Orange Book Blog

District Court Denies All Challenges to FDA Decision on Norvasc Exclusivity; Generic Cos. Likely to Appeal

Mylan Labs. et al. v. Leavitt et al., No. 07-579 (D.D.C. 2007)

In an April 18 decision, the FDA determined that Pfizer is entitled to six months of pediatric exclusivity on Norvasc (amlodipine besylate), that Mylan may continue to sell its generic version of Norvasc, that FDA will approve Apotex's generic Norvasc ANDA if and when the Federal Circuit issues a mandate from its March 22 decision, and that no other Norvasc generics will be approved unless Pfizer's Norvasc patent is removed from the Orange Book.

Last week, Mylan, Apotex, and Teva filed motions in the U.S. District Court for the District of Columbia challenging various aspects of the FDA's decision.  This morning, in a 22-page Opinion and Order, Judge Ricardo M. Urbina denied all three motions.

Judge Urbina noted at the outset that FDA's decision is subject to the "arbitrary and capricious" standard of review, under which the court "must consider whether the agency's decision was based on a consideration of the relevant factors and whether there has been a clear error of judgment."  According to the Supreme Court, "The scope of review under the arbitrary and capricious standard is narrow and a court is not to substitute its judgment for that of the agency."  With this in mind, Judge Urbina addressed each of FDA's decisions:

FDA's Decision that the Effective Date of the Federal Circuit's Ruling is the Date it Issues its Mandate

Judge Urbina agreed with FDA's decision that Pfizer is entitled to pediatric exclusivity, though he used different reasoning to get there.  He reasoned that because 21 USC 355a(c)(2)(B) is silent "as to the particular court which may determine the patent dispute," the January 24, 2006 Northern District of Illinois Order in Pfizer v. Apotex triggered Pfizer's pediatric exclusivity.  And, moreover, that decision "is effective and remains so during the pendency of the appeal unless the district court's judgment is stayed or until the Federal Circuit issues its mandate."

I expect Apotex will file a motion for stay very shortly.

FDA's Decision that Apotex Will Cease to Be Subject to Pfizer's Exclusivity if the Mandate Issues Before September 25, 2007

If FDA had followed its "longstanding practice to deem paragraph IV certifications as paragraph II certifications upon patent expiration," Pfizer's pediatric exclusivity period (which began upon patent expiration on March 25, 2007) would block final approval for Apotex's ANDA.  However, Judge Urbina deferred to FDA's reasoning that Section 355a "manifests a clear Congressional intent that pediatric exclusivity not block the approval of an ANDA where the ANDA applicant has prevailed in the paragraph IV litigation."  He concluded that "FDA's decision to exempt Apotex in light of its status as a prevailing party in challenging Pfizer's patent is reasonable and is not contrary to the language in Hatch-Waxman."

FDA Decision that Apotex is the Sole Statutory Beneficiary of the Federal Circuit's Apotex Ruling

Here, the FDA ruled that because the Federal Circuit invalidated only three claims of Pfizer's Norvasc patent and left several claims untouched, Pfizer's patent remains valid as to the remaining claims and is presumed to be properly listed in the Orange Book.  Judge Urbina agreed, concluding: "Until Teva succeeds in its own patent litigation with Pfizer or until administrative or legal action completely de-lists Pfizer's patent from the Orange Book, the FDA's decision to withhold market approval for Teva's generic drug remains in effect.

FDA's Decision that Mylan's Eligibility for 180-Day Exclusivity does not Extend Beyond Patent Expiration

This one is interesting.  It sounds like Mylan meant to hold its challenge to this decision in reserve, but mistakenly filed a brief on it now.  The court proceeded anyway.

Mylan argued that "nothing in the text or legislative history of the Hatch-Waxman Act indicates that generic exclusivity is forfeited upon patent expiration."  Judge Urbina quickly dispensed with this argument, observing that "[u]nder Hatch-Waxman, paragraph IV certifications are no longer valid upon patent expiration" and must be changed to paragraph II certifications.  At that time, the ANDA becomes eligible for immediate final approval.

