By Kevin E. Noonan —

The Federal Circuit today issued its ruling in Unigene Labs., Inc. v. Apotex, Inc., and the decision illustrates the extent of the effects of the Supreme Court's decision in KSR Int'l Co. v. Teleflex Inc. on the Federal Circuit's obviousness jurisprudence.  In addition, the decision provides a contrast between how the Court views chemical obviousness for pharmaceutical formulations today, and the views contained in the Court's opinion in Pfizer, Inc. v. Apotex, Inc.

The case involved litigation over Unigene's drug Fortical®, a nasal formulation of salmon calcitonin for treating post-menopausal osteoporosis.  This drug is an alternative formulation of another salmon calcitonin-based drug, Miacalcin®, sold by Novartis.  The patent-in-suit was Unigene's U.S. Patent No. RE40,812, a reissue of U.S. Patent No. 6,440,392, and specifically asserted claim 19:

A liquid pharmaceutical composition for nasal administration comprising about 2,200 MRC units of salmon calcitonin, about 20 mM citric acid, about 0.2% phenylethyl alcohol, about 0.5% benzyl alcohol, and about 0.1% polyoxyethylene(2) sorbitan monooleate.

The District Court noted that calcitonin was known in the art to be difficult to administer, since it was known to be readily degraded, unstable, and poorly absorbed.  Both Miacalcin® and Fortical® contain 2200 IU salmon calcitonin, but the formulations differ:  the Novartis formulation contains sodium chloride, nitrogen, hydrochloric acid, water, and benzalkonium chloride (to promote absorption), while Unigene's formulation contains 20mM citric acid, polyoxyethylene(2) sorbitan monooleate (also termed "polysorbate 80"), phenylethyl alcohol, and benzyl alcohol.  Unigene received FDA approval of Fortical® under an NDA pursuant to 21 U.S.C. § 355(b)(2) using Miacalcin® as "reference drug."

Litigation ensued after Apotex filed an ANDA containing a Paragraph IV certification.  In its certification, Apotex asserted noninfringement, invalidity, and unenforceability for inequitable conduct.  The District Court found (on summary judgment) that the claims were nonobvious over "forty four prior art references" and that Apotex had not adduced sufficient evidence of an intent to deceive to support the inequitable conduct allegation; in this regard, the Court also refused to breach the attorney-client privilege under the crime-fraud exception.  The key for the District Court's determination of nonobviousness was that the art did not disclose using 20 mM citric acid in the formulation "to achieve 'both shelf stability and enhanced bioavailability' in a nasal salmon calcitonin formulation."  With regard to the other affirmative defenses, the District Court "held that all of Apotex's defenses and counterclaims . . . had been conceded, waived, barred, abandoned, or improperly raised."

The Federal Circuit affirmed in an opinion written by Chief Judge Rader and joined by Judges Moore and O'Malley.  In the opinion, the Court recited several rubrics from KSR that showed the nuances developed by the Federal Circuit in its application of the Supreme Court precedent.  These include:

• "Obviousness requires more than a mere showing that the prior art includes separate references covering each separate limitation in a claim under examination.  KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)."

• "Rather, obviousness requires the additional showing that a person of ordinary skill at the time of the invention would have selected and combined those prior art elements in the normal course of research and development to yield the claimed invention.  Id. at 421"

• "A person of ordinary skill at the time of the invention interprets the prior art using common sense and appropriate perspective.  KSR, 550 U.S. at 421."

The opinion cites the portion of the KSR opinion regarding the relationship between what is "obvious to try" and what is obvious:

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.

The opinion notes that "[a]ccordingly, when design need and market pressure may dictate a commonsensical path using a finite number of identified predictable solutions to one of ordinary skill, deviations from that path are likely products of innovation."  In addition, the opinion notes that the "teaching-suggestion-motivation (TSM)" test provides "one way to identify 'sources of evidence that an ordinary skilled artisan might have found and combined at the time of the invention,'" citing Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1364-65 (Fed. Cir. 2008).

Applying these principles, the Court held that "the patent claims a new composition or formulation to deliver an FDA-approved active ingredient.  Thus, the claimed invention is not obvious if a person of ordinary skill would not select and combine the prior art references to reach the claimed composition or formulation," citing Eli Lilly v. Zenith Goldline Pharm., 471 F.3d 1369, 1380 (Fed. Cir. 2006).  Under the circumstances of this case (a reformulation of a known formulation of a known compound), the opinion states that "[a] prima facie case of obviousness in the chemical arts is often based on a known compound, called a 'lead compound,' which serves as a starting point for a person of ordinary skill developing the claimed invention," citing Eisai Co. Ltd. v. Dr. Reddy's Labs., 533 F.3d 1353, 1357 (Fed. Cir. 2008).  Such a lead compound then provides a basis to show "structural similarities" between the prior art and the claimed lead compound.  But for formulation cases "where the patented formulation was made to mimic a previously FDA-approved formulation," the Court says the term "reference composition" is a better way to frame the issue, since the "functional and pharmaceutical properties" of the composition may be more informative ("appropriate") than the chemical structure of the lead compound.  The Court then looks to the comparison between the Norvartis Miacalcin® product, which the Court finds is the substitution of 20 mM citric acid for BZK.

The Court recognized that the art provided "design need and market demand" for a nasal formulation of calcitonin, identifying the "design need" as the bioequivalent formulation, and the market demand for a composition that treats the same symptoms.  The Court's opinion then focused on the citric acid component — in part from statements made at oral argument — and says that "the inclusion of 'about 20 mM citric acid' in the composition provides the strongest case for nonobviousness."

