Structural uncertainty: understanding the Federal Circuit's lead compound analysis.

• Author: Barron, Briana

1. INTRODUCTION 401 A. Obviousness and Chemical Compounds 402 B. Development of Lead Compound Analysis 405 C. Current Application of the Lead Compound Analysis 410 1. Selection of the Lead Compound 410 2. Motivation to Modify the Lead Compound 412 3. Likelihood of Success 414 II. PROBLEMATIC ASPECTS OF LEAD COMPOUND ANALYSIS 416 A. Application to Combination Drugs 417 B. Application to Formulations 419 C. Lead Compound Analysis and the Requirements of KSR 420 III. TAKEAWAYS 423 IV. CONCLUSION 425 I. Introduction

   Recently, the Federal Circuit and lower courts have applied a new test to assess the question of obviousness for chemical compounds. While courts have always considered the presence of some lead compound to be relevant to the question of obviousness, beginning at the turn of the millennium, the Federal Circuit began assessing obviousness in a more formulaic fashion, applying what is commonly referred to as the lead compound analysis to determine if a litigant has established a prima facie case of obviousness.

   This Paper describes the development of the lead compound analysis, (1) and its application. (2) This Paper then discusses some of the shortcomings and weaknesses of the doctrine's applications (3) and how understanding the lead compound analysis and how it is likely to be applied in typical situations can be useful in understanding both how to draft stronger patents and what ways might be available to attack the obviousness of a chemical compound or a court's application of the lead compound analysis. (4)

   1. Obviousness and Chemical Compounds

      While the obviousness analysis has always been factually intensive, the parameters for assessing obviousness have remained relatively steady since the United States Supreme Court first addressed obviousness under the 1952 Patent Act in Graham v. John Deere Company. (5) In Graham v. John Deere the Supreme Court laid out four factors for approaching obviousness. First, the scope and the content of the prior art and the claims should be determined. (6) Second, the differences between the prior art and the claims at issue must be ascertained. Third, the level of ordinary skill in the art is determined. And finally, courts consider additional factors such as the commercial success, long felt but unresolved needs, and failure of others. (7)

      The Supreme Court's most recent take on obviousness emphasized that the John Deere factors still defined the controlling inquiry. (8) In KSR v. Teleflex, the Supreme Court held that the Federal Circuit's teaching suggestion motivation (TSM) test was overly rigid and the Court emphasized that any approach to obviousness must be a flexible approach. (9) Under the TSM test, the Federal Circuit would determine obviousness of a combination by looking to see if the prior art had some teaching, suggestion, or created some motivation to combine certain elements in the way that the invention did. (10) If a court found that the prior art did contain a teaching, suggestion or motivation, the invention would be obvious.

      The TSM test was a high standard for proving obviousness of a chemical compound because it required the prior art to contain language not often found, suggestions of what could be done. KSR lowered the standard for asserting obviousness, holding that the Federal Circuit's standard was not the only approach to obviousness, and that using it alone constituted too rigid of an analysis. After KSR, while a teaching suggestion or motivation might be relevant, lower courts are free to look at things outside the prior art, such as common sense and ordinary creativity. (11)

      In the earliest cases at the Court of Customs and Patent Appeals (C.C.P.A.) specific to chemical compounds, structural similarity was deemed as sufficient to support a finding of obviousness. (12) A person who knew the structure of a related compound would then, in turn, be motivated to make analogs of that compound. However, as technology for elucidating structures came on the market, and more structures became known, courts, perhaps recognizing the complexity and unpredictability of chemical compounds, (13) moved away from the assumption that once a structure was known, it would be obvious to test all the analogs for similar properties.

