IP Law Daily Makers of generic chemotherapy drug would induce infringement through instructions to doctors
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Thursday, January 12, 2017

Makers of generic chemotherapy drug would induce infringement through instructions to doctors

By Thomas Long, J.D.

Generic versions of a chemotherapy drug (with accompanying product literature) would infringe methods of treatment claimed by a patent held by Eli Lilly & Co. and commercially embodied in Lilly’s brand-name drug ALIMTA®, the U.S. Court of Appeals for the Federal Circuit has held. Although no single actor performed all steps of the asserted claims because the actions of both physicians and patients were required, direct infringement was attributable to physicians who would prescribe the generic product, and drug companies seeking to market the generic products would be liable for inducing that infringement by instructing the physicians to prescribe the products only after administering certain vitamin pretreatments. The asserted patent claims were not invalid for indefiniteness, obviousness, or obviousness-type double patenting. Infringement and validity findings by the federal district court in Indianapolis were affirmed, as well as a final judgment barring the defending drug companies from launching their generic products before the expiration of the patent-in-suit (Eli Lilly and Company v. Teva Parenteral Medicines, Inc., January 12, 2017, Prost, S.).

Patent-in-suit. Lilly’s U.S. Patent No. 7,772,209 ("the ’209 patent")—issued in 2010—related to methods of administering pemetrexed disodium after pretreatment with folic acid and vitamin B12. Pemetrexed kills cancer kills by inhibiting the function of folates. The vitamin pretreatments reduced the toxicity of the drug in patients. Lilly marketed pemetrexed under the name ALIMTA® for treatment of certain types of lung cancer and mesothelioma.

Infringement allegations. In 2008 or 2009, defendants Teva Parenteral Medicines, Inc., APP Pharmaceuticals, LLC, Pliva Hrvatska D.O.O., Teva Pharmaceuticals USA Inc., and Barr Laboratories, Inc. submitted Abbreviated New Drug Applications (ANDAs) seeking Food and Drug Administration approval to market generic versions of ALIMTA®. After the ’209 patent issued, the defendants sent Lilly notices that they had filed certifications declaring that the ’209 patent was invalid, unenforceable, or would not be infringed. Lilly filed suit against the defendants under 35 U.S.C. §271(e)(2), alleging that the defendants’ generics would be administered with folic acid and vitamin B12 pretreatments and, thus, result in infringement of the ’209 patent.

District court proceedings. The defendants conditionally conceded induced infringement under then-current law set forth in Akamai Technologies, Inc. v. Limelight Networks, Inc. (Akamai II), 692 F.3d 1301 (Fed. Cir. 2012) (en banc) (per curiam), rev’d, 134 S. Ct. 2111 (2014). At the time, the Akamai II decision was the subject of a petition to the Supreme Court for a writ of certiorari. The defendants reserved the right to litigate infringement if the Supreme Court reversed or vacated Akamai II. The parties proceeded with a bench trial on invalidity, and the district court decided that the asserted claims were not invalid for obviousness or obviousness-type double patenting. The court had previously decided that the claims were not invalid for indefiniteness. When an appeal of the finding on validity was pending, the Supreme Court reversed Akamai II, holding that liability for inducement cannot be found without direct infringement. In light of that decision, this case was remanded to the district court for the limited purpose of litigating infringement.

After a second bench trial, in a decision issued August 25, 2015, the district court concluded that the defendants would induce infringement of the ’209 patent. The district court applied the Federal Circuit’s holding in another subsequent decision in the Akamai line of cases, which had broadened the circumstances in which others’ acts may be attributed to a single actor to support direct infringement. The defendants appealed the finding of induced infringement and the district court’s finding that the asserted claims were not invalid.

