Prodrugs — Federal Circuit Holds That A PTE Does Not Cover Their Metabolites


A. Introduction

A prodrug is a medication or compound that after administration is metabolized (i.e., converted in the body) into a pharmacologically active drug (e,g., a metabolite). Often, the prodrug has no function other than delivering the active metabolite to the human body, hopefully to a specific location. If a patent claims a metabolite of a prodrug or its use, administering the prodrug that converts to the claimed metabolite after administration infringes the metabolite patent.[1] Numerous drugs are administered as prodrugs. For example, from 2008-17, 12.4% of all new drugs approved by the FDA were prodrugs.[2] These include: Emend ® (2008), Toviaz® (2008), Romidepsin® (2009), Pradaxa® (2010), Edarbi® (2011), Zytiga® (2011), Tecfidera® (2013), Sovaldi® (2013), Sivextio® (2014), Entresto® (2015) and Emflaza® (2017).[3]

Recently, the Federal Circuit in Biogen International GmbH v. Banner Life Sciences LLC[4]decided the scope of protection for claims to a prodrug during the extension ("PTE") granted under 35 U.S. C. section 156(a). Since many pharmaceutical patents are extended under this provision, understanding the metes and bounds of protection applied in the Biogen case, is important for pharmaceutical companies.

B. Overview of Patent Term Extension

To compensate patentees for the loss of patent term for patents covering pharmaceutical products due to the prolonged regulatory approval process, Congress enacted 35 U.S.C. section 156 as part of the Hatch-Waxman Act. As relevant here, section 156(a) provides, in pertinent part:

(a) The term of a patent which claims a product, a method of using a product, or a method of manufacturing a product shall be extended from the original expiration date of the patent. . . if

(4) the product has been subject to a regulatory review period before its commercial marketing or use, [and]

(5)(A). . . the permission for the commercial marketing or use of the product after such regulatory review period is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred....

Section 156(b) limits the rights granted by a PTE. In pertinent part, that section reads:

(b) ...[T]he rights derived from any patent the term of which is extended under this section shall during the period during which the term of the patent is extended —

(1) in the case of a patent which claims a product, be limited to any use approved for the product . . . [and]

(2) in the case of a patent which claims a method of using a product, be limited to any use claimed by the patent and approved for the product. . . .

Section 156(f) defines several terms used, inter alia, in sections 156(a) and (b). For purposes of this discussion, it reads:

(f) For purposes of this section:

(1) The term "product" means:

(A) A drug product. . .

(2) The term "drug product" means the active ingredient of —

(A) a new drug antibiotic drug, or human biological product (as those terms are used in the Federal Food. Drug, and Cosmetic Act and the Public Health Service Act) including any salt or ester of the active ingredient as a single entity or in combination with another active ingredient.

Although the term of the entire patent is extended under a PTE, the Federal Circuit has held that the extension does not allow the patentee to enforce its entire patent, but only the "rights derived" from section 156(a).[5] In that respect, section 156(b)(2) limits the "rights derived" from a PTE "to any use claimed by the patent and approved for the product."[6] Thus, under current Federal Circuit law, the extension does not extend to all products or uses covered by the patent, but only to those on which the extension was based, i.e., the FDA-approved product.[7] Controversy has often arisen in defining the term "product," particularly "the first permitted commercial marketing of the product," when a patentee seeks a PTE. These decisions — which do not address the scope of PTE protection — are nevertheless relevant to this discussion.

C. Decisions Interpreting Section 156

In Glaxo Operations UK Ltd. v. Quigg,[8] the Federal Circuit held that the term "active ingredient" in section 156(f)(2) referred to the molecule in the drug product to be administered, not any active ingredient formed later. There, the approved drug product was Ceftin,® which contained cefuroxime axetil before administration. That compound had not been previously marketed. Accordingly, the PTE was granted. As relevant here, the Federal Circuit rejected the PTO's position that since Ceftin® and other earlier compounds all metabolized into the same "therapeutically active substance," there prior compounds — which did not contain cefuroxime axetil as administered — blocked Glaxo's PTE. Accordingly, it was the drug as administered that controlled.[9]

