Orange Book Blog

FDA: Under the QI Act, No 30-Month Stay Will Apply to ANDAs Referencing "Old Antiboiotics" and Containing a P.IV Certification to a Later-Listed Patent

I'll have a post later.  For now, here is FDA's citizen petition response, released yesterday.

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.

King Pharmaceuticals Files Citizen Petition Relating to New Patent on Altace (Ramipril)

King Pharmaceuticals markets Altace (ramipril), which is indicated for the treatment of high blood pressure.  Until last year, when the Federal Circuit invalidated King's compound patent on ramipril, King earned about $700 million annually from U.S. sales of Altace.

Although Lupin was the ANDA filer who prevailed against King in the patent litigation, Cobalt Labs, as the first ANDA filer, won the 180-day exclusivity rights.  In a letter dated January 29, 2008, to attorneys for Lupin, FDA explained that Cobalt's exclusivity was triggered on December 10, 2007, and will expire on June 7, 2008.

Recently, on May 16, 2008, King submitted a citizen petition requesting that FDA require ANDA applicants for generic ramipril to submit a paragraph III or IV certification to U.S. Patent No. 7,368,469, which issued May 6, 2008, prior to final approval.  The '469 patent claims methods "for reducing the risk of a cardiovascular event" by administering an ACE inhibitor such as ramipril.

According to the FDA website, at least seven ANDA filers have tentative approval for ramipril and thus appear to have planned on obtaining final approval on June 7, when Cobalt's 180-day exclusivity expires.  Those plans may now be in doubt, as it may take FDA some time to decide how to rule on King's petition.

RELATED READING:

• Sept. 11, 2007 OBB post on Fed. Cir. decision
• Oct. 8, 2007 OBB post on FDA request for comments re: 180-day exclusivity
• Nov. 6, 2007 OBB post on comments submitted to FDA
• Feb. 4, 2008 OBB post on FDA decision re: 180-day exclusivity

OBB News Briefs

• Last Monday, the Federal Circuit affirmed a district court decision in McNeil-PPC v. Perrigo, concerning a generic version of Pepcid Complete.  The decision was affirmed without an opinion, under Rule 36.
• Tuesday, AstraZeneca and Ranbaxy announced a settlement of their patent litigation over generic Nexium (esomeprazole), with Astra granting Ranbaxy exclusive rights to sell a generic version of Nexium in 2014, six months before the first patent expires.  Teva and Dr. Reddy's plan to continue challenging Astra's patents.  Astra press release; Ranbaxy press release; AP; Bloomberg; Pharmalot; WSJ Health Blog.
• In a very surprising decision, a D.C. district court recently ruled in favor of Teva in a case in which Teva alleged that the FDA wrongfully delisted a patent on Risperdal (risperidone) from the Orange Book, depriving Teva of 180-day exclusivity.  FDA Law Blog has a full report.
• Earlier this month, Depomed announced a settlement of patent litigation against Teva over generic Glumetza (metformin HCl).  Depomed press release; AP story.
• Pharmalot recently had two interesting posts about biosimilars: the first suggested, based on a report about the Food and Drug Law Institute's annual meeting, that biosimilars legislation may actually be passed this year; the second reported on lobbying for a biosimilars bill.
• FDA Law Blog recently updated their coverage of the generic Depakote (divalproex sodium) litigation between Nu-Pharm (a former subsidiary of Apotex) and FDA, in which Nu-Pharm is seeking an injunction requiring FDA to grant final approval to its divalproex ANDA.
• Pharmalot posted a summary of a recent article in the Seattle Post-Intelligencer about a citizen petition that has stymied Nastech Pharmaceutical's bid to market a generic version of Miacalcin (calcitonin), a treatment for postmenopausal osteoporosis.
• Takeda announced earlier this month that on March 31, the Supreme Court denied Alphapharm's cert petition from the Federal Circuit's decision last year in the Actos (pioglitazone) litigation.