Direct infringement. When no single actor performed all steps of a method claim, direct infringement only occurred if the acts of one were attributable to the other such that a single entity was responsible for the infringement, the Federal Circuit explained. The performance of a method step was attributable to a single entity when that entity directed or controlled another’s performance. The district court relied in part on the defendants’ proposed product labeling as evidence of infringement. The labeling would be materially the same as the labeling for ALIMTA®, including instructions regarding the administration of folic acid—which the district court found would be performed by patients but attributable to physicians. Taking folic acid in the manner specified was a condition of the patient’s participation in pemetrexed treatment; physicians would prescribe an exact dose of folic acid and direct that it be ingested daily. Therefore, the performance of all steps of the asserted claims would be attributable to physicians.

The defendants correctly stated that the reduction in toxicities was not a benefit that physicians could "condition," in the Federal Circuit’s view, but the court’s discussion of reducing pemetrexed toxicities in relation to its direction-or-control analysis was not erroneous. A reduction in pemetrexed toxicities was relevant only if pemetrexed treatment was administered, and it provided a reason why physicians would condition the receipt of pemetrexed treatment on folic acid administration. Therefore, pemetrexed treatment was the benefit to be conditioned on the taking of folic acid. The evidence showed that folic acid was an "absolute requirement" for use of the drug, and that it was the physician’s responsibility to initiate the supplementation of folic acid. In addition, the evidence supported a finding that doctors would not prescribe the drug if patients did not comply with the requirement to take folic acid supplements. Physicians did not merely guide or instruct patients to take folic acid; if a patient failed to take folic acid as instructed, a physician need not provide pemetrexed treatment. This sort of "conditioning," for purposes of finding infringement under Akamai, did not require doctors to verify patients’ compliance, the court said. Nor did conditioning the performance of a step in a method require a legal obligation. Accordingly, the Federal Circuit affirmed the district court’s determination that direct infringement was attributable to physicians.

Induced infringement. The appellate court also affirmed the finding that the defendants would induce infringement through their proposed product labeling. The label instructions regarding vitamin supplementation were clear enough to allow an inference of specific intent to induce infringement. The labeling included repeated instructions and warnings to physicians about the importance of and reasons for folic acid treatment. The instructions were unambiguous and encouraged or recommended infringement, the Federal Circuit said.

Indefiniteness. The district court did not err in holding that the limitation "vitamin B12" was not indefinite. Depending on the context, "vitamin B12" could be used in the art to refer either to cyanocobalamin specifically or, more broadly, to a class of compounds including pharmaceutical derivatives of cyanocobalamin. However, expert testimony indicated that a person of ordinary skill in the art would understand that the patent claims referred to the former meaning. In addition, the claim language and prosecution history supported the district court’s holding.

Obviousness. The Federal Circuit rejected the defendants’ contention that the district court erred in determining that the asserted claims were not obvious in light of prior art. The appellate court left standing the district court’s finding that a skilled artisan would not have been motivated to use vitamin B12 pretreatment with pemetrexed, let alone the appropriate doses and schedules of such vitamin B12 pretreatment.

Obviousness-type double patenting. Finally, the Federal Circuit held that the district court did not err in holding that the asserted claims were not invalid for obviousness-type double patenting over U.S. Patent No. 5,217,974 ("the ’974 patent"), an earlier patent also owned by Eli Lilly. The appellate court affirmed the district court’s determination that the use of pemetrexed, use of vitamin B12, and doses and schedules of the asserted claims were patentably distinct from claim 20 of the ’974 patent because there would have been no reason for a skilled artisan to add vitamin B12 to the folic acid pretreatment.

The case is No. 2015-2067.

Attorneys: Adam Lawrence Perlman (Williams & Connolly LLP) for Eli Lilly and Co. William M. Jay (Goodwin Procter, LLP) for Teva Parenteral Medicines, Inc., APP Pharmaceuticals, LLC, Pliva Hrvatska D.O.O., Teva Pharmaceuticals USA Inc., and Barr Laboratories, Inc.

Companies: Eli Lilly and Company; Teva Parenteral Medicines, Inc.; APP Pharmaceuticals, LLC; Pliva Hrvatska D.O.O.; Teva Pharmaceuticals USA Inc.; and Barr Laboratories, Inc.

MainStory: TopStory Patent FedCirNews

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