Tag Archives: Orange Book

Amarin v. Hikma: Federal Circuit reverses Inducement Dismissal in Skinny-Label Case

June 25, 2024PatentFDA approval, Federal Circuit, Generic drugs, Hatch-Waxman, Induced infringement, Method of treatment patents, Motion to dismiss, Off-label use, Orange Book, Paragraph IV certifications, patent litigation, pharmaceutical patents, Pleading standards, Skinny labelsDennis Crouch

by Dennis Crouch

Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc., No. 2023-1169 (Fed. Cir. June 25, 2024).

This is another “skinny label” generic pharmaceutical patent case. The basic setup involves a drug that has several different approved uses; with the branded manufacturer holding patents covering only some of the uses. The generic company is then permitted to sell the drug, but is labelled only for non-patented uses. These labels are known as carve-out or “skinny” labels under 21 U.S.C. § 355(j)(2)(A)(viii).

It is inevitable that people will purchase and use the generic drugs for the patented uses, and that the generic distributer will be accused accused of inducing those infringing acts. Although the generic typically makes a profit on these sales, it those profits pale in comparison to the profits lost by the branded company.

Amarin v. Hickma highlights some of the challenges that generics are facing when marketing drugs with these carved-out labels. One difficulty is that the FDA severely limits what the generic can say about the drug and its uses, and the carve-out is generally based upon statements made by the patentee. Here, the court follows a label-plus approach. The skinny label itself will not be enough to show inducement, but that evidence can be combined with other evidence (such as marketing) to prove liability. (more…)

Amgen Scores Partial Victory in Efforts to Maintain OTEZLA Exclusivity

April 21, 2023PatentDamages, eligibility, en banc, enantiomers, Hatch-Waxman, obviousness, Orange Book, patent infringement, patent law, patent term extension, patent validity, PDE4 inhibitors, reasonable expectation of success, Section 101, Section 271(e)(1)Holman

By Chris Holman

Amgen Inc. v. Sandoz Inc., 2023 WL 2994166, — 4th — (Fed. Cir. Apr. 19, 2023)

In 2019, Amgen acquired worldwide rights to apremilast (OTEZLA) from Celgene $13.4 billion in cash, in connection with Celgene’s merger with Bristol-Myers Squibb. Apremilast was the only oral, non-biologic treatment for psoriasis and psoriatic arthritis, and in 2020 apremilast generated $2.2 billion for Amgen.

At the time Amgen’s acquired apremilast, Celgene was involved in Hatch-Waxman litigation with numerous generic challengers, including Sandoz. Celgene had asserted three of its 11 Orange Book-listed patents against Sandoz, and in 2020 Amgen was substituted as plaintiff.

The primary patent asserted is U. S. Patent 7,427,638, which is directed to pharmaceutical compositions comprising stereochemically pure apremilast. The original expiration date of this patent was in 2024, but the patent received a patent term extension of more than three years, resulting in an effective patent expiration date of February 16, 2028, according to the Orange Book.

Celgene also asserted U. S. Patent 7,893,101, which is directed to enantiomerically pure solid forms (e.g., crystalline polymorphic forms) of apremilast. This patent is due to expire December 9, 2023.

The third patent asserted by Celgene was U. S. Patent 10,092,541, directed to methods for treating a patient using dose titration of apremilast. According to the Orange Book, this patent was set to expire on May 29, 2034.

The district court found the claims of the ‘638 and ‘101 patents to be infringed and not invalid, and enjoined generic apremilast until the expiration of the ‘638 patent in February 2028. On appeal the Federal Circuit affirmed, an outcome that Amgen characterizes as a win.

On the other hand, the district court found the asserted claims of the ‘541 patent to be invalid for obviousness, which reportedly “pleased” Sandoz because the ruling “enables Sandoz to launch [its] generic apremilast product in the U. S. in 2028, six years prior to the expiry date of the latest-expiring Amgen patent asserted in litigation.” On appeal, the Federal Circuit affirmed with respect to the obviousness of the ‘541 patent.

Here is a brief overview of the court’s decision regarding the asserted obviousness of these patents.

The ‘638 patent claims apremilast, which is the stereochemically pure (+) enantiomer of a compound falls that within a class of molecules referred to as phosphodiesterase-4 (“PDE4”) inhibitors. Sandoz’s obviousness argument was based primarily upon a prior art Celgene patent, U. S. Patent 6,020,058, which includes an Example 12 that describes a racemic mixture containing apremilast, but that does not disclose the purified (+) enantiomer. The Federal Circuit found that the district court had not erred in holding that Sandoz had not proven that a skilled artisan would have had sufficient motivation to purify the (+) enantiomer from the racemic mixture disclosed in Example 12, nor that a skilled artisan would have had a reasonable expectation of success in resolving that mixture into its enantiomeric components, given the unpredictable nature of resolving racemic mixtures.