      In the 1970s, the C.C.P.A. found that prior art disclosure of a structural analog alone was insufficient to provide real motivation to make a new compound. (14) In Stemniski, the applicant claimed a tin composition useful in lubricants as an antioxidant while the prior art analog compositions had no known utility. (15) The court decided that without a known utility for the prior art compound, the applicant had no reason or motivation to synthesize the claimed analogs. (16) It was also immaterial that the prior art compounds actually had these properties since they were unknown at the time of invention. (17)

      A subsequent line of cases confirmed Stemniski. (18) These cases mainly conclude that some utility is required for the prior art compound to give a person of ordinary skill in the art the requisite motivation to synthesize analogs. (19) This new approach not only allowed for the patenting of a large number of chemical compounds, but also confirmed the idea that structural similarity for chemical compounds is more unpredictable than the structural similarity of other systems. For example, two mechanical structures with a substantially similar structure are likely to operate in the same way, but chemical compounds do not operate under this same assumption. In contrast, chemical compounds display a wide range of properties from their steric effects to the electronic effects of substitutions, as well their interactions with chiral systems such as the body.

      With the switch from the C.C.P.A. to the Federal Circuit, the Federal Circuit considered what is still considered a lead case for the obviousness of structurally similar chemical compounds en banc in In re Dillon. (20) In Dillon, a patent applicant claimed a composition of hydrocarbon fuel and tetra-orthoester, producing less soot during combustion, but the prior art disclosed the use of tri-orthoesters in fuel for dewatering purposes and of tetra-orthoesters as water scavengers in hydraulic fluids. Tri-ortho esters differ from tetra-ortho esters in the addition of one ester group to the compound. The Board of Patent Appeals and Interferences found that the claims were prima facie obvious in light of the prior art. (21) The court found that the "sufficiently close relationship" between the tri-orthoesters and the tetra-orthoesters and the knowledge within the prior art created an expectation that the tetra-esters would have the same or similar properties as the triesters. (22)

      The Federal Circuit summarized the analysis as having different considerations: (1) "the new compound or composition [must be] [] structurally similar to the reference compound or composition," and (2) that "there is some suggestion or expectation in the prior art that the new compound or composition [would] [] have the same or similar utility as [the compound asserted by the applicant] []." (23) If the previously disclosed properties of a prior art compound provided sufficient motivation to trigger a prima facie obviousness rejection, even though the new compound has unrelated, different, and unexpected properties, the analysis then turns to rebuttal, by showing that his compound has unexpected properties relative to prior art compounds, "that the prior art was so deficient that there was no motivation to make what otherwise might appear to be obvious changes," or any other pertinent argument. (24)

   2. Development of Lead Compound Analysis

      The earliest case establishing the modern "lead compound" analysis is Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc. (25) Yamanouchi was the result of a successful motion for judgment as a matter of law (JMOL) upholding the validity of the '408 patent. (26) The '408 patent was directed at compounds that inhibit gastric acid secretion. (27) At issue was a claim for the compound famotidine. (28) Famotidine is a member of a larger class of compounds called [histamine.sub.2] ([H.sub.2]) antagonists, which have a general structure containing a substituted heterocycle which is connected to a polar tail by an "alkyl containing" chain. (29) Danbury filed an Abbreviated New Drug Application (ANDA) with the Food and Drug Administration (FDA) and made a Paragraph IV certification that the patent on famotidine was invalid. (30) Paragraph IV certifications are considered acts of infringement, (31) and after receiving the certification, Yamanouchi filed suit.

      At the district court, Danbury argued that famotidine was invalid as an obvious result of combining features of compounds from the prior art, and then performing a bioisosteric substitution to reach resulting compound. (32) Specifically, Danbury presented two [H.sub.2] antagonists from the prior art, tiotidine and E44, and argued that famtotidine was the result of combining the heterocylce of tiotidine with the polar tail of E44 followed by a routine bioisosteric substitution of a sulfomoyl group for a carbamoyl group substitution in the polar tail. (33)

      The Federal Circuit upheld the JMOL noting at the outset that Danbury did not show the motivation for selecting either of the compounds. (34) While the E44 showed increased activity, the court noted that the activity alone was not a sufficient motivation to choose E44 as a lead compound because other compounds had been shown to be more active. (35) The court further noted that Danbury had failed to show the motivation to combine the heterocycle of tiotidine with the polar tail of E44. (36) An expectation that the compound would show baseline [H.sub.2] antagonist activity was not enough to show the reasonable expectation of success for the compound. (37) Finally, the court noted that the prior art did not suggest any order of manipulating the compounds, so there...