ADDERALL XR® - USA

On Mar. 22, 2018, U.S. District Judge William G. Young of district of Massachusetts found Amphetamine patents infringed by Abhai, LLC in a Hatch-Waxman case.

On Nov. 20, 2015, the plaintiffs Shire LLC and Shire US Inc. (collectively, “Shire”), brought this action against the defendant Abhai, LLC (“Abhai”), for patent infringement of the United States Reissued Patent No. RE42,096 (the “‘096 Patent) and patent infringement of the United States Reissued Patent No. RE41,148 (the “‘148 Patent”) ”), in response to Abhai’s submission of ANDA with Paragraph IV certification to ADDERALL XR patents. ADDERALL XR is marketed for the treatment of Attention-Deficit/Hyperactivity Disorder (“ADHD”). The drug contains a combination of amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and dextroamphetamine saccharate. The bench trial began on March 27, 2017 & on April 4, 2017, after four days of trial; Abhai filed a motion to amend its pretrial memorandum to include eight new trial exhibits. The exhibits purported to show that the dissolution tests reported by Abhai on its product were performed incorrectly and the data was invalid.

Shire asserted that Abhai’s ANDA Product infringes on Claim 1 of the ‘096 Patent & Claims 1, 11 and 13 of the ‘148 Patent. Adderall XR contains two types of drug-containing beads, “Immediate-Release (IR) pellets” (the “IR Beads”) and “Delayed-Release (DR) pellets”.  Abhai’s ANDA Product is a capsule filled with two types of beads: IR Beads and DR Beads. Using an in vitro dissolution method, Abhai tested all strengths of its ANDA Product to determine the amount of drug release at different time points.

A. Abhai’s ANDA Product Infringes Claim 1 of the ‘096 Patent

Claim 1 of the ‘096 patent includes:

A pharmaceutical composition for delivery of one or more pharmaceutically active amphetamine salts, comprising: (a) one or more pharmaceutically active amphetamine salts covered with an immediate release coating; and (b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating that provides for delayed pulsed enteric release, wherein said enteric release coating releases essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric [release] release; wherein the pharmaceutically active amphetamine salts in (a) and (b) comprise mixed amphetamine salts.

Abhai admitted that its ANDA Product meets all limitations of claim 1 & only disputes that its ANDA Product meets the following limitations of claim 1: (1) “one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating the provides for delayed pulsed enteric release”; and (2) “wherein said enteric release coating releases essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric release.” 

During deposition it was admitted that the Eudragit L30D-55 in Abhai’s ANDA Product was used as an enteric coating. Therefore, the DR Polymer Layer in Abhai’s ANDA Product, comprising Eudragit L30D-55, constitutes an “enteric release coating.” This “enteric release coating” covers the one or more pharmaceutically active amphetamine salts in the DR Beads of Abhai’s ANDA Product. Abhai tested 12 capsules of each strength of its ANDA Product using the FDA’s recommended in vitro dissolution method. Applying four-hour normalization to Abhai’s batch dissolution data, the results showed rapid and complete release from the DR Beads.  Percent release of drug from the DR Beads exceeded 90% for the first hour of exposure to pH 6.0 for each strength. Abhai’s ANDA Product contains an enteric release coating that releases “essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric release,” as stated in the ‘096 Patent. Therefore, “essentially all” of the contents of the DR Beads are released within about 60 minutes. Thus Abhai’s ANDA Product infringes claim 1 of the ‘096 Patent.

B. Abhai’s ANDA Product Infringes Claims 1, 11, and 13 of the ‘148 Patent

Claim 1 of the ‘148 patent includes:

A pharmaceutical formulation for delivery of a mixture of amphetamine base salts effective to treat ADHD in a human patient comprising: an immediate release dosage form that provides immediate release upon oral administration to said patient; a delayed enteric release dosage form that provides delayed release upon oral administration to said patient; and a pharmaceutically acceptable carrier; wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate; wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt, and the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration previously reached after release of said immediate release dosage form; and wherein said pharmaceutical formulation, when containing about a total dose of 20 mg, will produce in a human individual a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of about 467 to about 714 ng hr/ml.

