Orange Book Blog

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.

Pharma News Briefs

• SCOTUSblog reported on Wednesday that the Supreme Court has denied Pfizer's emergency application for relief from the Federal Circuit's ruling in the Norvasc case.  TheStreet.com also has an article on the Supreme Court's decision.
• On Tuesday, the Federal Circuit granted Mylan's motion for summary reversal of the district court decision that had found Pfizer's Norvasc patent valid and infringed by Mylan.  The Fed. Cir. also reversed and vacated a separate district court decision finding the Norvasc patent valid and infringed by Synthon.  Both decisions came without opinion.
• FDA Law Blog reports today that a provision of the FDA Revitalization Act will reform the citizen petition process.
• The Washington Post on Monday reported on continued wrangling between the DOJ and FTC on the legality of reverse payment settlements, such as the one in Joblove.
• Via SCOTUSblog, here is petitioner's supplemental brief in Joblove, responding to the Solicitor General's recommendation that the Court decline to hear the case.
• Barr Labs announced earlier this week that Barr and Lilly agreed to dismiss their litigation over Prozac Weekly.
• Kaisernetwork.org reports that the markup session for the Waxman-Schumer follow-on biologics bill has been delayed to June 20.  Supporters of the bill still hope to attach it to the FDA Revitalization Act and pass it into law this year.

Pfizer and Mylan Fight to Defend Norvasc Exclusivity; Apotex, Teva and Others Battle for FDA Approval

A dozen companies have submitted letters in response to FDA's March 29 request for "comments from interested parties" on Norvasc (amlodipine besylate) exclusivity issues.  Last week, as we reported here, FDA promised the U.S. District Court for the District of Columbia that by Wednesday, April 11, it will decide whether to approve any ANDAs for generic Norvasc besides Mylan's.  Meanwhile, the district court has allowed Teva, Apotex and Mutual to intervene in the case for the limited purpose of responding, if necessary, to Mylan's motion for a temporary restraining order against FDA.

In its March 29 request for comments, FDA presented the following questions:

1. What date controls FDA's giving effect to the decision in Pfizer v. Apotex holding that Pfizer's patent on Norvasc is invalid?
2. If FDA must await the issuance of the Federal Circuit mandate, does pediatric exclusivity bar approval of all unapproved ANDAs in the meantime?
3. If and when the Apotex decision is implemented, what is the effect of the decision on the obligation of an ANDA applicant to change its patent certification?
4. If and when the Apotex decision is implemented and the patent is treated as invalid, does pediatric exclusivity attach to Pfizer's patent with respect to any unapproved ANDAs?
5. Does 180-day exclusivity triggered before a patent expires continue to bar approvals of other ANDAs after the patent expires?

The letters submitted in response are posted at this FDA web-page.  The positions are summarized very briefly below:

• Pfizer was awarded pediatric exclusivity on Norvasc and argues that all unapproved amlodipine ANDAs (i.e., all ANDAs besides Mylan's) remain subject to that exclusivity.
• Mylan was the first to file a Norvasc ANDA with a paragraph IV certification and claims it is entitled to 180-day exclusivity.
• Apotex argues it is the only company not subject to Pfizer's pediatric exclusivity because it is the only company having a Federal Circuit decision in its favor.
• Teva argues that neither Pfizer nor Mylan is entitled to exclusivity.
• Mutual argues that no other ANDAs may be approved until Pfizer's pediatric exclusivity or Mylan's 180-day exclusivity expires in September.
• Caraco argues that Mylan's 180-day exclusivity was triggered upon launch and extends to September 23, 2007.
• Roxane suggests that all tentatively approved ANDAs should be granted final approval when the Federal Circuit issues a mandate.
• Watson argues that Mylan's 180-day exclusivity ended when Pfizer's patent expired, and that Pfizer is not entitled to pediatric exclusivity.
• Daiichi Sankyo filed a paragraph III certification in its 505(b)(2) application and says it is subject to Pfizer's pediatric exclusivity.
• Aurobindo, an API supplier, argues that the Federal Circuit decision triggered Mylan's 180-day exclusivity period.
• Orchid filed a paragraph III certification in its ANDA and takes no position on the questions.
• Medco, a pharmacy benefit manager, argues that FDA should grant final approval to all tentatively approved amlodipine ANDAs now.

FDA Law Blog is expected to have more information on this interesting case.

