Orange Book Blog

Mutual Pharmaceutical Jumps the Gun By Sending Paragraph IV Notice Letter Before Acceptance of ANDA

GlaxoSmithKline v. Mutual Pharm., No. 08-549 (E.D. Pa. 2008)

The U.S. District Court for the Eastern District of Pennsylvania recently granted a motion for judgment on the pleadings in a paragraph IV case because the ANDA filer sent its notice letter prematurely, before FDA had accepted the ANDA for filing.  The case concerns Mutual Pharmaceutical's generic version of GlaxoSmithKline's heart medication Coreg CR (carvedilol phosphate).

Mutual submitted its ANDA for carvedilol phosphate 80 mg capsules on November 19, 2007.  On December 21, Mutual filed an amendment to its ANDA, with a paragraph IV certification with respect to Glaxo's U.S. Patent No. 7,268,156.  At the same time, Mutual sent Glaxo a paragraph IV notice letter, but FDA had not yet accepted Mutual's ANDA at the time.

On February 4, 2008 (the 45th day after receiving Mutual's notice letter), Glaxo filed a complaint for declaratory judgment that, among other things, Mutual's paragraph IV notice letter was "improper, null, void, and without legal effect."  Mutual counterclaimed for a declaratory judgment that the '156 patent is invalid.  On March 17, following FDA's acceptance of Mutual's ANDA for filing, Mutual sent Glaxo a second notice letter.  The following day, Glaxo filed a motion for judgment on the pleadings.

In opposition to Glaxo's motion, Mutual argued that the relevant statute "says nothing that prohibits giving voluntary notice before the FDA has issued filing acceptance."  According to the court, Mutual "seems to suggest that an ANDA applicant may send a Paragraph IV notice letter and thus trigger patent litigation, at any time it chooses."

In a decision on April 28th, however, the court concluded that "under the statute and regulations, the sending of a notice of a Paragraph IV certification is expressly predicated upon the ANDA applicant receiving its own notice and acknowledgment from the FDA that the submitted ANDA has been received."  The court noted that the "Paragraph IV notice sequence ensures that the statutory litigation triggers do not result in unnecessary patent infringement litigation initiated by incomplete ANDAs."  The court cited legislative history and FDA's interpretation of the statute in support of its decision.

Furthermore, the court rejected Mutual's argument that even if the court dismissed Glaxo's patent infringement claim without prejudice, it retained subject matter jurisdiction over Mutual's counterclaim for a declaratory judgment of patent invalidity.  Here, the court contrasted the facts of the case with those of the Teva v. Novartis and Caraco v. Forest cases.  Additionally, the court reasoned that "due to the unfiled status of the ANDA, Defendants were not alleged infringers at the time this case was brought."

On April 30, Glaxo filed a second suit against Mutual, within the 45-day period from receipt of Mutual's second notice letter.  Interestingly, on May 27, Mutual filed a Notice of Appeal of the district court's decision on the first lawsuit.

FDA Denies King Pharma's Citizen Petition Concerning Altace, Approves Ramipril ANDAs

We reported last month that King Pharmaceuticals filed a citizen petition that could delay final approval of numerous ANDAs for generic versions of Altace (ramipril), which were set to earn final approval on June 7.  King's citizen petition asked FDA to require ANDA applicants for ramipril to file patent certifications with respect to newly-issued U.S. Patent No. 7,368,469, a method-of-use patent.

On June 18, FDA denied King's citizen petition, concluding that the ANDAs may be approved with section viii "carve out" statements and that patent certifications are not necessary.  The same day, FDA granted final approval to the ANDAs.

FDA's letter decision explains that King sought for FDA to

confirm that label information describing cardiovascular outcomes from the Heart Outcomes Prevention Evaluation (HOPE) trial and the related indication may not be omitted from the labeling of any [ANDA or 505(b)(2) application] that relies upon an Altace product and seeks approval for treatment of hypertension.  Accordingly, the Petition seeks to confirm that ANDAs and 505(b)(2) applications that reference an Altace product must contain an appropriate patent certification to [the '469 patent] and may not contain a statement pursuant to section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the Act explaining that the patent does not claim a use for which the applicant is seeking approval.

FDA's letter concludes

that ANDA and 505(b)(2) applicants seeking approval of ramipril products can omit from the product labeling the information from Altace labeling related to a reduction in risk of myocardial infarction, stroke, and death from cardiovascular causes (the HOPE indication) without rendering the proposed drug product less safe or effective than Altace products for the remaining conditions of use (treatment of hypertension and use in heart failure post-myocardial infarction).

