January 13, 2017
By Barbara R. Rudolph, Ph.D.
In recent years, certain court decisions have suggested that copying is not a significant secondary consideration of non-obviousness in pharmaceutical patent infringement cases brought under the Hatch-Waxman Act. The notion of "‘no copying in ANDA cases" appears to come from Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., No. IP 99-38-CHK, 172 F. Supp. 2d 1060 (S.D. Ind. Oct. 29, 2001). In that case, at issue was a patent covering a drug molecule, and the court noted that the ANDA procedures established by the Hatch-Waxman Act require generic drug manufacturers to copy the approved drug to help ensure that a generic drug will be as safe and effective as the approved version. The court also stated:
The fact that copying is likely to be present in many Hatch-Waxman Act cases does not allow the court to ignore the copying as evidence of non-obviousness, even though it may be entitled to relatively little weight. In this case, in this field of new drug design, the very need for copying results from and emphasizes the unpredictability of medicinal chemistry. . . . To gain FDA approval, therefore, a company in Zenith’s position must copy the patented invention as closely as possible. Small changes in chemical structure may have dramatic and unpredictable biological effects. To that extent, the evidence of copying adds a little weight against a finding of obviousness, though it is not essential to this court’s ultimate conclusion.
Thus the idea that copying has very little weight in ANDA cases appears to be premised on the idea that an ANDA filer cannot simply design around a drug molecule patent and because, in effect, copying of the drug molecule(s) is mandated by the statute governing ANDAs.
But what about copying where the generic company had other, non-infringing alternatives but nevertheless opted to copy the patented invention? Many Orange Book-listed patents cover other aspects of an approved drug product, such as a particular API polymorph, salt, or drug product formulation, where the patent is directed to, e.g., the kind, number, and amounts of inactive ingredients (excipients) that make up the drug product along with the active drug molecule(s). The FDA permits some variations in physical form, salt form, and formulation of the approved API, so should copying of those patents be given increased weight?
The Federal Circuit has held, since Eli Lilly, that all evidence of secondary considerations must be considered as part of the obviousness analysis, and that secondary considerations cannot be disregarded. See, e.g., In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1078-1079 (Fed. Cir. 2012). Nonetheless, the basic idea from Eli Lilly has been expanded over time, such that generic defendants have argued, and indeed some courts have held, that copying is irrelevant in the ANDA context as to asserted patents beyond those covering the drug molecule. The Federal Circuit itself seemed to have acknowledged this approach, finding in one case that allegations of copying are "not probative of nonobviousness because a showing of bioequivalence is required for FDA approval." Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369, 1377 (Fed. Cir. 2013).
As another example, in Intendis GMBH v. Glenmark Pharm. Ltd., 117 F. Supp. 3d 549, 593 (D. Del. 2015) (Robinson, J.), the district court rejected the plaintiffs’ reliance on the fact that the defendant copied the claimed formulation invention despite of the availability of non-infringing alternatives, including a prior art formulation with the same active ingredient and other formulations of different drugs for the same indication. Nonetheless, the district court found that patent nonobvious, and the Federal Circuit affirmed that decision on appeal without any comment on the copying aspect of the district court’s holding. Intendis GMBH v. Glenmark Pharm. Inc., USA, 822 F.3d 1355 (Fed. Cir. May 16, 2016).
Other courts have been more willing to consider copying in the ANDA context. For example, one court found the evidence of copying to be compelling where the generic company had the option to market one version of the active ingredient in the same market, but continued to pursue a separately patented, prodrug version because it could "make a profit at selling" it. Merck Sharp & Dohme Corp. v. Sandoz Inc., No. 3:12-cv-03289, 2015 BL 277644 (D.N.J. Aug. 27, 2015) (Sheridan, J.) (finding copying weighed in favor of non-obviousness even when defendant had not established a prima face case of evidence). And another court found copying to be evidence of non-obviousness when it showed that the defendant considered but rejected design-around alternatives of the claimed formulations. Bayer Pharma AG v. Watson Labs., Inc., No. 12-cv-517, 2016 BL 133233 (D. Del. Apr. 27, 2016) (Sleet, J.) (on appeal).