OBB News Briefs

• Last Friday, Rep. Anna G. Eshoo (D-CA) announced that she and Rep. Joe Barton (R-TX) introduced H.R. 5629, the "Pathway for Biosimilars Act" (click here for summary; click here for text of bill).  BIO immediately applauded the bill, while GPhA immediately denounced it.  For more, visit FDA Law Blog; Pharmalot; or the WSJ Health Blog.
• Barr Labs and Teva are two of the world's largest, and most litigious, generic drug companies.  Their CEO's gave extensive interviews to separate newspapers last week: Barr's CEO Bruce Downey to Investor's Business Daily and Teva's CEO Shlomo Yanai to Globes.
• We reported in January that Teva filed a citizen petition asking FDA to relist J&J's patent on Risperdal and to grant it 180-day exclusivity on the generic.  Recently, FDA law blog and Patent Baristas reported that FDA denied Teva's petition on February 26, and Teva responded by filing suit against FDA on March 4.  Also see: Reuters and Teva press release.
• The Wall St. Journal reported last week that Thailand is poised to disregard patents on several cancer drugs.  The WSJ Health Blog has a summary of the article.
• Teva announced last month that it received approval for the first biosimilar G-CSF in Europe.

Teva Seeks Relisting of J&J's Risperdal Patent and Asserts Right to 180-Day Exclusivity

A reader recently e-mailed me about an interesting citizen petition that Teva filed last August.  In the petition, Teva requests that FDA:  (1) relist U.S. Patent No. 5,158,952 in the Orange Book for Risperdal (risperidone) tablets; (2) confirm Teva's right to 180-day exclusivity for risperidone tablets; and (3) refrain from approving any other ANDAs for risperidone tablets until Teva's exclusivity expires.  Risperdal is Johnson & Johnson's blockbuster treatment for schizophrenia and other neurological disorders.

Teva filed its ANDA for risperidone tablets on August 28, 2001, with a paragraph III certification to U.S. Patent No. 4,804,663 and a paragraph IV certification to the '952 patent.  At the time, both patents were listed in the Orange Book for Risperdal.  On October 12, 2001, FDA notified Teva that it had delisted the '952 patent from the Orange Book and informed Teva that it would not accept Teva's ANDA for filing unless Teva amended its paragraph IV certification to reflect the fact that the '952 patent had been delisted.  Teva complied by amending its ANDA.

Five years later, in Ranbaxy v. Leavitt, the D.C. Circuit ruled that FDA had improperly delisted two patents on Zocor because the effect of delisting would be to deny the first ANDA filer of 180-day exclusivity on simvastatin tablets.  According to Teva's citizen petition, following that decision "Teva began reviewing its portfolio of pending ANDAs to determine whether FDA's unlawful delisting practices had deprived Teva of its entitlement to 180-day exclusivity for any other generic product."

In its risperidone petition, Teva contends that because the '952 patent was listed in the Orange Book when it filed its ANDA for risperidone tablets, it had no choice but to certify as to the '952 patent.  "Teva thus did precisely what it was obligated to do under the plain text of the governing statute and Agency regulations, and it therefore earned its exclusivity as the first applicant to file a paragraph IV certification to a patent listed as claiming the reference listed drug."  Teva argues that the Ranbaxy decision compels FDA to relist the '952 patent and restore Teva's right to 180-day exclusivity.  Teva further argues that "the fact that FDA never accepted Teva's paragraph IV ANDA for filing has no bearing on the fact that FDA must relist the '952 patent."

The '663 patent (whose validity was affirmed in a Federal Circuit decision last year) expired on December 29, 2007.  Pediatric exclusivity on Risperdal extends to June 29, 2008.  Thus, FDA must decide the issues presented in Teva's citizen petition before then.  FDA will post its decision in the docket established for Teva's petition.

OBB News Briefs

• Teva announced last week that it was granted 180-day exclusivity for its generic Kytril injection product (granisetron HCl, 1 mg/mL in 1 mL vials).  Thus, it appears the FDA decided the 180-day exclusivity issue raised in Teva's citizen petition--namely, whether Teva's failure to market its generic product within 30 months of ANDA submission caused forfeiture of its exclusivity.  FDA is expected to release a formal response to Teva's petition in the near future.
• King Pharma and CorePharma settled their patent litigation over generic Skelaxin (metaxalone).  According to this AP story, however, analysts disagreed over the impact of the settlement.
• Taro Pharma and Breckenridge Pharma announced settlements with Novartis of their patent cases concerning generic Trileptal (oxcarbazepine).  According to their press releases, Taro and Breckenridge are sharing 180-day exclusivity for the product.
• Bloomberg published an interesting article earlier this week about the faltering biotechnology industry in China.
• Both Pharmalot and the WSJ Health Blog had posts this week about a Bloomberg story that reported the FDA approved only 19 new drugs last year, the fewest since 1983.
• Pharmalot also posted this week on a new report from Cutting Edge Information entitled "Combating Generics 2008," which found that 66 percent of brand name drug companies do not begin strategizing against generics until at least two years after product launch.

