Can Pacira BioSciences' new ‘940 patent keep out generics for Exparel?

Zachary Silbersher

Pacira BioSciences has been busy protecting Exparel from generic competition.  For the past few years, Pacira has launched multiple patent lawsuits against Jiangsu Hengrui Pharmaceuticals, along with its regulatory agent, eVenus Pharmaceutical Laboratories.  In December 2024, Pacira acquired a new patent and immediately commenced another patent suit against Jiangsu Hengrui.  The patent is U.S. Patent No. 12,156,940, and it will not expire until 2044.  It is the parent patent in a new family, and Pacira has already filed a follow-up application to the ‘940 patent, which suggests more patents are in the pipeline.  What is the ‘940 patent?  And how successful will it be for prolonging Pacira’s monopoly pricing for Exparel?

What is the invention in the ‘940 patent?

Pacira’s ‘940 patent is unlike typical patents asserted in Hatch-Waxman litigations.  Rather than being directed to a chemical compound, a method of use or a formulation, the patent is directed to commercial batches of “bupivacaine encapsulated multivesicular liposomes (MVLs).”  In this way, the patent is directed to the manufacturing process that would be used by generics to manufacture commercial-size batches of their generic formulation for Exparel. (Manufacturing patents are not unheard of in Hatch-Waxman litigation, but nevertheless less common.) 

The first independent claim of the ‘940 patent is very long, and is copied below.

1. Batches comprising compositions of bupivacaine encapsulated multivesicular liposomes (MVLs), the composition comprising:

bupivacaine residing inside a plurality of internal aqueous chambers of MVLs separated by lipid membranes, wherein the lipid membranes comprise 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, cholesterol, and tricaprylin; and

an aqueous medium in which the bupivacaine encapsulated MVLs are suspended,

wherein the aqueous medium also comprises unencapsulated bupivacaine;

the total bupivacaine concentration in the composition is from 12 mg/mL to 17 mg/mL;

wherein the batches are manufactured within a period of six months, and

each of the batches has a volume of about 100 liters to about 300 liters;

wherein each batch has a cumulative percentage release of bupivacaine from 46% to 71% at a 24-hour time point, measured from two to six aliquots of each batch using a rotator-facilitated in vitro release assay for at least 48 hours, after storage of the aliquots of each batch at 2° C. to 8° C. for about 12 months from batch manufacture date; and 

wherein an average rate of change in the cumulative percentage release of bupivacaine of the batches at the 24-hour time point is 0.05%/month to 0.5%/month after storage of the aliquots of each batch at 2° C. to 8° C. for about 12 months. 

During examination of the ‘940 patent at the Patent Office, Pacira argued that prior to this purported invention, Exparel was manufactured in smaller batch sizes, including the “UK 200 L process” and the “45 L process.”  The UK 200 L process was approved by the FDA in July 2021.  By contrast, Pacira claimed that the ‘940 patent was directed to a purportedly new and larger batch process, known as the “SCC process,” which uses batch sizes of approximately 250-300L. 

Pacira also claimed that the SCC process purportedly has an improved in vitro release assay, or basically, better shelf-life or storage stability.  Data within the ‘940 patent (FIGs. 3 and 5) purport to show that the SCC process has superior cumulative percentage release of bupivacaine compared to batches produced by the 45 L process or the UK 200 L process over a 12 month period.   

The purported improvements of the SCC stability profile over the 45 L and UK 200 L processes was embodied by Pacira in the limitations from claim 1 and claim 13 of the ‘940 patent.  For instance, claim 1 recites: “wherein an average rate of change in the cumulative percentage release of bupivacaine of the batches at the 24-hour time point is 0.05%/month to 0.5%/month after storage of the aliquots of each batch at 2° C. to 8° C. for about 12 months.”  Accordingly, during examination of the ’940 patent, Pacira claimed that the 45 L process does not meet this limitation, whereas the SCC process does, and that is what makes the ‘940 patent purportedly inventive.

The patent examiner initially expressed concern that the purported invention in the ‘940 patent was the result of “routine optimization.”  The SCC process appeared to be a scaled up version of a prior art process, which is not necessarily a basis to be awarded a patent.  Yet, Pacira overcame these objections from the examiner primarily through submission of a declaration from a Pacira scientist.  That scientist, Eran Levy, argued that the changes of the SCC process compared to the 45 L and UK 200 L process yielded unexpected results, including purportedly surprising storage stability.  

Will the ‘940 patent be infringed or invalidated?

How likely is it that Pacira will prove that generics are infringing the ‘940 patent?  Unlike method-of-use patents, which are typically assessed against the pharmaceutical drug’s label, the ‘940 patent is a manufacturing patent.  The generic’s manufacturing process is not typically public.  The patent claims are nonetheless lengthy, which means Pacira must show that the generics meet many different limitations in their manufacturing process.  That increases the odds that there are one or two items in the patented process that the generics are not practicing.