Because there's so much money at stake, I would be surprised if one or more of the generic companies didn't appeal to the D.C. Circuit.

RELATED READING:

• Mylan press release
• Bloomberg article

Supreme Court Upholds "TSM Test" of Obviousness; Mixed Impact for Pharmaceutical Patent Owners

KSR Int'l v. Teleflex, 550 U.S. ___ (2007)

In a unanimous decision released this morning, the Supreme Court reversed the Federal Circuit's decision in KSR v. Teleflex.  The Court rejected the Federal Circuit's rigid application of its "Teaching, Suggestion or Motivation" ("TSM") test in this particular case, but stopped short of discarding the test entirely.  Justice Kennedy wrote the opinion for the Court.

Under the TSM test, an invention is obvious (and therefore unpatentable) only if there is a teaching, suggestion or motivation to combine prior art references.  The TSM test is especially relevant to patents on "combination inventions," such as those on pharmaceutical formulations.  Indeed, in today's decision the Supreme Court cited with approval the Federal Circuit's flexible application of the TSM test in Alza v. Mylan, in which the Federal Circuit invalidated Alza's patent on an extended-release formulation of Ditropan.

Pharmaceutical patent owners are likely relieved that the Supreme Court did not reject the TSM test outright and replace it with a much more stringent standard, such as "Synergism" (as applied in a 1976 Supreme Court case) or "Extraordinary Level of Innovation" (as suggested by the Solicitor General).  On the other hand, today's decision does seem to raise the bar to patentability.

While the Court's decision today didn't establish a clear test of obviousness, it did suggest "predictability" as a touchstone for obviousness:

• "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results."
• "[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result."
• "If a person of ordinary skill can implement a predictable variation, Section 103 likely bars its patentability."
• "[A] court must ask whether the improvement is more than the predicatable use of prior art elements according to their established functions."

PhRMA, BIO, and IPO all filed briefs in support of Teleflex and a flexible TSM test.  Paul Berghoff, Jeremy Noe, and I contributed to the IPO brief.

[Incidentally, nothing seems to bring the Supreme Court together as much as a patent case.  In his confirmation hearings last year, Chief Justice Roberts spoke of his desire to bring more unity to the Court.  It seems like every Supreme Court patent decision in the past year has been unanimous or nearly so.  Maybe this explains the Court's recent interest in patent cases!]

RELATED READING:

• Patently-O; Pharmalot; WSJ Health Blog
• Legal Times article, quoting Chief Judge Michel

Pfizer Wins Attorney's Fees from Synthon in Case Involving Synthon's Amlodipine Process Patent

Synthon IP v. Pfizer, No. 05-1267 (E.D. Va. 2007)

Last month the Federal Circuit invalidated three key claims of Pfizer's Norvasc patent and currently a district court in Washington, D.C. is deciding whether to allow a flood of Norvasc generics on the market.  But the news for Pfizer hasn't been all bad lately.  Though it might be small consolation, a district court in Virginia recently awarded Pfizer $3.2 million in attorney's fees and costs in a case in which Synthon (who is also one of the Norvasc generic applicants) accused Pfizer of infringing its patent on a process for making amlodipine, the active ingredient in Norvasc.

As we previously reported, last August a jury in the Eastern District of Virginia found that Pfizer did not infringe Synthon's amlodipine process patent (U.S. Patent No. 6,653,481).  As we also reported, in February Judge T.S. Ellis, III (of the same court) found the '481 patent unenforceable due to inequitable conduct.  Pfizer subsequently filed a motion for attorney's fees and costs pursuant to 35 USC 285.  On April 16, Judge Ellis granted Pfizer's motion.

Under 35 USC 285, courts hearing patent disputes "in exceptional cases may award attorney's fees to the prevailing party."  The prevailing party must prove the exceptional nature of the case by clear and convincing evidence.  Even if that burden is met, the district court has discretion to determine whether an award of attorney's fees is appropriate in the circumstances.

