Standard (US) for determining obviousness in chemical cases

This post provides an overview of the Federal Circuit's decision in Unigene Labs. and Upsher-Smith Labs v. Apotex (Fed. Cir. 2011) with respect to determination of an inventive step.  Long post follows.

Summary: Unigene reflects the extent to which the Federal Circuit has evolved KSR v. Teleflex (KSR's) obviousness jurisprudence.  Instead of following the KSR direction of 'obvious to combine', the Federal Circuit differentiated formulating known compounds with novel compounds and therefore pushes the boundaries of non-obviousness to new levels.  That said, this case also gives new guidelines for application of a novel compound in different settings. The Teaching, suggestion and motivation (TSM) test has been used again and it seems to me that the Federal Circuit has underscored that pharmaceutical formulation arts are unpredictable and that there is a real threat of hindsight reconstruction to successful novel formulations of known compounds.


Shamnad in a previous post had discussed the implications of KSR on another pharmaceutical case, Pfizer v. Apotex and its implications for the Novartis case.  Our readers may remember that in Pfizer, the Federal Circuit had reversed a finding of non-obviousness as determined by the district court using the TSM test, relying on a reference that disclosed multiple anions for making pharmaceutically-acceptable salts, including the one in the patent - benzene sulphonate, used to make amlodipine besylate.  In Pfizer, the choice of salt was considered merely one of the possible choices readily available to one skilled in the art and disclosed in the references.  The Federal Circuit discounted the beneficial/unexpected properties. With Unigene, it seems that the decision pendulum of the Federal Circuit has reached its opposite end.   

In Unigene, because teachings about a composition in oral administration were ignored when the same compound was used in a different setting, nasal administration, one possible practice pointer here is that substitution of one ingredient may not be rendered as obvious by prior art that teaches the use of that ingredient in a different setting.  Additionally, Unigene may also be used as cite against the Examiner when she combines references in a manner that was never intended by one skilled in the art.    

Facts:  This case involved Unigene's drug Fortical®, covered under its reissued patent RE40,812 ("812E patent") for U.S. Patent No. 6,440,392.  Unigene owns the ’812E patent through assignment from inventor Dr. William Stern.  Fortical® is an FDA approved pharmaceutical nasal spray formulation of salmon calcitonin (active ingredient) for treating post-menopausal osteoporosis and is a bioequivalent formulation of another salmon calcitonin-based drug, Miacalcin®, from Novartis.   Unigene’s New Drug Application (“NDA”) listed Miacalcin® as its reference drug, and for FDA approval, all Unigene had to prove was that Fortical® was a bioequivalent of Miacalcin®.

Key differences and similarities between Fortical® and Miacalcin®:

Differences

Similarities

i. Miacalcin® has been marketed since 1995, before the ’812E patent’s February 4, 2000 priority date; ii. Different formulations: Miacalcin® contains 8.5 mg of sodium chloride, which acts as a tonicity agent; nitrogen, which acts as a sparging agent; hydrochloric acid, which acts as a pH adjuster; and purified water, which acts as a carrier.  Miacalcin® also contains 0.10 mg of benzalkonium chloride (“BZK”) which functions as a preservative, absorption enhancer, and surfactant.  Fortical® contains 20 mM of citric acid, which functions as an absorption enhancer and stabilizer/buffer; polyoxyethylene(2) sorbitan monooleate (“polysorbate 80”), which acts as a surfactant; and phenylethyl alcohol and benzyl alcohol, which serve as preservatives.

Both use salmon calcitonin at a concentration of 2,200 I.U./mL as their active ingredient. Both are nasal sprays as calcitonins are relatively unstable in pharmaceutical compositions, and for effectiveness salmon calcitonin (a natural polypeptide hormone), must reach the blood stream.

 

Apotex, a Canadian pharmaceutical company, filed Abbreviated New Drug Application (“ANDA”) with the FDA.  The ANDA contained provisions where Apotex intended to make, use, offer to sell, sell, and/or import a generic version of Unigene’s Fortical® product before the expiration of the ’812E patent.  Because a paragraph IV certification is an act of infringement under 35 U.S.C. § 271(e)(2),  Unigene lodged a Complaint for infringement in the district court.   Claim 19 was the focus of the litigation and covered:

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.

District Court:  The district court found that the ’812E patent would NOT have been obvious at the time of invention.  In considering forty-plus pieces of prior art submitted by Apotex, the district court found that NO prior art teaches using 20 mM citric acid to achieve “both shelf stability and enhanced bioavailability” in a nasal salmon calcitonin formulation.   The district court also found that it would not have been obvious to a person of ordinary skill in the art to modify Miacalcin® to reach the formulation of claim 19.   The patent office had also considered the same forty-plus references during prosecution of the ‘812E patent.

