The United States Court of Appeals for the Federal Circuit found in favor of Eisai in Aciphex patent infringement suit against Teva Pharmaceuticals and Dr. Reddy’s Laboratories .  Eisai v. Dr. Reddy’s and Teva (07-1397/98)

After Eisai filed infringement actions contesting Teva Pharmaceuticals and Dr. Reddy’s Laboratories’ submission of abbreviated new drug applications (ANDAs) to the Food and Drug Administration for Aciphex (rabeprazole), the district court found that Dr. Reddy’s and Teva failed to prove the remaining allegations of inequitable conduct and that Eisai had established that Dr. Reddy’s and Teva infringed Eisai’s patent (US 5,045,552).

The ’552 patent claims rabeprazole and its salts.  Rabeprazole is part of a class of drugs known as proton pump inhibitors, which suppress gastric acid production by inhibiting action of the enzyme H+K+ATPase.  Rabeprazole’s sodium salt is the active ingredient in Aciphex, a pharmaceutical approved for the treatment of duodenal ulcers, heartburn, and associated disorders.  Aciphex has over $1 billion in worldwide yearly sales.

Dr. Reddy’s and Teva each filed Abbreviated New Drug Applications (ANDAs) under the Hatch-Waxman Act looking to manufacture a generic version of Aciphex before the expiration of the ’552 patent.

The factual determinations of obviousness include 1) the scope and content of the prior art, 2) the level of ordinary skill in the art, 3) the differences between the claimed invention and the prior art, and 4) evidence of secondary factors, also known as objective indicia of non-obviousness.  Where the patent at issue claims a chemical compound, the analysis of the third Graham factor (the differences between the claimed invention and the prior art) often turns on the structural similarities and differences between the claimed compound and the prior art compounds.

The court stated:

Obviousness based on structural similarity thus can be proved by identification of some motivation that would have led one of ordinary skill in the art to select and then modify a known compound (i.e. a lead compound) in a particular way to achieve the claimed compound.  See Takeda Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007).   In keeping with the flexible nature of the obviousness inquiry, KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1739 (2007), the requisite motivation can come from any number of sources and need not necessarily be explicit in the art.  See Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed. Cir. 2007).  Rather “it is sufficient to show that the claimed and prior art compounds possess a ‘sufficiently close relationship . . . to create an expectation,’ in light of the totality of the prior art, that the new compound will have ‘similar properties’ to the old.”  Id. (quoting Dillon, 919 F.2d at 692).

Teva tried to argue that a combination of three prior art references made the ’552 patent obvious: 1) European Patent No. 174,726, claiming lansoprazole (EP ’726); 2) United States Patent No. 4,255,431, claiming omeprazole (’431 patent); and 3) an article by Brändström, et al., entitled “Structure Activity Relationships of Substituted Benzimidazoles” (Brändström).

The court noted that omeprazole is structurally farther afield from rabeprazole than is lansoprazole and that rabeprazole, lansoprazole, and omeprazole are all Brändström core structure compounds.

In the end, the court found that potential solutions are less likely to be genuinely predictable in the chemical arts:

Under these assumptions, one of skill in this art may have considered [rabeprazole] a candidate for a lead compound in the search for anti-ulcer compounds.  To the contrary, the district court emphasized the differences between anti-ulcer action and gastric acid inhibition.  The trial court specifically noted that Teva’s expert testified with respect to the EP ’726 data that “[t]he level of acid secretion . . . from these [anti-ulcer] data . . . cannot be determined.”  SJ Validity Order at 13.  In this context, this court consults the counsel of KSR that “any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.”  127 S. Ct. at 1742.  Thus lansoprazole’s candidacy as a starting point to develop new anti-ulcer compounds versus new gastric acid inhibitors does not resolve the lead compound analysis, at least not in the absence of any contrary indications.  Cf. Takeda, 492 F.3d at 1359 (negative side effects could dissuade one of skill from using a particular compound as a starting point).

In KSR, the Supreme Court noted that an invention may have been obvious “[w]hen there [was] . . . a design need or market pressure to solve a problem and there [were] . . . a finite number of identified, predictable solutions.” 127 S. Ct. at 1742 (tense changes supplied to clarify, as the Court stated and as per 35 U.S.C. § 103, that the obviousness inquiry must rely on evidence available “at the time” of the invention, see Takeda, 492 F.3d at 1356 n.2).  The Supreme Court’s analysis in KSR thus relies on several assumptions about the prior art landscape.  First, KSR assumes a starting reference point or points in the art, prior to the time of invention, from which a skilled artisan might identify a problem and pursue potential solutions.  Second, KSR presupposes that the record up to the time of invention would give some reasons, available within the knowledge of one of skill in the art, to make particular modifications to achieve the claimed compound.  See Takeda, 492 F.3d at 1357  (“Thus, in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound.”).  Third, the Supreme Court’s analysis in KSR presumes that the record before the time of invention would supply some reasons for narrowing the prior art universe to a “finite number of identified, predictable solutions,” 127 S. Ct. at 1742.  In Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008), this court further explained that this “easily traversed, small and finite number of alternatives . . . might support an inference of obviousness.”  To the extent an art is unpredictable, as the chemical arts often are, KSR’s focus on these “identified, predictable solutions” may present a difficult hurdle because potential solutions are less likely to be genuinely predictable.

In other words, post-KSR, a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound.  Teva cannot create a genuine issue of material fact on obviousness through the unsupported assertion that compounds other than lansoprazole might have served as lead compounds.  Further, the record contains no reasons a skilled artisan would have considered modification of lansoprazole by removing the lipophilicity-conferring fluorinated substituent as an identifiable, predictable solution.  In sum, the district court properly concluded that the record did not support a case of obviousness of the ’552 patent as a matter of law.

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2 Comments

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    Stephen, for an ignorant European, can you offer a quck explanation of the “lead compound” concept. In this case, that means, I suppose, “most promising springboard for finding a new and better anti-ulcer drug”. But the claim in suit is to the molecule per se, not to the drug, so how can the concept of the “lead compound” be so purpose-narrow. If you want to defeat the obviousness attack with the argument “lead compound not the obvious starting point” don’t you need “anti-ulcer drug” in the claim? Or did Judge Rader read that technical feature into the claim, as an implicit feature?

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