The Federal Circuit's subsequent decision in Pfizer v. Dr. Reddy's Laboratories[10] had caused some confusion. There, Pfizer had received a PTE for its FDA-approved product, amlodipine besalyate. Dr. Reddy's sought FDA approval of amlodipine maleate. Pfizer accused Dr. Reddy's of infringement during the extended period. Dr. Reddy's argued that, since Pfizer's PTE was based on the FDA's approval of amlodipine besalyte, its maleate product did not infringe. Relying on the specific wording of section 156(f)(2), which notes that "salts or esters" of the active ingredient are the same product for purposes of section 156, the court held that Dr. Reddy's maleate salt infringed Pfizer's claims to the besylate salt.[11]

One could argue that the active ingredient in Pfizer was "amlodipine," not its salt. Thus, in one sense, the Federal Circuit focused on the active metabolite, and it did not focus on the drug as administered as it had done in Glaxo. Accordingly, what controls — the drug as administered or its active metabolite?

In PhotoCure ASA v. Kappos,[12] the Federal Circuit held that no conflict existed between Glaxo and Dr. Reddy's. There, the court stated that Pfizer merely held that a defendant cannot avoid infringement during the extended period "simply [by] changing the salt of the active ingredient."[13] As to Glaxo, the PhotoCure court stated that "a compound can only qualify as the — active ingredient' of a drug if that compound itself is present in the drug."[14] In PhotoCure, the court granted the requested PTE for methyl aminolevolonate hydrochloride (MAL) because it had not been marketed previously, even though MAL and a previously-approved drug both contained aminolevolonate acid of the active ingredient. In so doing, the court rejected the PTO's argument that the term "active ingredient" does not mean the approved drug but only its "active ingredient." As further the support for its ruling, the court noted that the PhotoCure drug for which a PTE was granted was a "new drug," i.e. a separately patented product that "had been" previously marketed requiring a full approval."[15] Similarly, in Ortho-McNeil Pharmaceutical Inc. v. Lupin Pharmaceuticals, Inc.[16], the court granted the requested PTE and noted that the PTE covered a drug requiring separate regulatory review and approval.

That a drug needs its own regulatory review and approval and is covered by its own patent may affect the court's view on whether one drug is the same as another — at least when a PTE is sought or, as relevant here, possibly during the extended period.

D. Biogen v. Banner

Biogen held the NDA for TecFidera.® The active ingredient was dimethyl fumarate ("DMF"). Once DMF was ingested, it metabolized into monomethyl fumarate ("MMF"). The Federal Circuit recognized that the two compounds were "virtually identical." DMF contains two methyls, which are part of the ester functional groups, whereas MMF has only one methyester group, the other group being a carboxylic acid. The patent-in-suit claimed the use of both compounds to treat multiple sclerosis.[17]

Banner filed for FDA approval of its generic MMF product. Biogen had obtained a PTE and filed suit alleging that Banner's proposed use of MMF to treat multiple sclerosis infringed the claims during the extended period. Banner moved to dismiss, arguing that the section 156(b)(2) limited the scope of the extension to methods of using the FDA approved product as defined in section 156(f), i.e., DMF (its salts or esters) — not MMF. Drawing a distinction between method of treatment and product patents, Biogen argued that the extension of the former covered all uses of any product within the original claims (which would include MMF). It also argued that the term "product" in section 156 covered the "active moiety" of the ingested drug, which would include MMF.[18]

The Delaware District Court, per Judge Stark, reviewed the decisions cited above as well as sections 156(b)(2) and 156(f)(2) and held that the "active ingredient" of Biogen's FDA – approved product was DMF; therefore, the "rights derived" from the PTE were limited to the use that product.[19] Accordingly, Banner's proposed use of MMF did not infringe. Judge Stark also dismissed Biogen's allegations of infringement under the doctrine of equivalents as the application of that doctrine was limited by the section 156 itself. [20]

On appeal, the Federal Circuit affirmed. Biogen argued that the Pfizer court had held that the term "product" has a different meaning under section 156(b) versus 156(a), and the term "active ingredient" means "active moiety." According to Biogen, Glaxo and PhotoCure were inapposite because they addressed section 156(a), which dealt with products, not uses. Banner, however argued that section 156(f) provides a consistent definition of "product," i.e., the drug as administered, and that reading excludes MMF. [21]