Amphastar and Teva Prevail Over Aventis in Generic Lovenox Trial, But Still May Not Receive FDA Approval

Aventis Pharma v. Amphastar Pharms., No. 03-887 (C.D. Cal. 2007)

          by Robert S. Dailey

In a ruling issued last Friday, Judge Mariana R. Pfaelzer of the U.S. District Court for the Central District of California held Aventis’s U.S. Patent No. 5,389,618 and its U.S. Reissue Patent No. 38,743 unenforceable due to inequitable conduct.  The patents cover Lovenox (enoxaparin), a low-molecular weight heparin composition exhibiting anticoagulant properties and indicated for the prevention and treatment of deep vein thrombosis.  The drug was Aventis’s top seller as of Q3 of 2006, and was on pace to gross nearly $2 billion in U.S. sales for the year.  Amphastar and Teva have filed ANDAs for generic Lovenox, and await FDA approval.

In 2005 the district court found the same patents unenforceable on summary judgment.  On appeal last year, the Federal Circuit affirmed the district court on the materiality prong of inequitable conduct, but remanded the case for a full trial on the intent prong.  Friday's ruling follows a five day bench trial on that issue, held in December.

The standard rule on inequitable conduct requires the defendant to prove materiality and deceptive intent independently by clear and convincing evidence judged by the totality of the circumstances.  Several recent Federal Circuit inequitable conduct opinions have come close to articulating what appears to be a burden shifting test for determining deceptive intent.  Last year’s Ferring v. Barr Labs. probably stands as the high-water mark.  Other cases in the same vein include Bruno Independent Living and Frazier.  When the facts of these cases are examined closely, however, it becomes clear that they signal no significant departure from the general rule.

These recent cases all involve (i) highly misleading statements and/or omissions to the PTO, (ii) circumstances which the make the conduct appear particularly egregious, and (iii) plaintiffs who proffer no explanations for their conduct.  The rule could be stated as follows: A plaintiff whose conduct reeks of bad faith cannot avoid inequitable conduct simply by coming to court and remaining silent.  This is not burden shifting, but a gloss on how to apply the totality-of-the-circumstances test with a particular class of defendants.  After all, none the Federal Circuit’s post-Ferring opinions profess to abandon the totality-of-the-circumstances test in favor of a burden-shifting mechanism.  Moreover, the Federal Circuit has consistently held that defendants must prove more than an absence of good faith, and that plaintiffs are under no obligation to prove anything.

But these nuances were lost on the district court when it ruled against Aventis last week.  In its analysis, the court made express use of a burden shifting test for determining inequitable conduct.  The court cited the aforementioned line of cases and took language from Paragon Podiatry (Fed. Cir. 1993), to craft a rule which would allow a defendant to shift its burden of proof simply by showing an unexplained violation of the duty of candor.  But Paragon Podiatry involved a summary judgment motion.  Of course the court used a burden shift in that instance because that is what courts are required to do in ruling on summary judgment motions.  This was a trial, however, not a mere summary judgment hearing.  The regular totality-of-the-circumstances test ought to have been used in this case.  Instead, the court shifted the burden to Aventis and largely forced the Aventis scientist to prove that he had in fact acted in good faith.  Aventis will most likely appeal the decision to the Federal Circuit.

Even though last Friday's ruling is a blow to Aventis, it is far from clear that Aventis will be facing competition from Generic Lovenox anytime soon.  Neither Amphastar nor Teva has received approval from the FDA to market generic Lovenox and some analysts reportedly believe they never will.  Enoxaparin is a complex heterogeneous mixture of polysaccharides that is difficult to characterize and may be impossible for generic companies to replicate.  Indeed, Aventis filed a citizen petition in 2003 urging the FDA not to approve generic versions of Lovenox until enoxaparin is fully characterized or until the generic companies conduct full clinical trials to establish safety and efficacy.  The FDA has not yet ruled on Aventis's petition.

Robert Dailey, Ph.D. is a physical chemist and a third-year law student at the University of North Carolina at Chapel Hill.  Dr. Dailey was a member of the 2006 class of summer associates at McDonnell Boehnen Hulbert & Berghoff.

RELATED READING:

• Feb. 9 Reuters article, with reaction to Friday's district court decision
• Feb. 9 Forbes article, reporting that Momenta Pharmaceuticals may have the best chance of obtaining FDA approval for generic Lovenox
• Feb. 9 Sanofi-Aventis press release