In a nine-page Order, Judge Ellis explained that "the Federal Circuit has recognized many types of misconduct that may create an exceptional case for purposes of awarding fees, including inequitable conduct before the PTO, litigation misconduct such as vexatious or unjustified litigation or frivolous filings, and willful infringement."  According to Judge Ellis, "[t]hese principles, applied here, compel the conclusion that this case is appropriately deemed 'exceptional' in light of Synthon's inequitable conduct before the Patent and Trademark Office."  He continued:

And significantly, while Synthon's inequitable conduct before the PTO is alone sufficiently compelling to render this case exceptional, it should also be noted that Synthon's litigation strategy and conduct in the course of these proceedings further supports an exceptional case finding.  Indeed, a review of the record as a whole makes clear that Synthon copied and sought patents on what it knew to be Pfizer's work and then, once those patents had issued, filed against Pfizer what it knew, or should have known with reasonable investigation, was a baseless suit for willful infringement of two invalid patents.

Although Judge Ellis granted Pfizer's motion, he didn't give Pfizer everything it asked for.  He reduced Pfizer's request for fees and nontaxable costs and expenses by 20% due to what he called "unnecessary work and excessiveness."  He also refused Pfizer's request for reimbursement of $345,000 in expert witness fees, as well as Pfizer's request for pre-judgment interest.

Mylan, Apotex, and Teva File Motions Challenging FDA's Decision on Generic Norvasc

Apparently not too many companies other than Pfizer are happy with the FDA's decision last week regarding Norvasc (amlodipine besylate) exclusivity.  On Monday, Mylan, Apotex, and Teva all filed motions with the U.S. District Court for the District of Columbia for injunctive relief from FDA's decision.  Today, everyone filed briefs in opposition to each others' motions.

Mylan, currently the only generic on the market, is unhappy that FDA intends to approve Apotex's ANDA if and when the Federal Circuit issues a mandate from its March 22 decision.  Apotex, who won that decision, wants final approval of its ANDA now--and Mylan's approval revoked.  Teva, another ANDA applicant for amlodipine, argues that all ANDA applicants should be granted final approval.

Here are the briefs:

• Mylan motion for preliminary injunction
• Apotex motion for preliminary injunction
• Teva motion for injunctive relief
• FDA opposition to all motions
• Mylan opposition to Apotex motion
• Mylan opposition to Teva motion
• Apotex opposition to Mylan motion
• Apotex opposition to Teva motion
• Mutual Pharma opposition to Apotex and Teva's motions
• Mylan reply brief
• Apotex reply brief
• Teva reply brief
• Mutual Pharma reply brief

Considering the expedited briefing schedule and the fact that one month of Pfizer's six-month pediatric exclusivity period has already elapsed, I would expect to see a ruling from the district court sometime next week.  Given how much money is at stake in this case (Norvasc had sales of $2.5 billion in the U.S. last year), any decision is likely to be appealed.

Pharma News Briefs

• Pharmalot had a post today, "Kennedy Circulates Biogenerics Bill," regarding a new draft of a bill that would establish an abbreviated pathway for FDA approval of follow-on biologics.
• Rep. Jay Inslee (D-WA) and two co-sponsors introduced a new follow-on biologics bill in the House last week, H.R. 1956.  See also Press Release; Bill Summary.
• In "Abbott Blinks, Big Pharma Cringes," the Wall St. Journal Health Blog reported Monday about new developments in Abbott's battle over patent rights with the Thai government.
• Recent comments by FTC and DOJ officials on reverse payment agreements were quoted by AP in "FTC Head Defiant Over Drug Co. Payments."
• Last week, a new PhRMA-sponsored study concluded that authorized generics do not deter paragraph IV filings.  These two blogs recently had excellent posts on the study: Antitrust Review and FDA Law Blog.
• A new paper on authorized generics, written by Tom Chen, appears in this month's Virginia Law Review.  The paper approaches the authorized generics issue from an antitrust law perspective.

Purdue Pharma Tries to Salvage 30-Month Stay in OxyContin Case Against Mallinckrodt

Purdue Pharma has been fighting in court for nearly a decade to protect OxyContin--a blockbuster painkiller and by far Purdue's best-selling drug product--from generic competition.  Purdue settled its patent litigation with Endo and Teva last year, and with Impax a few weeks ago.  Recently, Purdue filed complaints against Mallinckrodt and KV Pharma.  Purdue's case against Mallinckrodt is particularly interesting, since it raises some new questions about 30-month stays.