According to the Federal Circuit, neither Glaxo nor Pfizer controlled:

"Active ingredient" is a term of art, defined by the FDA as "any component that is intended to furnish pharmacological activity or other direct effect," and it must be present in the drug product when administered. The active ingredient of a given drug product is defined by what is approved and is specified on the drug's label. MMF is not the approved product, nor is it specified as the active ingredient on the Tecfidera® label.[22]

After distinguishing both Glaxo and PhotoCure, the court concluded:

All these precedents, and now this case, rest on the same holding: the term "product," defined in § 156(f) as the "active ingredient . . . including any salt or ester of the active ingredient," has a plain and ordinary meaning that is not coextensive with "active moiety." It encompasses the active ingredient that exists in the product as administered and as approved – as specified by the FDA and designated on the product's label – or changes to that active ingredient which serve only to make it a salt or an ester. It does not encompass a metabolite of the active ingredient or its de-esterified form.[23]

Accordingly, the court rejected Biogen's argument that section 156(b)(2) is not limited to the "approved product," but covers all "approval uses." Rather, according to the court, section 156(f), which defines the term "product," controls both sections 156(a) and (b)(2).

Lastly, although the doctrine of equivalence can apply during an extended period, the court dismissed Biogen's reliance on that doctrine as precluded by the statue itself.

E. Conclusion

Determining which patent from a patent portfolio to extend under section 156(a) is often a difficult analysis. The purpose of this brief review is to ensure that such decisions consider prodrug patents and their scope during the extended period.

Patentees should take Biogen into account in making PTE decision. Although only one patent can be extended for each product, a patentee usually has more than one patent eligible for potential PTE. When patents covering prodrugs — even if they also cover their metabolites — are involved, determining which patent to extent often raises difficult analysis. Indeed, in certain limited circumstances, especially with biotech drugs, one might even consider extending a process patent.[24]


[1]See Coggio, "In Vivo Conversion as Inducement to Infringe," Pharmaceutical Compliance Monitor (Feb. 14, 2014).

[2] Najjar, A., Karman, R., "The Prodrug Approach in the Era of Drug Design," Expert Opin. Drug Discov. (2019).

[3] Jarkko Rautio, Nicholas A. Meanwell, Li Di, Michael J. Hageman, "The Expanding Role of Prodrugs in Contemporary Drug Design and Development," Drug Discovery, Vol. 17, 559 (2018).

[4] 2020 WL 1920990 (Fed. Cir. April 21, 2020).

[5]See Genetics Institute v. Novartis Vaccines and Diagnostics, 655 F.3d 1291, 1300 (Fed. Cir. 2011).

[6]Id. at 1301.

[7]Merck & Co. v. Kessler, 80 F.3d 1543 (Fed. Cir. 1996).

[8] 894 F.2d 392 (Fed. Cir. 1990).

[9]Id. at 394-95.

[10] 359 F.3d 1361 (Fed. Cir. 2004) (2-1) (Mayer, C.J., dissenting).

[11]Id. at 1366-67.

[12] 603 F.3d 1372 (Fed. Cir. 2010).

[13]Id. at 1376.

[14]Id. at 1375-76 (emphasis added).


[16] 609 F.3d 1377 (Fed. Cir. 2010).

[17] 2020 WL 1920990 at *2-*3.

[18]Id. at *1.

[19]Biogen Int'l GmBH v. Banner Life Scis. LLC, 424 F. Supp. 3d 303, 304-07 (D. Del. 2020).

[20]Id. at 310-13.

[21]Id. at 314-15.

[22] 2020 WL 1920990 at *3 (citations omitted).

[23]Id. at *4 (citations omitted) (emphasis added).

[24]See Coggio and Ludwig, "Process Patents Are Vital in Biotech — Why Not Extend Them?" Law360 (Aug. 10, 2015).


More questions? Contact the authors or visit Fish's Intellectual Property Law Essentials.