Pfizer v. Apotex (formerly known as TorPharm, Inc.)

Statement made in an FDA submission showed a “reasonable expectation of success,” used to find the claims obvious.

(Fed. Cir. 2007, 06-1261, 06-1261o) 

 

Pfizer alleged that Apotex’s filing with the FDA of an Abbreviated New Drug Application (“ANDA”) seeking approval to commercially sell amlodipine besylate tablets before the expiration Pfizer’s U.S. Patent No. 4,879,303 (“the ’303 patent”), infringed claims 1-3 of the ’303 patent.   The District Court (N.D. Ill.) found for Pfizer on the issues of validity.  On appeal, the CAFC reversed, finding that the claims were invalid as obvious, and thus unenforceable.  On May 21st, 2007, a petition to the CAFC for rehearing and rehearing en banc was denied.

The technology at issue, amlodipine besylate tablets, is commercially sold in the United States by Pfizer under the trademark Norvasc®.  Amlodipine is a member of a class of compounds referred to as dihydropyridines. Active drug molecules, such as amlodipine, are frequently made into pharmaceutically-acceptable acid addition salts to improve their bioavailability. Amlodipine besylate is an acid addition salt form of amlodipine, formed from the reaction of amlodipine, a weak base, and benzene sulphonic acid.  Amlodipine has anti-hypertensive and anti-ischemic pharmacological properties and is used in the treatment of hypertension and angina.

During development, Pfizer had first designated a maleate salt of amlodipine for further development.  However, upon further testing, the maleate salt was determined to have poor stability and processing characteristics (too sticky).  The besylate salt was later recommended to resolve these issues, and it was the besylate salt that was pursued for patent protection in the ‘303 patent. Pfizer also submitted a supplemental to the FDA stating that the dosage form anticipated for commercial use would be a tablet of amlodipine besylate and that all future clinical trials with amlodipine would use this new formulation.  Notably, in the supplement, Pfizer stated: “We feel that the change in salt form is justified since benzenesulfonate is a commercially acceptable salt, as exemplified by the tranquilizer mesoridazine (Serentil).”

As a preliminary matter, the CAFC stated that the District Court erred in holding that the court must accept a finding of obviousness by an Examiner asserted during prosecution of the ‘303 patent.  “Our case law consistently provides that a court is never bound by an examiner’s finding in an ex parte patent application proceeding.” An Examiner’s interim finding of prima facie obviousness the claims of an issued patent prima facie obvious! Since the court must presume a patent valid, the patent challenger bears the burden of proving the factual elements of invalidity by clear and convincing evidence.   The burden of proof never shifts to the patentee to prove validity.   The basis (as opposed to the mere existence) of an Examiner’s initial finding of prima facie obviousness of an issued patent is at most only one factual consideration that the court must consider “in determining whether the party asserting invalidity has met its statutory burden by clear and convincing evidence.”

Motivation to Combine Prior Art References to Achieve the Claimed Invention

In conducting the obviousness analysis (citing Dystar), the CAFC first stated:

Subsumed within the Graham factors is a subsidiary requirement articulated by this court that where, as here, all claim limitations are found in a number of prior art references, the burden falls on the challenger of the patent to show by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so. . . . A reasonable fact-finder could only conclude that Apotex has shown by clear and convincing evidence that the skilled artisan would indeed have been so motivated to combine the prior art to produce the besylate salt of amlodipine.

A suggestion, teaching, or motivation to combine relevant prior art teachings to achieve a claimed invention does not have to be found explicitly in the prior art references sought to be combined.  Rather, the suggestion, teaching or motivation “may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself.”  Specifically, the testimony of record evidences that one skilled in the art would have been motivated to choose an anion having a different structure than that of maleate. 

The CAFC further held that irrefutable evidence showed that a skilled chemist at the time would simply make known pharmaceutically-acceptable salts of whatever active ingredient with which he or she was working at the time. Indeed, an inventor of the ’303 patent testified that it “would have been a mistake” to choose a novel anion.   One of ordinary skill in the art would have favorably considered benzene sulphonate because of its known acid strength, solubility, and other known chemical characteristics as reported in several other publications Pfizer had admitted were prior art.  Thus, the district court clearly erred when it ignored the significance of prior art references suggesting the besylate salt, even though the pharmaceuticals disclosed in those prior art references were not described as useful to treat hypertension or angina.

Reasonable Expectation of Success

The district court found that the skilled artisan would have had no expectation of success in making a besylate salt of amlodipine because there was no reliable way to predict the influence of a particular salt species on the active part of the compound.  The CAFC disagreed.  Obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.

The evidence would convince a reasonable finder of fact that the skilled artisan would have had a reasonable expectation of success that an acid addition salt of besylate would form and would work for its intended purpose.  In particular, the CAFC pointed to the suggestion in Pfizer’s supplemental filing with the FDA that it was known that the besylate salt of amlodipine would work for its intended purpose!

“Obvious-to-Try”

The CAFC also weighed in on the “impermissible” obvious-to-try  standard for obviousness.   “Undue dependence on mechanical application of a few maxims of law, such as “obvious to try,” that have no bearing on the facts certainly invites error as decisions on obviousness must be narrowly tailored to the facts of each individual case.”  Simply put, to conclude that amlodipine besylate would have been obvious, “the prior art, common knowledge, or the nature of the problem, viewed through the eyes of an ordinary artisan” merely had to suggest reacting amlodipine base with benzene sulphonic acid to form the besylate acid addition salt, and that that acid addition salt form would work for its intended purpose.  The CAFC held that they did.

Secondary Considerations

The CAFC further noted that evidence of secondary considerations, such as unexpected results, can be used to rebut a prima facie case of obviousness.  The District Court had cited unexpected results (stability and processability) in finding the claims nonobvious.  However, when unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.  The CAFC noted that Pfizer had simply failed in this matter to prove that the results were unexpected.

Amlodipine besylate is obvious because the prior art suggested, and Pfizer researches expected, that every other potential salt form of amlodipine would be adequate for its intended purpose, i.e., to increase bioavailability of amlodipine, and would solve the stickiness problem of the maleate salt. The fact that amlodipine besylate was the best of the acid addition salts actually tested proved nothing more than routine optimization that would have been obvious to one of ordinary skill in the art.

REVERSED.

JW Note:  Although the holding here was levied before KSR v. Teleflex, it is worth noting that the CAFC applied an apparently adjusted framework for obviousness analyses in anticipation of the KSR ruling (See, e.g., Dystar Textilfarben GMBH & Co Deutschland KG v. C.H. Patrick, Co., et al.,  Alza Corporation v. Mylan Laboratories, Inc., et al., and Ormco Corporation, et al. v. Align Technology, Inc. etc).