Generic Drug Labeling and Induced Patent Infringement

For every new drug application, the Hatch-Waxman Act requires pharmaceutical companies to identify each patent that claims the drug, its formulation, or a method of using it.[1] When the drug is approved, the FDA publishes these patents in the "Orange Book,"[2] which provides notice to generic manufacturers of certain types of patents the brand-manufacturer could reasonably assert if "a person not licensed by the owner engaged in the manufacture, use, or sale of the drug."[3] If a generic manufacturer seeks approval to sell a generic version of the brand drug before the patents listed in the Orange Book expire, the manufacturer may sue for patent infringement. If the manufacturer is successful, the FDA will not approve the generic drug until the relevant Orange Book patents expire.[4]

Using a Generic Drug Manufacturer's Proposed Label to Prove "Specific Intent" to Induce Infringement

Brand-name manufacturers often have patents claiming methods of treating patients with a drug, but generic manufacturers typically do not treat patients. How, then, can a brand-name manufacturer assert a method of treatment patent against a generic manufacturer? To assert such patents, a plaintiff will have to prove that the generic manufacturer will indirectly infringe by either contributing to or inducing another's infringement.[5] A plaintiff cannot succeed in proving inducement without first showing a patient or physician will directly infringe the method patent.[6] But the "mere existence of direct infringement by physicians, while necessary to find liability for induced infringement, is not sufficient for inducement."[7] A plaintiff must also prove that the generic manufacturer "possessed specific intent to encourage another’s infringement."[8] That is, the plaintiff must show that the generic manufacturer's "actions induced infringing acts and that he knew or should have known his actions would induce actual infringements."[9]

Courts may infer the requisite specific intent from statements that appear in the generic manufacturer's label. "When proof of intent depends on the label accompanying the marketing of a drug, 'the label must encourage, recommend, or promote infringement.'"[10] Below, we review cases where plaintiffs met their burden—and those that fell short—on proving specific intent based on the proposed generic label.

Strategy: Prove the Instructions in the Label Induce Physicians or Patients to Use the Drug in an Infringing Way

Hatch-Waxman plaintiffs have proven specific intent to induce infringement by showing that the instructions in the "Dosage and Administration" and "Indications and Usage" sections in the label induce infringement.[11]

For example, in BTG International Ltd. v. Amneal Pharms. LLC, the claims covered a method of treating prostate cancer using 1000 mg of abiraterone in combination with 10 mg of prednisone.[12] The "Indications and Usage" section of the proposed label stated the drug was "for the treatment of metastatic castration-resistant prostate cancer."[13] The "Dosage and Administration" section recommended administering 1000 mg/day of abiraterone acetate and 10 mg/day of prednisone.[14] The court concluded that the proposed generic label promoted the exact use covered by the claims.[15]

But the label does not have to be that explicit. In AstraZenec LP v. Apotex, Inc., AstraZeneca's patent covered a method of treating pediatric asthma by administering the drug "at a frequency of not more than once per day."[16] The proposed generic label made no mention of once-daily dosing.[17] The "Dosage and Administration" section taught "[i]n all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved."[18] The section also provided a table of recommended starting doses of 0.5 mg total dose administered twice daily in divided doses (e.g., 0.25 mg twice daily) or 1 mg total dose administered twice daily in divided doses. The proposed generic label stated the drug would be sold in two strengths, 0.25 mg and 0.5 mg in a 2 mL vial.[19] The court found that, to follow the recommendation to "downward-titrate to the lowest effective dose," a patient starting with the 0.25 mg twice-daily dose would necessarily infringe the method claim by reducing the administration to once-daily dosing.[20] The instructions would necessarily lead to infringement for some users—a finding that Apotex and amici challenged as insufficient. may not have been enough to show specific intent to induce infringement.[21] But there was more.