Person skilled in the art:  A person of ordinary skill was an individual with a masters degree in chemistry, pharmaceutical chemistry, biochemistry, or a similar field with at least eight years of practical experience in pharmaceutical liquid dosage form development, or an individual with a Ph.D. in the same fields with at least four years of practical experience in pharmaceutical liquid dosage form development. 

Specifically, the district court determined first that BZK serves as an absorption enhancer, a preservative, and a surfactant in Miacalcin®.  Then, the court relied on expert testimony to conclude that a person of ordinary skill would have been motivated to find other FDA-approved compounds that serve as both absorption enhancers and preservatives of calcitonin.  Further, the district court found that the prior art taught alternative methods of improving bioavailability and absorption of calcitonin.    

Federal Circuit:  Is it clear that the patentee designed around Miacalcin® by using citric acid instead of BZK?  No, said the Federal Circuit.

To reach this determination, the Federal Circuit developed several nuances of the KSR precedent.  One of these include: “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 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," Eli Lilly v. Zenith Goldline Pharm., 471 F.3d 1369, 1380 (Fed. Cir. 2006).  Then it discussed uses of a “lead compound/reference composition” in chemical arts.  This lead compound serves as a starting point for a person of ordinary skill developing the claimed invention.   Where the patent at issue claims a chemical compound, a lead compound is often used to show structural similarities between the claimed compound and prior art.   In the context of a composition or formulation patent where the patented formulation was made to mimic a previously FDA-approved formulation, the functional and pharmaceutical properties of the “lead compound” can be more relevant than the actual chemical structure (though not always mutually exclusive).  Thus the term “reference composition” is more appropriate than “lead compound” when considering obviousness for a chemical composition that the infringer deliberately imitates.  In this case, Miacalcin® serves as the “reference composition” for development of the claimed composition.  In Miacalcin®, BZK acts as a preservative, absorption enhancer, and surfactant.  Claim 19 of the ’812E patent is the result of effort to design around Miacalcin®.  Unigene did not dispute that “about 20 mM citric acid” in claim 19 functions as an absorption enhancer and surfactant in Fortical®.  

Apotex argued at the Federal Circuit that claim 19 was obvious in view of three pieces of prior art: Miacalcin®, the Day reference, a publication about pharmaceutical preformulation and formulation, lists benzyl alcohol

and phenylethyl alcohol as two of nine listed preservatives on a table of “Excipients used in aqueous nasal products”, and 5912014 (“014 patent”) which listed Dr. Stern  (inventor of 812E patent).

“...[T]his 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.  See KSR, 550 U.S. at 421.  The ’014 patent claims a solid oral dosage of salmon calcitonin, not a liquid formulation.  While the experiments discussed in the ’014 patent found that “the bioavailability of salmon calcitonin increased nearly 10 fold when the amount of citric acid in the formulation was increased only 5 fold,” ’014 patent col.11 ll.33-35, a person of ordinary skill (not Dr. Stern, a co-inventor of the ’014 patent) would not glean from the ’014 results a reason to use about 20 mM citric acid in a nasal calcitonin formulation.  The ’014 patent itself describes a solid oral formulation of salmon calcitonin.  Although the ‘014 patent mentions citric acid, that discussion refers to concentrations of citric acid much higher than those in claim 19.  Moreover, the ’014 patent examined citric acid for bioavailability in the context of a liquid injection into a rat duodenum, not a human use in a liquid pharmaceutical formulation.  These significant differences 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.”  (Emphasis added).

In the opinion, there is no indication whether the citric acid at any other concentration level could be used for any other purpose (other than for performing the functions of BZK), including use as a pH adjuster in one of the references. 

To a person of ordinary skill in the art, citric acid, even at about 20 mM concentrations, would not be an obvious substitute for BZK’s functions as an absorption enhancer and as a surfactant because citric acid has a vague role in even the closest prior art.   U.S. Patent No. 5,124,315 (“’315 patent”) describes liquid pharmaceutical compositions for nasal administration containing a polypeptide as an active ingredient.  Example 5 of the ’315 patent uses 20.5 mM of citric acid in a liquid nasal formulation containing salmon calcitonin as its active ingredient.  ’315 patent col.3 l.43.  The ’315 patent makes clear however that “citric acid was not used as an absorption enhancing agent, but it is merely the acidic component of the buffer.”   Id.  at col.4 ll.18-23.  (Emphasis added.)   

In fact, the ’315 patent teaches away from using about 20 mM citric acid as an absorption enhancing agent or stabilizing agent in a liquid formulation with a salmon calcitonin active ingredient.  The ’315 patent discusses U.S. Patent No. 4,476,116 (“’116 patent”), directed toward nasal compositions having enhanced peptide absorption.  The ’116 patent lists over fifty examples, including citric acid, of pharmaceutically acceptable chelating agents to serve as absorption agents.  ’116 patent col.11 l.1.  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].”  ’315 patent col.2 ll.13-16, 19-21.   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.  (Emphasis added).

The Federal Circuit affirmed the decision of the district court and concluded 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, 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."