In 2005, Mallinckrodt filed an ANDA for generic OxyContin (oxycodone HCl controlled-release) Tablets with paragraph IV certifications to Purdue's U.S. Patent Nos. 5,508,042; 5,549,912; and 5,656,295.  Purdue received notice of Mallickrodt's ANDA filing on October 4, 2005.  According to Purdue, however, various orders and injunctions in other OxyContin litigation "prevented Purdue from filing suit against Mallinckrodt at that time."  Purdue waited until November 9, 2006 before it sued Mallinckrodt for patent infringement.

In December, Purdue filed a Motion for Order of 30-Month Stay in the district court, asserting "that the 45-day period related to Mallinckrodt's notice of its ANDA filing was equitably tolled until October 17, 2006, and, therefore, that the filing of the complaint on November 9, 2006, within the 45-day period, triggered a 30-month stay of FDA approval of Mallinckrodt's ANDA under the Hatch-Waxman Act."  At the same time, Purdue filed a Petition for Stay of Action with the FDA, asking FDA to stay any approval of Mallinckrodt's ANDA until the district court has ruled on its motion.

Purdue acknowledges that a patent owner or NDA holder is allowed only 45 days after receipt of a paragraph IV notice letter to file a patent infringement suit if it wishes to obtain a 30-month stay.  However, Purdue argues that a January 5, 2004 district court finding of unenforceability in the litigation against Endo, various collateral estoppel orders in related cases against other ANDA applicants, and a June 7, 2005 Federal Circuit opinion affirming the district court's unenforceability opinion, prevented Purdue from filing suit against any other ANDA applicants.

On February 1, 2006, the Federal Circuit withdrew its June 7, 2005 opinion and remanded the case to the district court for further proceedings on inequitable conduct.  Since the February 1, 2006 Federal Circuit opinion, Purdue settled with Endo, Teva, and Impax, and filed proposed stipulated orders vacating the collateral estoppel orders in those cases.  Purdue argues that it was blocked from filing suit against Mallinckrodt until October 17, 2006, when it filed the last remaining proposed stipulated order.

In its Opposition to Purdue's Motion for Order of 30-Month Stay, Mallinckrodt argues first that the statute is "plain and unambiguous": a 30-month stay is available only if suit is filed within 45 days of receiving notice of a paragraph IV certification; the statute simply does not grant a court authority to order a 30-month stay otherwise.  Second, Mallinckrodt argues that the Doctrine of Equitable Tolling does not apply to the 45-day period because the period is not a statute of limitation; and even if the doctrine did apply, "Purdue's repeated failures to take action to protect its interests would bar Purdue from the benefit of the doctrine."

The parties have requested an oral hearing on Purdue's motion for a 30-month stay, although it appears that the court has not yet scheduled a hearing.  In the meantime, Purdue might file a motion for preliminary injunction.  Judge Sidney H. Stein in the Southern District of New York is presiding over the case.

Federal Circuit Affirms Invalidity of AstraZeneca Prilosec Process Patent

In re Omeprazole Patent Litigation, No. 04-1562 (Fed. Cir. 2007)

In a 2-1 decision released today, the Federal Circuit affirmed a 2004 district court decision finding AstraZeneca's U.S. Patent No. 6,013,281 invalid as inherently anticipated.  The '281 patent covers a process for making Prilosec, Astra's blockbuster anti-ulcer medication.

The case arose from the efforts of several generic drug companies, including Andrx, Genpharma, and Kudco, to market generic versions of Prilosec.  In the same litigation, the Federal Circuit previously found that Andrx's generic Prilosec infringed two Astra patents on Prilosec formulations: U.S. Patent Nos. 4,786,505 and 4,853,230.

In today's decision, Judge Rader (writing for himself and Judge Bryson) concluded that a Korean patent application to Chong Kun Dan Corp. ("CKD") inherently anticipated claim 1 of the '281 patent, which recites a process for making a pharmaceutical formulation by "forming in situ a separating layer" between an active ingredient core and an enteric coating.  In support, J. Rader cited numerous statements--apparently admissions--that Astra made in Korean litigation and Korean patent office proceedings, as well as the district court's finding that Andrx's expert was more credible than Astra's.