Prior art references considered by the District Court and relevant to the panel opinion include U.S. Patent No. 5,912,014 (which named the inventor of the patent-in-suit as an inventor), which disclosed an oral calcitonin formulation comprising enteric coating and further disclosed experiments on the effects of citric acid on bioavailability and absorption in vivo (albeit showing but minor effects).  With regard to this reference, the opinion states that "this court agrees that no reasonable juror could conclude that the '014 patent would give a person of ordinary skill sufficient reason or motivation to use about 20 mM citric acid in a liquid nasal salmon calcitonin composition."  The Court's reasoning distinguished the formulation claimed in the '812 reissue patent from the oral formulations disclosed in the '014 patent on the difference between an oral dosage form and a liquid formulation, and the "significant" differences in route of administration and formulation.  These facts "would not cause a person of ordinary skill to replace BZK in Miacalcin® with 20 mM of citric acid in the normal course of research and development" in the Court's opinion.  In addition, other prior art referenced — including U.S. Patent Nos. 5,124,315 and 4,476,116 — showed only a "vague role" played by citric acid in formulations disclosed in those patents.  The Court cited the '116 patent as teaching from using citric acid as disclosed in the '812 reissue patent, because the '116 patent:

[L]ists over fifty examples, including citric acid, of pharmaceutically acceptable chelating agents to serve as absorption agents . . . .  Both parties agree that the '315 patent reports that the compounds listed in the '116 patent yielded "discouraging" test results, and that "only ammonium tartrate is a satisfactory stabilizing agent for liquid nasal compositions containing polypeptides as active ingredient [sic]."  . . .  One of ordinary skill in the art reading the '315 and '116 patents would have considered about 20 mM citric acid undesirable in a liquid nasal formulation containing salmon calcitonin."

Yet another prior art reference, the Day reference, lists benzyl alcohol and phenylethyl alcohol, two other components of the claimed formulation, as "Excipients used in aqueous nasal products."  The Court characterized this reference as follows:

BZK is one of the nine listed preservatives in Day, along with benzethonium chloride, chlorobutanol, methylparaben, phenylmercuric acetate, propylparaben, and thimerosal.  Citric acid is not included in the list of preservatives, but appears instead as a pH adjuster or buffer.  The Day reference also lists polysorbate 20 and 80 as one of three surfactants used as excipients in aqueous nasal products.  With reference to this prior art, there is no evidence to support the conclusion that a person of ordinary skill would expect a combination of citric acid, benzyl alcohol, phenylethyl alcohol, and polysorbate 80 to contain a buffer, pH adjuster, preservative, and surfactant, but no absorption enhancer or excipient to promote bioavailability.

Finally, the opinion states that the affirmatively recited limitation "about 20.0 mM citric acid" "alone supports" the District Court's nonobvious determination:

When used as an absorption enhancer in the '116 patent, citric acid was one of over fifty options.  See KSR, 550 U.S. at 421.  Further, when the prior art used citric acid at about 20 mM, as in the '315 patent, it was used only as a buffer.  There is no genuine dispute of material fact that a person of ordinary skill attempting to make a liquid composition to deliver salmon calcitonin into a human body through nasal administration, would not have considered using about 20 mM citric acid with the narrowly claimed amounts of benzyl alcohol, phenylethyl alcohol, and polysorbate 80, because the formulation would not be expected to perform properly to meet the specificity of a pharmaceutical use.  Thus, even accepting that there was a design need and market pressure to develop a pharmaceutical formulation that is bioequivalent to Miacalcin®, there is no evidence in the record that claim 19 would be an obvious solution to those motivations.

This outcome is in contrast with the decision in Pfizer v. Apotex, issued in the shadow of the (then) impending KSR decision.  That case involved a novel formulation of a known compound, amlodipine, as a besylate salt, sold under the trademark Norvasc® for treating hypertension and chronic stable and vasospastic angina.  The patent in the Pfizer case, U.S. Patent No. 4,879,303, claimed the besylate salt, while prior art (U.S. Patent No. 4,572,909) disclosed the maleate salt of the active ingredient, 2-[(2-aminoethoxy)methyl]-
4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.  In Pfizer, the Federal Circuit reversed a District Court finding of nonobviousness (determined under the TSM test), relying in part on a reference (Berge) that disclosed 53 FDA-approved anions for making pharmaceutically-acceptable salts, including the anion — benzene sulphonate — used to make amlodipine besylate.  There, the choice of salt was considered merely to reflect a design choice and the beneficial and purportedly unexpected properties were discounted by the panel.  In today's opinion, the Court appears to have returned to its prior tendency to understand that the pharmaceutical formulation arts are sufficiently unpredictable that there is a real threat of hindsight reconstruction in the face of successful novel formulations of known compounds.  As Judge Rader stated in his dissent to the Court's refusal to rehear the Pfizer case en banc, "[w]ith unpredictable pharmaceutical inventions, this court more wisely employs a reasonable expectation of success analysis," and since salt selection is unpredictable, there would be no reasonable expectation of success (as three District Court judges had previously found).

Thus, the Federal Circuit appears to have absorbed the thrust of the Supreme Court's KSR opinion, to give more credence to the skilled worker's capacity to recognize beneficial combinations of the prior art, and to consider whether the totality of the teachings of the art support the conclusion that even if it would be obvious to try, a novel formulation is "not obvious if a person of ordinary skill would not select and combine the prior art references to reach the claimed composition or formulation."

Unigene Labs., Inc. v. Apotex, Inc. (Fed. Cir. 2011)
Panel: Cheif Judge Rader and Circuit Judges Moore and O'Malley
Opinion by Chief Judge Rader