Procter & Gamble Co. v. Teva Pharmaceuticals USA, Inc., No. 04-940 (D.Del. Feb. 28 2008) and (2) Bayer Schering Pharma AG et al. v.  Barr Laboratories, Inc., No. 05-2308 (D. N.J. March 3, 2008) illustrate the role experts play in obviousness determinations.   A good expert is often crucial to the outcome of a case.

While the validity of P&G’s patent claims were upheld, Bayer’s patent claims were held invalid based on obviousness. 

P&G’s patent claim 4 recited risedronate (which P&G commercially markets as Actonel® used for the treatment of osteoporosis and Paget’s disease), claim 16 recited a pharmaceutical composition, and claim 23 defined a method of treatment. 

Teva contended that P&G’s patent would have been obvious to one skilled in the art during the relevant time frame in light of the prior art patent because of (1) the structural similarity between risedronate and 2-pyr EHDP (a compound in the prior art), (2) the prior art patent’s disclosure of a method of treating osteoporosis using bisphosphonates, and (3) a standard technique in medicinal chemistry of making different pyridyl positional isomers.

In response, P&G argued that (1) the prior art taught away from the claimed invention, (2) there was no reasonable expectation that risedronate would be successful because there was no reliable understanding of the structure-activity relationships of bisphosphonates, and (3) the P&G patent would not have been obvious because of the unexpected results it showed with respect to potency and toxicity.

The Court’s opinion summarizes the testimony of two of Teva’s experts and seven of P&G’s experts/witnesses.  Teva’s expert Dr. George R. Lenz “admitted he was not a person of ordinary skill in the art in the mid-1980’s.  (Lenz 203.)  Until preparing for the present case, Dr. Lenz had no specialized experience in the area of bisphosphonates. (Lenz 154, 203.)  He has never synthesized bisphosphonates, and until Teva retained him for this case, he was unfamiliar with the structural mechanics of bisphosphonates, and the test used to interpret their activity and toxicity. (Lenz 154-166, 176.)  P&G at 5-6. 

Teva’s other expert Dr. Jesse David was called to testify as Teva’s expert on the commercial success of risedronate.  The opinion points out that Dr. David testified that he had spent less than twenty hours working on the two expert reports for Teva, and Dr. David did not explain why he did not review any information on Actonel®, the drug at issue in the case.

In its opinion, the Court quoted Takeda Chemical Industries, Ltd. v. Alphapharm Pty., Ltd, 492 F.3d 1350, 1356 (Fed.Cir. 2007) as a leading case on the test for prima facie obviousness of chemical compounds.  The Court noted that it was not persuaded by the testimony of Dr. Lenz and held (1) there was no prima facie case of obviousness and (2) in the alternative, even if Teva could establish a prima facie case, P&G demonstrated sufficient evidence of unexpected results to rebut such a showing.

Bayer v. Barr is more of the typical case where the experts are often miles apart.  Bayer’s patent claimed an oral contraceptive comprised of a combination of known drugs, drospirenone and ethinylestradiol, that are micronized and delivered in an immediate release tablet.  Bayer argued that since drospirenone degrades under conditions which may exist in the stomach, the prior art taught away from micronizing and immediately releasing the drospirenone.  Barr contended that there was nothing new about the claimed invention since micronization and enteric coatings are ordinary drug formulation techniques, “like arrows in the quiver of a bowsman . . . .” 

In regards to the inventiveness of the use of micronization, Bayer’s expert, Dr. McGinity argued that micronization can lead to agglomeration of particles and thus decrease dissolution.  Barr’s expert, Dr. Chambliss countered that any cause of agglomeration could be overcome through routine techniques.  The Court concluded that while there would be some concern about dissolution of a poorly water soluble acid sensitive drug, the person of ordinary skill in the art would conclude that micronization was a viable option. 

Bayer asserted that another non-obvious aspect of the claimed invention was that micronized drospirenone need not be protected with an enteric coating.  Since oral contraceptives must be over 99% effective, any inter- and intra-subject variability in bioavailability associated with enteric coatings becomes a significant obstacle to its use in formulation. 

Bayer’s expert testified that enteric coatings do not ordinarily affect the amount of a drug that becomes available to the patient.  In contrast, Barr asserted that enteric coating a drug is a complicated, expensive, and cumbersome manufacturing process that has inherent variability concerns.  The Court noted how the positions of Barr and Bayer were extremely polarized and that the prior art was more centered.  The Court held that since inter- and intra- subject variability is a major disadvantage, the person of ordinary skill in the art would not rule out formulating a micronized drospirenone without enteric coating. 

The Court summarized its decision as follows:

“As noted, in KSR the Supreme Court ruled that a patent claim may be obvious if the combination of elements was “obvious to try.” KSR, 127 S.Ct. at 723- 24. In this case, the testimony was limited to discussion about whether or not to employ two common formulation techniques – micronization and enteric coating.  As in KSR, “there are a finite number of identified predictable solutions.”  Id at 724.  In this case, based on the prior art as a whole, micronizing and immediately releasing drospirenone was obvious to try.”

Although in both cases, there is no doubt that the experts played a significant role - after all is said and done, all the experts have testified, and all the evidence is considered,  the compound claims were found to be inventive and the formulation claims were found to be obvious.  Something to consider.