For instance, Jiangsu Hengrui is a generic that already has FDA approval for its ANDA for Exparel.  Jiangsu Hengrui has already claimed (in its declaratory judgment suit, which is discussed below) that there are at least two features of the ‘940 patent process that it does not practice in making generic Exparel.  Jiangsu Hengrui claims its batches do not have a “volume of about 100 liters to about 300 liters” and they do not have the average rate of change in the cumulative percentage release of bupivacaine as required by the patent claim.  An interesting question that may arise during this lawsuit is whether Pacira, which may already have access to Jiangsu Hengrui’s ANDA through earlier lawsuits, was or was not aware that these features of the ‘940 patent may or may not be practiced by Jiangsu Hengrui.

How strong is the validity of the ‘940 patent?  The patent was granted on the basis of a Pacira scientist’s claim that the SCC process showed surprising storage stability compared to earlier, smaller batch processes.  The data and claims of that declaration have not been fully vetted in the way that they will be during litigation.  The generics will have the opportunity to introduce their own experts, run their own experiments, and challenge the claims regarding surprising and unexpected results that were made by Pacira during examination of the patent.  This is always a consequential risk of patents awarded on the basis of a secondary consideration (such as unexpected results or unmet but long felt need) as opposed to patents granted on the basis of a clear distinction over the prior art without the need of a declaration from the patent owner’s scientist.

In addition, Jiangsu Hengrui has also claimed that the patent may be invalid due to prior sales.  The ‘940 patent is the parent application in a new patent family.  The priority date for the patent is very recent, roughly May 2024.  Jiangsu Hengrui has therefore claimed that Pacira may have been selling Exparel covered by the SCC process sufficiently prior to this date to invalidate the patent.  On the other hand, Pacira claimed during examination of the ‘940 patent that the SCC process was not approved by the FDA until February 2024, which may not be sufficient.  This is likely a fact issue that will be run to ground during the litigation.

Jiangsu Hengrui has accused Pacira of patent harassment.

Pacira’s campaign to exclude generics for Exparel took a slightly unusual turn shortly after the ‘940 patent was granted. Jiangsu Hengrui Pharmaceuticals, along with its regulatory agent, eVenus Pharmaceutical Laboratories, separately sued Pacira for a declaratory judgment of non-infringement and invalidity of the ‘940 patent.  In that suit, Jiangsu Hengrui claimed that, when it filed its ANDA for Exparel in August 2021, Exparel was covered by only a single patent in the Orange Book, which was set to expire a few months later in December 2021.  Yet, Pacira started adding more and more patents to the Orange Book, and brough five separate patent lawsuits against Jiangsu Hengrui within three years.  Jiangsu Hengrui has publicly accused Pacira of “patent harassment.”

Pacira’s prior patent lawsuits against Jiangsu Hengrui were filed in New Jersey, but its latest lawsuit against Jiangsu Hengrui for infringement of the ‘940 patent has been filed in Illinois.  Jiangsu Hengrui has therefore claimed that Pacira is resorting to “forum shopping” by starting its new suit on the ‘940 patent in a different judicial district.   

On its face, Pacira’s move to Illinois is not without suspicion.  Pacira has already litigated multiple patents against the same party (Jiangsu Hengrui) related to the same drug (Exparel) in New Jersey.  Moreover, in 2024, after a trial, that court invalidated one of Pacira’s other patents (U.S. Patent No. 11,033,495).  Jiangsu Hengrui is therefore essentially suggesting that Pacira is not happy with the unfavorable rulings it has received in New Jersey, and it is attempting to find another court that might be more favorable.

Accordingly, Jiangsu Hengrui’s declaratory judgment suit is essentially an attempt to highlight its claim that Pacira is forum shopping, and also likely an attempt to drag the suit for the ‘940 patent back to New Jersey.  The Illinois court is likely to have questions for Pacira for why it filed its latest suit against Jiangsu Hengrui in Illinois after litigating against the same party for years in New Jersey.  The likelihood that Pacira’s suit for the ‘940 patent is sent back to New Jersey is non-negligible.

Overall, Pacira’s strategy of racing to get more patents and asserting them against Jiangsu Hengrui, even after Jiangsu Hengrui has FDA approval, is not necessarily uncommon.  That said, it is not without its risks.  Corcept Therapeutics pursued a very similar piecemeal strategy to protect Korlym from Teva’s generic.  Eventually, the court vocally lost its patience with Corcept, and Corcept now faces a lawsuit from Teva that alleges antitrust allegations.