Claim 1 of US’148 require “a delayed enteric release dosage form that provides delayed release upon oral administration,” and the Court has construed it to include a “rapid and complete” release. Court further held that each of Abhai’s dosage strengths meet the Pharmacokinetic Claim Limitations in the asserted claims of the ‘148 Patent. Absorption and elimination of amphetamine in Abhai’s ANDA Product doses exhibit first-order kinetics. Moreover, the analyses discussed above relating to the pharmacokinetic elements (“peak plasma concentration,” “AUC,” and “maximum concentration”) will also apply to all dosage strengths even though Abhai performed its ANDA Studies on the 30 mg dosage strength. Therefore, the pharmacokinetic elements are met for all five dosage strengths of Abhai’s ANDA Product. Thus Abhai’s ANDA Product infringes claims of ‘148 Patent for the reasons explained above.

ABHAI’S LITIGATION MISCONDUCT AND SANCTIONS:

But above all particularly, Court lambasted Abhai for its gross negligence & misconduct during litigation. When Rule 30(b)(6) deposition of Abhai, conducted on Oct. 14, 2016, Abhai discovered that it incorrectly performed its 18 month dissolution test for the 15 mg and 25 mg sample dosage, and it incorrectly performed its 24 month dissolution test for the 10, 20, and 30 mg sample dosage for its ANDA Product. Specifically, Technicians collected samples from the dissolution medium after the ANDA Product had been in the buffer solution (pH 6.0) for three hours (5 hours after testing began), instead of one hour (3 hours after testing began). The mistakes made in Abhai’s stability dissolution testing indicate that neither the analysts nor their supervisors understood the FDA-recommended two-stage dissolution method. Abhai then revised its dissolution procedure for each strength of its ANDA Product following the investigation. Results from the re-testing which was conducted in November 2016 were submitted to FDA as the “18-month” results for the 15 and 25 mg strengths, and as the “24-month” results for the 10, 20, and 30 mg strengths.

On Nov. 9, 2016, when Shire requested production of all versions of methods of analysis, including dissolution testing protocols, Abhai produced all of KVK’s methods of analysis and dissolution protocols, except for the revisions made on October 25, 2016. On November 17, 2016, Dr. Namburi signed an errata report for his 30(b)(6) deposition but did not correct his statements regarding Abhai’s stability testing on the 18- and 24- month ANDA Products. At this time, Dr. Namburi was aware that there were errors with the data and that Abhai had retested the 18- and 24-month Products using KVK’s revised dissolution testing and methods of analysis. Abhai also failed to supplement any of its prior discovery production with the revised methods of analysis or any other documents relating to the errors in its stability testing. Abhai also failed to notify the FDA of the errors in its testing. Importantly, neither Vepuri nor Dr. Namburi notified Abhai’s attorneys of the errors in the dissolution data, despite their awareness of the error and the ongoing litigation. On March 31, 2017, KVK created an “Escalation to Management Form” & identified that the 24 month data was revised in 11/2016 and not reported to Regulatory.” Later that same day, Abhai finally informed its counsel of the errors in its data. On April 4, 2017, Abhai filed a Motion to Amend Pretrial Memorandum where it admitted to errors in its dissolution testing and that further dissolution retesting was conducted to update the 18 and 24-month data.

The Court then came very harsh on Abhai & said that the conduct of Abhai and KVK reflects an appalling lack of awareness of a litigant’s responsibility to our justice system. The FDA would be well advised to take notice of this pervasive corporate unwillingness to play by the rules. See United States v. Aegerion Pharmaceuticals, Inc., Criminal Action No. 17-10288-WGY, 2017 WL 5586728 (D. Mass. Nov. 20, 2017). The Clerk is therefore directed to send a certified copy of this opinion to the General Counsel of the FDA. Sanctions are amply warranted here. Court further said that Abhai’s litigation misconduct is not simply a private matter of adjusting the legal fees to be borne by Shire. It has a direct impact on the citizens of the United States. The necessity of a sanctions analysis has occupied an additional writing day. Thus, Abhai’s misconduct has occasioned over a full week of court time. Pursuant to the authority discussed above, and finding that Abhai has recklessly squandered five days during which this Court could better have devoted itself to teaching American jurors and attending to litigants prepared to follow the straightforward rules of civil procedure. Court thus sanctioned Abhai in the amount of $30,000.00 for causing drain on judicial resources. Based upon this array of reported misconduct, Shire also came up with a whopping $2,750,000.00 claim for attorneys’ fees.  But Court said that this is too much & asked Shire to submit a revised claim for attorneys’ fees and costs. Abhai may have fifteen days thereafter to respond. The Court then will award appropriate monetary sanctions.