Let’s Play a Game: What’s Missing from FDA’s Recent Approval Letter for Generic COPAXONE 40 mg/mL?

No, the first part of the title of this post is not some Halloween reference to Jigsaw, the game master of the “Saw” movie franchise.  Instead, it’s a reference to a more gentle game.  If you have (or have had) young children, then you’ve probably played a “What’s Missing?” memory-type game with them.  For example, in the board version of the game, a player removes one object from play, hiding it somewhere.  The other players then search the table to try to decipher what’s missing, yelling out the answer as soon as they think they know.  Today, we’re going to play a Hatch-Waxman version of the “What’s Missing” memory game.  Good luck!

Assuming, as we do, that our readers know what the typical ANDA “fact board” looks like, here’s what our Generic COPAXONE 40 mg/mL “memory board” looks like:

• On January 28, 2014, FDA approved a supplement to Teva Pharmaceuticals USA’s (“Teva’s”) NDA 020622 for COPAXONE (glatiramer acetate) Injection to add a “new dosing strength of 40 mg per mL administered three times per week.”
• Mylan Pharmaceuticals Inc. (“Mylan”) submitted ANDA 206936 to FDA on February 12, 2014 seeking approval to market a generic version of Glatiramer Acetate Injection, 40 mg/mL.
• On or about February 26, 2014, information on seven patents (five expiring on May 24, 2014, and two expiring on August 19, 2030) appeared in the Orange Book for COPAXONE NDA 020622. The two patents expiring on August 19, 2030 are U.S. Patent No. 8,232,250 (“the ‘250 patent”) and U.S. Patent No. 8,399,413 (“the ‘413 patent”). Subsequently, information on U.S. Patent No. 8,969,302 (“the ‘302 patent”); U.S. Patent No. 9,155,776 (“the ‘776 patent”); and U.S. Patent No. 9,402,874 (“the ‘874 patent”) was added to the Orange Book.
• FDA’s ANDA Paragraph IV Certifications List identifies February 26, 2014 as the first date on which an ANDA was submitted to FDA containing a Paragraph IV ccertification to patents listed in the Orange Book for COPAXONE Injection, 40 mg/mL.
• Teva timely sued Mylan in the U.S. District Court for the District of Delaware (Civil Action Nos. 14-cv-1278) and in the U.S. District Court for the Northern District of West Virginia (Civil Action No. 14-cv-0167), alleging infringement of the ‘250 and ‘413 patents (and later, the later-listed patents). The West Virginia District Court identified a 30-month stay “deadline” expiring “on or about February 28, 2017.” The Delaware District Court also identified a 30-month stay “deadline” expiring “on or about 2-28-2017.”
• On January 31, 2017, Mylan, in In Re Copaxone Consolidated Cases, prevailed with respect to, among other patents, the ‘250 and ‘413 patents.
• On October 3, 2017, FDA approved Mylan’s original ANDA 206936 for generic Glatiramer Acetate Injection, 40 mg/mL, and noted that Mylan, as a “first applicant,” is eligible for a period of 180-day exclusivity.
• According to FDA’s approval letter for Mylan ANDA 206936:

Your ANDA contains paragraph IV certifications to each of the patents¹ under section 505(j)(2)(A)(vii)(IV) of the FD&C Act stating that the patents are invalid, unenforceable, or will not be infringed by your manufacture, use, or sale of Glatiramer Acetate Injection 40 mg/mL, under this ANDA. You have notified the Agency that Mylan Pharmaceuticals Inc. (Mylan) complied with the requirements of section 505(j)(2)(B) of the FD&C Act and that litigation was initiated within the statutory 45-day period against Mylan for infringement of the ‘250 and ‘413 patents in the United States District Court for the District of Delaware and the Northern District of West Virginia [Teva Pharmaceuticals USA Inc., Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc., and Yeda Research and Development Co. Ltd. v. Mylan Pharmaceuticals Inc., Mylan Inc. and Natco Pharma Ltd., Civil Action Nos. 14-cv-1278 and 14-cv-0167] and for infringement of the ‘302, ‘776, and ‘874 patents in the United States District Court for the District of Delaware [Teva Pharmaceuticals USA Inc., Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc., and Yeda Research and Development Co. Ltd. v. Mylan Pharmaceuticals Inc., Mylan Inc. and Natco Pharma Ltd., Civil Action Nos. 15-cv-0306, 14-cv-1171, and 16-cv-1267].

