The USPTO Patent Trial and Appeal Board (PTAB) decided not to institute inter partesreview (IPR) of key claims of Jazz’s U.S. Patent 8,772,306, which is listed in the Orange Book for Xyrem®. Although the PTAB did institute proceedings for claims 19-34 of the ‘306 patent, claims 1-18 may be more relevant to the Xyrem® prescribing information, and may present a more significant hurdle to generic competition seeking the same labeling.  

The Jazz Xyrem Patent At Issue

U.S. Patent 8,772,306 is one of many patents listed in the Orange Book for Xyrem®, and has an expiration date of March 15, 2033. The claims are directed to methods of adjusting the dose of gamma-hydroxybutyrate (GBH) when the patient also is administered valproate. This is important because, according to the patent, “valproate increases the effect of GHB on the body, thereby potentially causing an unsafe condition.”

Claim 1, which was challenged by both Ranbaxy Inc. and Par Pharmaceutical, Inc. but for which institution was denied, reads as follows:

1. A method for treating a patient who is suffering from excessive daytime sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleep time disturbances, hypnagogic hallucinations, sleep arousal, insomnia, or nocturnal myoclonus with gamma-hydroxybutyrate (GHB) or a salt thereof, said method comprising: orally administering to the patient in need of treatment at least 5% decrease in an effective dosage amount of the GHB or salt thereof when the patient is receiving a concomitant administration of valproate, an acid, salt, or mixture thereof.

Claim 19, which also was challlenged by both Ranbaxy Inc. and Par Pharmaceutical, Inc., and for which the PTAB instituted IPR based on the issues raised by Ranbaxy, reads as follows:

19. A method for treating a patient who is suffering from narcolepsy, said method comprising:
administering a therapeutically effective amount of a formulation containing a GHB salt to a patient starting at a concentration of between 350 and 750 mg/ml with a pH of between 6 and 10;
determining if the patient is also being administered valproate, an acid, salt or mixture thereof;
warning of a potential drug/drug interaction due to the combination of valproate, an acid, salt or mixture thereof and the GHB salt; and
recommending reducing the dose of the GHB salt at least 15%.

Why Claim 1 Was Spared IPR

In its decision rendered in Ranbaxy v. Jazz (IPR2016-00024), the PTAB noted the following reasons for denying institution with regard to claims 1-18:

• Petitioner “did not account for the prior art’s teaching away from the co-administration of GBH and valproate.”

• Petitioner did “not demonstrate[] sufficiently that a skilled artisan would have had a reasonable expectation of success in treating the claimed sleep disorders with such a reduced dosage of GHB.”

The PTAB rejected Ranbaxy’s “routine optimization” argument, noting that the evidence cited by Patent Owner of alternative GBH clearance pathways made the effects of co-administration unpredictable, such that at the very least “further experimentation” would have been required with no reasonable expectation that a suitable reduced dose of GBH would be identified.

The PTAB noted similar reasons for denying institution in Par v. Jazz (IPR2016-00002).

Why Claim 19 Was Not Spared IPR

The PTAB treated claims 19-34 differently based on the “warning” and “recommending” steps. Ranbaxy argued that those clauses were not entitled to be given patentable weight under the “printed matter” doctrine. As summarized by the PTAB:

“Printed matter [is subject] matter claimed for what it communicates,” which is not entitled to patentable weight unless the “claimed informational content has a functional or structural relation” to the claimed invention. In re Distefano, 808 F.3d 845, 850 (Fed. Cir. 2015).  “Printed matter” is not limited to the addition of written information to a known product, but rather “extends to the situation . . . wherein an instructional limitation is added to a method . . . known in the art.” King Pharm.[, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1279 (Fed. Cir. 2010)].

The PTAB agreed with Ranbaxy on the current record, and determined that when those steps are not given patentable weight the references cited by Ranbaxy demonstrate a reasonable likelihood of establishing obviousness. Nevertheless, the PTAB “invite[d] the parties to address the ‘printed matter’ doctrine more fully in their post-institution filings.”

The Federal Circuit addressed the printed matter doctrine in a case involving AstraZeneca’s budesonide kit claims, which I discussed in this article

The Xyrem Prescribing Information

The prescribing information for Xyrem® includes this guidance:

2.4 Dose Adjustment with Co-administration of Divalproex Sodium
Pharmacokinetic and pharmacodynamic interactions have been observed when Xyrem is co-administered with divalproex sodium. For patients already stabilized on Xyrem, it is recommended that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of Xyrem by at least 20%. For patients already taking divalproex sodium, it is recommended that prescribers use a lower starting Xyrem dose when introducing Xyrem. Prescribers should monitor patient response and adjust dose accordingly [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

As noted above, claim 1 of the ‘306 patent recites a GBH dose reduction of “at least 5%.” Claim 2 recites a GBH dose reduction of “at least about 15%,” and claim 4 recites ranges of GHB dose reductions that include 20%.

The Amneal IPR Petition

While Jazz may be pleased that claims 1-18 were spared IPR in these recent PTAB decisions, they are not safe yet. Amneal filed a petition for IPR against the ‘306 patent that was accorded a filing date on February 8, 2016. I will discuss Amneal’s arguments in a separate article.