The Federal Circuit stated: "[T]he district court's specific intent finding was not based solely on the proposed label, but also on Apotex's decision to proceed with its plan to distribute the drug despite being aware that the label presented infringement problems."[22] The Director of Regulatory Affairs at Apotex testified that she discussed with FDA three potential amendments to the label that would have taught against once-daily dosing. FDA however did not authorize the changes.[23] To the contrary, the FDA referred Apotex to a decision where the FDA noted that the instruction for downward titration would lead to once-daily dosing for some patients.[24] That Apotex proceeded with the proposed label knowing that its instructions would lead to direct infringement supported the conclusion that Apotex had the specific intent to induce infringement.[25]

Beware: Permissive Statements May Fall Short of Evidencing a Specific Intent to Induce Infringement

In HZNP Medicines LLC v. Actavis Labs.UT, Inc., the Federal Circuit concluded that a plaintiff relying solely on a proposed generic label advising a patient to take infringing steps under certain conditions did not prove specific intent.[26] A patient would infringe the method patent by 1) applying the drug to the skin; 2) waiting for the skin to dry; and 3) applying sunscreen, insect repellent, or a second topical medication.[27] The "General Dosing Instructions" section of the proposed generic label directed patients to perform the first step.[28] The "Special Precautions" section advised patients to "[w]ait until the treated area was dry before applying sunscreen, insect repellent, lotion, moisturizer, cosmetics, other topical medication."[29] The Federal Circuit found the warning was just that a warning, not a requirement: "If the user wants to apply another substance over it, then the patient should wait until the area is dry."[30] The Federal Circuit agreed with the district court's reasoning that the label "merely provided guidance to patients" about what to do in certain circumstances.[31]

Strategy: Prove Clinical Data in the Label Induces Physicians and Patients to Use the Drug in an Infringing Way

A plaintiff may rely on information contained in sections of a proposed generic label other than the "Dosage and Administration" and "Indications and Usage" sections to prove specific intent.

Plaintiffs have successfully relied on the "Clinical Studies" section to prove specific intent. For example, in Sanofi v. Watson Labs. Inc., the patent-in-suit covered methods for decreasing the risk of cardiovascular hospitalization among patients with certain risk factors.[32] The "Indications and Usage" section stated the drug was indicated to "reduce risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF)."[33] That section referenced the "Clinical Studies" section for more information about the patients with AF who may benefit from the drug.[34] The "Clinical Studies" section set forth the results of a study showing that the drug reduced hospitalization among patients with the risk factors covered by the patent-in-suit. At trial, the generics' experts admitted that physicians read the labels "for information about the use of the drug in special or specific populations."[35] The expert for Sanofi testified that physicians would understand from the label that the FDA had approved the drug based on the clinical trial results.[36] The expert also testified that the results of another study (also shown on the label) would encourage using the drug only in the groups covered by the claims because those were the only patients that benefitted from the treatment.[37] Taken together, the court found that the clinical trial results "encouraged" physicians to prescribe the drug to patient groups covered by the patent.[38]

Courts have also relied on clinical data in the "Pharmacokinetics" section in finding specific intent. In Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd., the patents-in-suit were directed to methods of treating pain by administering an opioid to patients having mild or moderate hepatic impairment.[39] The liver metabolizes medications, so those are at higher risk of toxicity from the opioid accumulating in the bloodstream.[40] The draft label stated that "no adjustment in starting dose...is required in patient with mild or moderate impairment."[41] Pernix's expert testified that due to the risks of prescribing an opioid to a person with hepatic impairment, a physician would rely on more than just dosing recommendations.[42] The physician would also examine the pharmacokinetic data.[43] The "Pharmacokinetics" section disclosed data showing the effect of the drug on patients with hepatic impairment that would assure the physician that the drug was safe even in patients with compromised liver function.[44] The court found the pharmacokinetic data were not "merely data statements" as suggested by Alvogen's expert.[45] Rather a physician would view them as a recommendation that the drug was suitable for use in patients with mild or moderate hepatic impairment, a recommendation that would induce infringement.[46]

Beware: Pre-Clinical Data May Not Be Enough to Show Specific Intent to Induce Treatment of Conditions Other than Those Specified in the Indications Section