• The “¹” reference is to an endnote in the ANDA approval letter stating: “The Agency notes that the ‘250, ‘413, ‘302, ‘776 and ‘874 patents were submitted to the Agency after submission of your ANDA. Litigation, if any, with respect to these patents would not create a statutory stay of approval.” (Note that the last sentence is typical for an approval letter – see, e.g., here, here, and here.)

Given these game pieces on our board, what’s missing? (Cue up the Jeopardy Theme)

If you take a look at the three approval letters linked to above, you’ll notice that in each case FDA addresses – either implicitly or explicitly – the absence, existence, or termination of a 30-month litigation stay that is triggered as a result of timely filed patent infringement litigation for patents listed at the time of ANDA submission. This occurs at the end of the paragraph of an ANDA approval letter beginning with either “Your ANDA contains paragraph IV certifications to each of the patents¹ under section 505(j)(2)(A)(vii)(IV) of the FD&C Act. . . ,” or “With respect to the ‘XXX and ‘XXX patents,¹ your ANDA contains paragraph IV certifications under section 505(j)(2)(A)(vii)(IV) of the FD&C Act. . . .” For example, FDA may conclude the paragraph with “You have also notified the Agency that the cases have been dismissed,” or with “this litigation is ongoing,” or with “Although these litigations remain ongoing, the 30-month period identified in section 505(j)(5)(B)(iii) of the FD&C Act, during which FDA was precluded from approving your ANDA, has expired.”

The paragraph in the approval letter for Mylan ANDA 206936 beginning with “Your ANDA contains paragraph IV certifications to each of the patents¹ under section 505(j)(2)(A)(vii)(IV) of the FD&C Act” ends rather abruptly and without any mention or allusion to a 30-month stay. That’s the missing piece!!  Instead, the “¹” reference – which is usually in a footnote, but appears in an endnote in the Mylan approval letter – says that the ‘250 and ‘413 patents that Mylan intially certified to (as well as the later-listed ‘302, ‘776 and ‘874 patents) do not create a statutory 30-month stay of ANDA approval.

So, what’s the deal?? After all, the statute and FDA’s regulations state that a patent is considered timely listed if information is submitted to FDA within 30 days of patent issuance or within 30 days of an NDA approval. And Teva appears to have timely submitted information to FDA on both the ‘250 and ‘413 patents for Orange Book listing after the January 28, 2014 approval of Glatiramer Acetate Injection, 40 mg/mL, under NDA 020622. Moreover, both the West Virginia District Court and Delaware District Court identified a 30-month stay “deadline” expiring “on or about February 28, 2017.” So, wouldn’t the timely listing of the ‘250 and ‘413 patents, combined with Paragraph IV certifications to them as of the date the patents were listed in the Orange Book, give rise to a 30-month stay?

While you’re chewing on that, we also note that the statute states, with respect to the availability of a 30-month litigation stay that:

If the applicant made a [Paragraph IV] certification . . . , the approval shall be made effective immediately unless, before the expiration of 45 days after the date on which the notice described in paragraph (2)(B) is received, an action is brought for infringement of the patent that is the subject of the certification and for which information was submitted to the Secretary under subsection (b)(1) or (c)(2) before the date on which the application (excluding an amendment or supplement to the application), which the Secretary later determines to be substantially complete, was submitted. If such an action is brought before the expiration of such days, the approval shall be made effective upon the expiration of the thirty-month period beginning on the date of the receipt of the notice provided under paragraph (2)(B)(i) or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action. . . .

FDC Act § 505(j)(5)(B)(iii) (emphasis added).

From what we gather, there was probably some ruckus at FDA about whether or not a stay on the approval of Mylan ANDA 206936, which was presumably initially submitted with a Paragraph I or “No Relevant Patents” certification, had been triggered by Mylan’s Paragraph IV certification amendment. In the end, it didn’t matter, because by the time FDA approved Mylan ANDA 206936 on October 3, 2017 any stay would have expired long ago, in February 2017. Nevertheless, FDA addressed the issue – rather covertly (or perhaps even inadvertently) – in the approval letter for ANDA 206936; and specifically in an endnote (instead of in a footnote) stating that Mylan’s February 26, 2014 Paragraph IV certifications the ‘250 and ‘413 patents did not create a statutory 30-month stay of ANDA approval.

While it’s relatively rare that an ANDA is submitted to FDA within 30 days of the date of the NDA reference listed drug approval, the scenario above shows that it can happen. What this means for all parties involved (NDA sponsors and ANDA applicants) is the need for speed. NDA applicants should submit patent information quickly after approval, and ANDA applicants should pounce at the opportunity to avoid a 30-month litigation stay by submitting as soon as possible after NDA approval.