J. Rader's opinion further stated:

Inherency is not necessarily coterminous with knowledge of those of ordinary skill in the art.  Artisans of ordinary skill may not recognize the inherent characteristics of functioning of the prior art.  Though [Astra's scientists] may not have recognized that a characteristic of CKD's Method A ingredients, disclosed in the CKD Patent Application, resulted in an in situ formation of a separating layer, the in situ formation was inherent.

Judge Newman, dissenting, wrote that the majority opinion applied a "novel theory" and a "flawed analysis" of inherent anticipation.  She stressed that the majority failed to appreciate that claim 1 of the '281 patent is directed to a process--not a composition of matter.  Moreover, she noted, "[i]t is not disputed that a sublayer does not form under the conditions in the CKD patent application."  J. Newman explained:

While some properties and uses of known compositions may indeed be 'inherently anticipated' in that their existence would have been known to persons in the field of the invention, even if unpublished, that is not this situation.  No prior art describes the Astra process, and there is no evidence that a person of ordinary skill would have known of its existence.  What is unknown cannot 'anticipate.'

RELATED READING:

• Patently-O; Peter Zura's 271 Patent Blog

Abbott Wins Preliminary Injunction Against Sandoz in Biaxin XL Case

Abbott Labs v. Sandoz, No. 05-5373 (N.D. Ill. 2007)

This past Monday, Judge David H. Coar of the U.S. District Court for the Northern District of Illinois granted Abbott's motion for a preliminary injunction to stop Sandoz from selling a generic version of Biaxin XL (clarithromycin extended release tablets).  Abbott earns about $300 million each year in the U.S. from sales of Biaxin XL, an antibiotic used primarily for the treatment of bacterial infections of the skin and upper respiratory system.

The preliminary injunction against Sandoz is a reversal of fortune for Abbott, considering that last December Judge Coar denied Abbott's motion for a temporary restraining order.  Now, in a 61-page opinion, Judge Coar explained that "after having the benefit of a full hearing, this Court is able to better decide the merits of enjoining Sandoz from further selling or marketing its extended release formulation of clarithromycin."

Abbott alleged that Sandoz's generic version of Biaxin XL infringes U.S. Patent Nos. 6,010,718 and 6,551,616, which claim extended release formulations of clarithromycin.  Judge Coar found that Abbott demonstrated "a substantial likelihood of proving Sandoz's product infringes upon claims 1 and 4 of the '718 patent."  Moreover, he found that Sandoz's obviousness and inequitable conduct defenses lack substantial merit.

With regard to inequitable conduct, Judge Coar wrote that although Sandoz showed a substantial likelihood of proving materiality and intent to deceive with respect to the '616 patent, Abbott abandoned the '616 patent claim in question on its own volition and "it seems wholly inequitable to hold a patent invalid for fraudulent conduct in the prosecution of a claim that was withdrawn before actual prosecution had even begun."  Judge Coar further observed that "[r]edemption is one of the core principles of the American ethos."

Besides Sandoz, Abbott is fending off generic competition to Biaxin XL from Andrx, Ranbaxy, Roxane, and Teva.  In January, the Federal Circuit affirmed a preliminary injunction against Andrx.  Last August, Abbott and Teva settled their litigation, although on Tuesday Teva filed a complaint in the Southern District of New York to enforce the settlement.

Thanks very much to a helpful reader for bringing this case to my attention!

FDA Refuses to Approve Any ANDAs for Generic Norvasc Besides Mylan's--For Now

Ever since March 22, when the Federal Circuit invalidated claims 1-3 of Pfizer's last remaining unexpired patent on Norvasc--U.S. Patent No. 4,879,303--Pfizer, Mylan and other ANDA filers have been scrambling.  On March 23, Mylan, the first ANDA filer, launched its generic version of Norvasc and Pfizer responded by launching an authorized generic.  On March 26, the day after the '303 patent expired, Mylan filed suit in the U.S. District Court for the District of Columbia to enjoin FDA from approving any other ANDAs for generic Norvasc.  FDA asked all interested parties for their views on Pfizer's pediatric exclusivity and Mylan's 180-day exclusivity, and on April 5 FDA published those comments.