In that vein, another recent case, Merck Sharp & Dohme Corp. v. Hospira Inc., No. 14-915, 2016 BL 336808 (D. Del. Oct. 7. 2016) (Andrews, J.), suggests that, in that context, copying can indeed play a larger role in the non-obviousness analysis. In this case, the Defendants filed an ANDA seeking approval for generic versions of Merck’s Invanz® product, which contains the antibiotic ertapenem. One of the patents asserted in that case covered stable pharmaceutical compositions containing ertapenem, whereby the unstable ertapenem molecule was protected from both hydrolysis and polymerization by reacting the drug molecule with a carbon dioxide source to create a carbamate adduct. Defendant Hospira argued that the claimed invention was obvious, relying on prior art references allegedly disclosing (1) conditions that would inherently lead to the claimed ertapenem carbamate adduct, (2) the stability of compounds similar to ertapenem, (3) the use of sodium bicarbonate to alter the pH of a compound similar to ertapenem, and (4) the importance of pH with respect to altering stability.
Merck relied on references which allegedly taught away from the claimed invention, wherein the creation of carbamate adducts of other similar compounds resulted in degradation or rearrangement of the molecule. Merck also relied upon various objective indicia of non-obviousness, including evidence that Hospira had tried to develop, but rejected, different, non-infringing formulations using stabilizers other than a carbon dioxide source. In the end, Hospira opted to use a process that led directly to the claimed ertapenem carbamate adduct. As per the district court, this is pertinent evidence of copying in the ANDA context:
Defendant argues that copying is "not compelling evidence of nonobviousness" in a Hatch-Waxman case, since a generic drug manufacturer is required to copy the approved drug. See Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 923 F. Supp. 2d 602, 676 (D. Del. 2013), aff’d, 752 F.3d 967 (Fed. Cir. 2014). Defendant is correct that 21 U.S.C. § 355(j)(2)(A) requires a generic to copy the active pharmaceutical ingredient of the reference drug, and to establish bioequivalency. The generic is not, however, required to copy inactive ingredients or the methods used in a manufacturing process. . . . Defendant’s decision to copy Plaintiff’s formulation and process "is an indicium of nonobviousness."
2016 BL 336808 (some citations omitted).
Based on the totality of the evidence before it, the district court ultimately decided that the claimed stable ertapenem compositions in one of the patents at issue would not have been obvious to one of ordinary skill in the art. However, the same copying evidence was not able to overcome a stronger prima facie case of obviousness, based upon different prior art, as to a separate patent in suit covering the process for preparing the carbamate adduct.
This Merck case in conjunction with earlier cases suggests that the tide could be turning for the use of copying as a secondary consideration of non-obviousness in ANDA cases, at least perhaps in the context of Orange Book-listed and asserted formulation and prodrug patents. However, another court in Delaware recently again found that evidence that could have suggested copying the formulation from a preferred patent example was not persuasive evidence of non-obviousness, relying in part on the Federal Circuit’s 2013 holding in Bayer v. Watson. Orexo AB v. Actavis Elizabeth LLC, No. 14-829, 2016 BL 379996 (D. Del. Nov. 15, 2016) (Robinson, J.). Appeal of the Bayer, Merck, and Orexo cases, and future district court and Federal Circuit ANDA obviousness decisions, should be monitored to see if the apparent tension over the applicability of copying in ANDA cases is resolved, such that this argument remains viable and is successfully applied in other cases.
Reproduced with permission from BNA’s Pharmaceutical Law & Industry Report Journal, 15 PLIR 73, [January 13, 2017]. Copyright © 2017 The Bureau of National Affairs, Inc. (800-372-1033) www.bna.com. This article is for informational purposes, is not intended to constitute legal advice, and may be considered advertising under applicable state laws. This article is only the opinion of the authors and is not attributable to Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, or the firm's clients.
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