If FDA had reached the opposite conclusion and required ANDA applicants to include the HOPE indication in their labeling, the applicants would have had to file a paragraph III or IV certification to the '469 patent.  Although a paragraph IV certification would not have led to a 30-month stay of FDA approval (because the ANDAs had already been filed when King submitted the patent for listing in the Orange Book), such a certification would have allowed King to sue the applicant under 35 USC 271(e)(2) for infringement of the '469 patent.  Thus, the applicant would have had to decide whether to launch their generic ramipril product at-risk of liability for patent infringement.

FDA's website shows that seven ramipril ANDAs were granted final approval immediately after FDA denied King's citizen petition and that Cobalt and Lupin also have final approval, for a total of nine generic ramipril products currently on the market.

Federal Circuit Refuses to Rehear Caraco v. Forest

We previously reported that on April 1, in a 2-1 decision in Caraco v. Forest, the Federal Circuit held that an ANDA applicant may in some circumstances bring a declaratory judgment action for noninfringement even if the patentee has granted the applicant a covenant not to sue.  Today, the Federal Circuit denied Forest's petition for rehearing or rehearing en banc, without opinion.

The Caraco v. Forest decision expanded declaratory judgment jurisdiction for ANDA applicants that have not been sued on an Orange Book-listed patent.  Indeed, several ANDA applicants have filed DJ complaints since the decision.

It would not be surprising if Forest now appealed to the Supreme Court.  However, given that the Court recently decided a declaratory judgment case, MedImmune v. Genentech, and that the Federal Circuit appeared to follow that decision in Caraco v. Forest, Supreme Court review seems unlikely.

Mylan Prevails Over AstraZeneca in Appeal of Prilosec Case

In re Omeprazole Patent Litigation, Nos. 2007-1476, -1477, -1478 (Fed. Cir. 2008)

Yesterday, the Court of Appeals for the Federal Circuit affirmed a June 2007 district court decision finding that Mylan's generic version of Prilosec (omeprazole) does not infringe two AstraZeneca patents, U.S. Patent Nos. 4,786,505 and 4,853,230.

Omeprazole is difficult to formulate because it is acid-labile.  Astra scientists developed a formulation that protects omeprazole from degradation in the acidic environment of the stomach.  Astra's formulation, which is claimed in the '505 and '230 patents, includes a core containing omeprazole and an alkaline reacting compound ("ARC"), a water soluble subcoat, and an outer enteric coating.

Mylan's ANDA product consists of an inert sugar/starch sphere; an active coating of omeprazole, talc and HPMC; two subcoatings; and an enteric coating.  Astra argued that the talc in Mylan's formulation contains carbonates, which serve as an ARC.  However, after a forty-two day bench trial, the district court determined that Astra failed to prove the presence of carbonates in Mylan's product.  The district court also determined that talc cannot satisfy the ARC limitation of the claims because the specification of the patents indicates that talc is not an ARC but rather an ordinary excipient, and because of statements Astra made during prosecution of the European counterpart of the '505 patent.

In the decision released yesterday, the Federal Circuit concluded that the district court's factual findings with respect to the presence or absence of carbonates in Mylan's formulation were not clearly erroneous.  Astra argued on appeal that the district court applied the wrong legal standard by requiring "conclusive evidence" that carbonates were present in the talc, but the Federal Circuit disagreed, finding that the district court correctly applied the preponderance of the evidence standard.  Having determined that the district court did not clearly err in finding that Astra failed to prove the presence of "non-negligible amounts of carbonates" in Mylan's formulation, the Federal Circuit declined to address Astra's remaining arguments.

The omeprazole patent litigation began in 2000, when Astra sued several companies who filed ANDAs for generic Prilosec.  The lawsuits were consolidated as a multidistrict litigation and tried in two waves.  Mylan, which launched its generic Prilosec in August 2003, was part of the second wave.  Other companies in the second wave included Lek Pharmaceutical, Apotex, and Impax Labs.  In the same June 2007 decision in which it ruled in favor of Mylan, the district court also found that Lek's products do not infringe Astra's patents, and that Apotex's and Impax's products do infringe.  Those determinations were appealed separately.

RELATED READING:

• Mylan press release
• 4-Jun-07 OBB post on district court decision

OBB News Briefs

• The Federal Trade Commission announced the release of its FY 2007 Summary of Pharmaceutical Company Settlement Agreements.  For commentary, see FDA Law Blog, Pharmalot.
• Wyeth sued Sandoz over a generic version of Protonix I.V.  The WSJ Health Blog recapped all the Protonix ANDA litigation.
• India's drugmakers recently threatened to stop production of 33 bulk drugs, Pharmalot reports.
• The Washington Legal Foundation announced that it filed an amicus brief urging the Federal Circuit to rehear the Caraco v. Forest Labs case.