As ordered by the district court, FDA reached a decision regarding Norvasc exclusivity today.  FDA's notice to the court announced: "FDA has decided not to approve ANDAs other than Mylan's at this time."  According to FDA's decision letter, addressed "Dear ANDA Applicant/Holder for Amlodipine Besylate Tablets" (and submitted to the district court):

In sum, FDA has concluded:

• All of the unapproved ANDAs are currently blocked by Pfizer's pediatric exclusivity.
• If and when the mandate effectuating the panel's March 22 decision issues in the Apotex case, Apotex's ANDA will not be blocked by Pfizer's pediatric exclusivity.
• FDA cannot determine on the current record whether other ANDAs will continue to be blocked by pediatric exclusivity at that time.
• Mylan's 180-day marketing exclusivity terminated when the patent expired.

In comments submitted to FDA on March 25 and April 5, Pfizer argued that FDA could not approve any other Norvasc ANDAs at least until the Federal Circuit issues a mandate from its March 22 decision, since only then would the decision become effective.  Apparently, FDA agrees.

A mandate cannot issue until disposition of a petition for rehearing or rehearing en banc, which Pfizer timely filed on April 5 (click here for Pfizer's petition).  If Pfizer's petition is granted, the mandate won't issue until the Federal Circuit makes a final decision following rehearing.  If Pfizer's petition is denied, the Federal Circuit will issue the mandate seven days after the decision to deny the petition.

Thus, Mylan's 180-day exclusivity period ended just two days after it began, but Mylan retains de facto generic exclusivity by virtue of Pfizer's pediatric exclusivity.  In other words, Mylan is riding Pfizer's coat-tails as the sole supplier of generic Norvasc--at least until the Federal Circuit issues a mandate from its March 22 decision (when Apotex's ANDA will be granted final approval).

Moreover, it appears that even if the Federal Circuit issues a mandate before Pfizer's pediatric exclusivity expires on September 25, 2007, FDA is unlikely to approve any additional ANDAs other than Apotex's.  That is because if, as seems likely, one or more of claims 4-11 of the '303 patent covers Norvasc, then the patent can remain properly listed in the Orange Book.  In such a case, the remaining unapproved ANDAs will be subject to Pfizer's pediatric exclusivity.  Therefore, unless another ANDA applicant successfully challenges FDA's decision, Mylan and Apotex likely will have the only Norvasc generics on the market until September 25.

Thanks to Kurt Karst of FDA Law Blog for passing along today's news.

RELATED READING:

• Mylan Labs press release--4/18/07
• "U.S. Decides Against Additional Norvasc Generics"--Reuters 4/18/07
• "FDA Backs Mylan on generic Norvasc"--Business Week 4/19/07
• "$4.7B Generic Norvasc Goes Out of Bounds"--Daily News & Analysis, India 4/19/07
• "Matrix Labs is Grinning"--Daily News & Analysis, India 4/19/07

Follow-on Biologics News

A number of interesting news reports concerning follow-on biologics have been published in recent days:

• "Hopes for Speedy Action on Generic Biologics Fade in Senate"--Biologic Drug Report 4/16/07
• "Lobbyists Take Aim at Generic Biologics"--Boston Globe 4/16/07
• "Senate HELP Panel to Review Comprehensive FDA Measure"--BioWorld Today 4/16/07
• "Eyeing a Lucrative Drug Market"--NJBiz.com 4/16/07
• "Biologics Legislation Will Speed Progress"--American Enterprise Institute 4/16/07
• "Sen. Clinton's Support for Generic Biotech Drug Legislation Could Deter Republicans, Lobbyists Say"--KaiserNetwork.org 4/13/07
• "CCPM Applauds Letter from Bipartisan Group of Governors Urging Congressional Action on Biogenerics"--Yahoo! News 4/13/07