In Bayer Schering Pharma AG v. Lupin Ltd., the Federal Circuit affirmed the lower court's decision finding no induced infringement because the label did not indicate to physicians that the specific three-pronged use claimed in the patent was safe and effective.[47] The patent stated that the claimed method simultaneously achieved three claimed effects. The label, however, only specified the use of the drug to achieve one of the claimed effects.[48] The "Pharmacodynamics" and "Clinical Pharmacology" sections stated that studies in animals and in vitro demonstrated effectiveness in achieving the other two effects.[49] The Federal Circuit, however, concluded the data from animal and in vitro studies did not "recommend[s] or suggest[s] to physicians that the drug is safe and effective for administration to patients for the purposes of inducing these effects," and therefore did not induce infringement.[50]

Conclusion

Plaintiffs should evaluate every section of the proposed generic label for evidence of specific intent to induce infringement. Even statements that implicitly (rather than explicitly) encourage infringement may suffice, especially when buttressed by expert testimony that explains how a physician would interpret the statements when evaluating whether to prescribe the drug.

[1] 21 U.S.C. § 355(b).

[2] Bayer Schering Pharma AG v. Lupin, Ltd., 676 F.3d 1316, 1318 (Fed. Cir. 2012). The full name of the Orange Book is "Approved Drug Products With Therapeutic Equivalence Evaluations."

[3] 21 U.S.C. § 355(b).

[4] Eli Lilly & Co. v. Teva Pharm. USA, Inc., 557 F.3d 1346, 1348 (Fed. Cir. 2009).

[5] 35 U.S.C. §271(b).

[6] Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., 845 F.3d 1357, 1368 (Fed. Cir. 2017); Inducement also requires proof that the defendant had knowledge of the asserted patents. 21 U.S.C. § 355(b). A generic manufacturer's abbreviated new drug application ("ANDA") seeking approval to make a generic drug provides that proof. See Allergan, Inc. v. Alcon Labs., Inc., 324 F.3d 1322, 1324 (Fed. Cir. 2003).

[7]Takeda Pharm. USA, Inc. v. West—Ward Pharm. Corp., 785 F.3d 625, 631 (Fed. Cir. 2015).

[8] DSU Med. Corp. v. JMS Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006) (en banc in relevant part).

[9] Sanofi v. Watson Labs. Inc., 875 F.3d 636, 644 (Fed. Cir. 2017).

[10] Id. (quoting Takeda Pharm., 785 F.3d at 631).

[11] AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1056 (Fed. Cir. 2010).

[12] BTG Int’l Ltd. v. Amneal Pharm. LLC, 352 F. Supp. 3d 352, 362 (D.N.J. 2018), appeal dismissed as moot, 923 F.3d 1063 (Fed. Cir. 2019).

[13] 352 F. Supp. 3d at 396-97.

[14] Id.

[15] Id.

[16] 633 F.3d at 1046-47.

[17] Id. at 1057.

[18] Id.

[19] Id.

[20] Id.

[21] Id. at 1060-61.

[22] Id.

[23] Id.

[24] 633 F.3d at 1058-1059.

[25] Id. at 1060.

[26] 940 F.3d 680, 702 (Fed. Cir. 2019).

[27] 940 F.3d at 702.

[28] Id. at 699-700.

[29] Id. at 700.

[30] Id. at 702 (emphasis in original).

[31] Id.

[32] Sanofi v. Watson Labs. Inc., 875 F.3d 636, 642 (Fed. Cir. 2017).

[33] Id. at 645.

[34] Id. at 644.

[35] Id.

[36] Id. at 645.

[37] Id.

[38] Id.

[39] 323 F. Supp. 3d 566, 576 (D. Del. 2018), aff’d sub nom. Persion Pharm., LLC v. Alvogen Malta Operations Ltd., 945 F.3d 1184 (Fed. Cir. 2019).

[40] 323 F. Supp. 3d at 574.

[41] Id.

[42] Id. at 585.

[43] Id.

[44] Id. at 586.

[45] Id.

[46] Id. at 588.

[47] Bayer Schering Pharma AG v. Lupin Ltd., 676 F.3d 1316, 1321-22 (Fed. Cir. 2012).

[48] 676 F.3d at 1321-22.

[49] Id. at 1322, 1324.

[50] Id. at 1322, 1326.