Pharma News Briefs

• FDA recently posted numerous comments from industry regarding Ramipril 180-day exclusivity issues on its website.  The comments come in response to FDA's request last month.  A summary of the new comments is in the works.
• FDA also established a docket for comments on Granisetron HCl 180-day exclusivity issues.  This too follows an FDA request made last month.
• Yesterday, the WSJ Health Blog had two pessimistic reports on the pharmaceutical industry: "Drug Drought Deepens as FDA Approvals Lag" and "Pharma Woes Won't Let Up Soon."
• On a happier note, Wednesday, the U.S. District Court for the Eastern District of Virginia granted GSK's motion for a preliminary injunction against the USPTO, halting implementation of the PTO's new claims and continuation rules (see Patent Docs).
• Also on Halloween, the New York Time published a spooky article entitled "Chinese Chemicals Flow Unchecked Onto World Drug Market."  Reuters published a similar article the next day.  This can't be good publicity for pharmaceutical companies--both innovators and generics alike--who are increasingly outsourcing production of key ingredients to China.
• On Tuesday, the Federal Circuit denied rehearing of BIO and PhRMA v. District of Columbia, in which the court previously found Washington, D.C.'s drug price control law to be unconstitutional (see Patently-O).
• Last week, Sen. Bernie Sanders (D-VT) introduced a new bill that would scrap patent and market exclusivity for drugs and replace it with a "medical innovation prize fund" (see FDA Law Blog and Pharmalot).  I suspect that this bill is DOA, and therefore nothing to fear.
• Also last week, the WSJ Health Blog reported on Amgen's big win in its patent infringement suit against Roche's Mircera drug.
• A couple weeks ago, BioPharma Reporter published an interesting article, "U.S. Dragging its Heels on Biosimilars, Report Says."

Pharma News Briefs

• Last Friday, FDA Law Blog wrote about yet another 180-day exclusivity letter from the FDA, this one requesting comment on the "failure to market" forfeiture provisions of the MMA.
• FDA Law Blog also posted a very nice summary of the FDA Amendments Act, which, among other changes, revises the citizen petition process.
• GSK sued the U.S. Patent & Trademark Office last Tuesday to block implementation of the PTO's new rules restricting patent claims and continuation applications.  Read more here: Patent Docs; Patently-O; Pharmalot; WSJ Health Blog.
• The Wall St. Journal had an interesting article last week on China's generic drug industry.  In case you're not a subscriber to the Journal, you can read the WSJ Health Blog's summary here or Pharmalot's here.
• On October 4, the FDA announced an initiative to streamline the generic drug approval process.  GPhA reacted with skepticism.

Pharma News Briefs

• Last week, the U.S. District Court for the District of Columbia denied Mylan's emergency motion for a temporary restraining order that would have forced FDA to relist Pfizer's Norvasc patent in the Orange Book.  Until June 22, when FDA delisted Pfizer's patent, Mylan and Apotex had the only approved ANDAs for generic Norvasc.
• Bloomberg reported Thursday that Pfizer and Sandoz have settled their litigation over Sandoz's ANDA for generic Zithromax.  The district court entered an order dismissing the case on June 25.
• Also Thursday, The Wall St. Journal Health Blog reported that the government of Brazil and Abbott Labs stepped back from the brink and agreed on a price for Kaletra, Abbott's AIDS drug.
• The National Law Journal had this article Friday on alleged abuse of the citizen petition process by pharmaceutical companies.
• FDA released a new final guidance document entitled "ANDAs: Pharmaceutical Solid Polymorphism -- Chemistry, Manufacturing, and Controls Information."  The guidance provides recommendations on assessing sameness when a drug substance exists in polymorphic forms.