The Federal Circuit further found that the district court had not erred in its finding of strong objective indicia of nonobviousness, particularly given the unexpected potency of apremilast relative to the apremilast-containing racemic mixture disclosed in Example 12. The court credited testimony from a Celgene researcher listed as an inventor on the ‘638 patent, who noted a 20-fold difference in potency between apremilast alone and the racemic mixture, and stated that the inventors “didn’t expect a 20-fold difference in potency… Normally, if a racemate is a 50/50 mixture of two enantiomers, you might expect a two-fold difference in potency, all things being equal.” The district court also did not err in determining that apremilast satisfied a long felt need for an improved psoriasis treatment suitable for oral administration, that others in the field had tried and failed to develop other PDE4 inhibitors as drugs, and that there had been a degree of skepticism about the safety of apremilast because of its structural similarity to thalidomide, a drug notorious for its teratogenic effects in fetuses leading to severe and debilitating birth defects.

The issue with respect to the ‘101 patent was whether it could rely upon the filing date of a provisional application to which it claims priority. The ‘101 patent claims crystalline Form B of apremilast, and the provisional application includes an Example 2 which discloses a synthetic procedure for preparing apremilast. Although Example 2 does not explicitly disclose that the resulting apremilast has the Form B crystalline structure, Amgen provided the court with the results of over a dozen experiments following the procedure of Example 2, all of which resulted in crystalline Form B of apremilast, while Sandoz had provided no evidence to establish that Example 2 was capable of producing a crystalline Form other than Form B. Although the district court had based its holding on its conclusion that the provisional application inherently disclose crystalline Form B of apremilast, the Federal Circuit found that it did not need to reach the issue of inherent disclosure because the evidence established that Example 2 actually disclosed crystalline Form B of apremilast, albeit without specifically disclosing the crystal structure of the resulting product.

The ‘541 patent claimed a method of treating a patient with apremilast that basically involves starting with a relatively low dose and, over a course of days, gradually increasing the dosage to arrive at a full dosage which is significantly higher than the initial dosage, i.e., a dose-titration schedule. The court found this to be an obvious method, in view of prior art disclosing a similar dosage schedule. The Federal Circuit observed that, as a general matter, varying doses in response to the occurrence of side effects is well-known and obvious to the skilled artisan.

Federal Circuit: System is Not a Method (and therefore patent must be delisted from Orange Book).

February 24, 2023Patenten banc, Orange Book, patent law, REMS, Section 101Dennis Crouch

by Dennis Crouch

Jazz Pharms, Inc. v. Avadel CNS Pharms, LLC (Fed. Cir. 2023)

In the pharmaceutical industry, there is a lot of interplay between the patents and FDA regulation. A party with an approved drug product will often list related patents in the Orange Book. Jazz’s approved drug is sodium gamma-hydroxybutyrate (“GHB”). GHB is an infamous date-rape drug and the FDA conditioned its approval on Jazz developing “Risk Evaluation and Mitigation Strategies” (REMS). Jazz created a set of strategies, and also obtained a patent covering the strategy. US8731963. The patent basically overs a computer system that keeps track of prescriptions and inventory using a “single-pharmacy system” as well as a focus on whether the drug was purchased by a cash-payer. Jazz listed this REMS patent in the Orange Book as covering its drug product. And, although the patents covering the drug use itself expired in 2022, the REMS patent is still in force. But, the FDA is actually no longer requiring Jazz to use the system.

In my view, this is a pretty weak patent, and a court will probably eventually hold that it is ineligible. But, the “beauty” of the orange book listing is that patent quality often does not really matter. As the Federal Circuit explained Orange Book listing “arm[s] the patent owner with the ability to trigger a presumptive, thirty-month suspension of the FDA’s approval of a competitive product.” In other words, if a competitor wants to enter the market, the mere existence of a listed Orange Book patent creates a 2.5 years delay in approval of their product. The law also makes it an act of infringement for a third party to submit a NDA alleging that it is either not infringing or that the patent is invalid/unenforceable.

In this case, Avadel is wanting to market its own GHB drug and has its own proposed REMS using multiple pharmacies. After Avadel filed its NDA, Jazz sued. Avadel responded with a counterclaim seeking a court order to delist the patent.

Orange Book listing is proper when the patent either (1) covers the approved drug; or (2) covers an approved method of using the drug. The Federal Circuit appeared ready to allow this type of REMS patent as an Orange Book Listing. But, here is the rub for Jazz — its patent doesn’t claim a method, but rather claims a computer system.

Each of the ’963 patent’s three independent claims describes a ‘computer-implemented system’ that comprises ‘one or more computer memories’ and a ‘data processor.’ . . . That the claimed systems can be used in the course of treating patients suffering from narcolepsy does not alter the fact that these are system claims.

Slip Op. Jazz unsuccessfully argued that the FDA required submission of a “system,” and that should alter the method requirement. In fact, the FDA does not directly review the submitted patents and has never definitively stated that REMS patents can be listed.

Thus, the Federal Circuit affirmed the lower court order to delist the patent.

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My key struggle with this case is the background law that a “system” claim automatically covers both the system itself and using the system. This stems from the definition of patent infringement that covers making, using, selling, etc. 35 USC 271(a).