Orange Book Blog

ACI "Maximizing Pharmaceutical Patent Life Cycles" Conference, New York, October 7-8

American Conference Institute is hosting a special 10th Anniversary Edition of its annual "Maximizing Pharmaceutical Patent Life Cycles" conference on October 7th and 8th in New York.  According to ACI, this is "the one and only event that consistently allows brand name and generic drug makers to benchmark their companies' current strategies and tactics against competitors in both camps."

Here's the agenda:

• The endgame reinvented:  preparing for an emerging pharmaceutical patent paradigm
• Patent reform and the pharmaceutical industry:  anticipating and adapting to change
• Follow-on biologics:  understanding the role of patents in health care reform and related consequences for life cycle strategies
• Wyeth v. Dudas:  revisiting patent term adjustment calculations
• Overcoming obviousness:  an analysis of the post-KSR treatment of primary and secondary patents and finding new ways to extend patent life
• In Re Bilski:  exploring its implications for pharmaceutical method claims
• Eye on the Federal Circuit and District Courts:  life cycle lessons derived from Paragraph IV litigation
• FTC keynote:  promoting competition in the pharmaceutical industry
• EC keynote:  the European Commission Pharmaceutical Sector Inquiry -- main findings and policy recommendations
• Rethinking life cycle strategies for established and emerging international markets:  focus on Europe and Asia
• A new look at Orange Book listings, delistings and related challenges
• FDA keynote:  update on FDA activities relative to pharmaceutical patent life cycles
• Exclusivity:  modes, methods and new interpretations
• Re-exploring the safe harbor:  learning to navigate the potential limits and boundaries of Proveris

In addition, an optional pre-conference workshop is offered on October 6th:  "Hatch-Waxman Boot Camp--a primer on IP basics and regulatory fundamentals".  And two optional master classes are offered on October 9th:  "Brand Name Master Class--new strategies for obtaining pharmaceutical patent extensions in a post-KSR world" and "Generic Master Class--updated drafting guidelines for paragraph IV certifications and notice letters".

ACI is offering Orange Book Blog readers a $500 discount off the standard registration fee (for a flat rate of $1695) when referencing the "Media Partner Discount".  For more information or to register, please visit the conference website.

Federal Circuit Affirms Invalidity of Bayer Patent on Yasmin

Bayer Schering v. Barr Labs, No. 2008-1282 (Fed. Cir. 2009)

A divided panel of the Federal Circuit today affirmed a district court decision holding Bayer's U.S. Patent No. 6,787,531 invalid due to obviousness.  The '531 patent, which claims pharmaceutical compositions of drospirenone and ethinyl estradiol, protects Bayer's popular birth-control pill Yasmin.  In today's decision, the majority (Judges Mayer and Friedman) held that "the invention would have been obvious to try."  Judge Newman dissented.

Drospirenone is an acid-sensitive and poorly soluble compound.  The use of drospirenone with ethinyl estradiol was known in the prior art, but, according to Bayer, formulations of micronized drospirenone in a normal (not enteric coated pill) would not have been obvious, especially since the prior art taught that an enteric coating is necessary to protect drospirenone from the acidic environment of the stomach.

The majority, however, disagreed.  Citing KSR, the majority stated that a person having ordinary skill in the art would have chosen

between two known options:  delivery of micronized drospirenone by a normal pill . . . or delivery of drospirenone by an enteric-coated pill . . . .  This is a finite number of identifed, predictable solutions.  The prior art would have funneled the formulator toward these two options; he would not have been required to try all possibilities in a field unreduced by the prior art . . . .

In dissent, Judge Newman argued that the actual experience of the Bayer scientists should be dispositive.  They testified, without contradiction, "that it was not reasonably expected that uncoated micronized drospirenone would be 99+% effective as an oral contraceptive when ingested into the acid stomach, when it was known to degrade rapidly in acid."  According to Judge Newman, "the exercise of judicial expertise to override the clear evidence of how persons of skill in this field actually behaved, is inappropriate."

RELATED READING:

• Bloomberg article
  
• Teva press release
• OBB post on district court decision

ACI's FDA Boot Camp Coming to Chicago and Boston

American Conference Institute's popular "FDA Boot Camp" conference is coming to Chicago next week, July 21-22, and to Boston on September 15-16.  The conference is billed as "basic training for products liability and patent lawyers."

Presentations likely of most interest to Orange Book Blog readers include:

• The Basics:  Understanding and Working with the FDA and the New Administration--Jurisdiction, Functions, Organizations, and Operations
• The Nature of the Approval Process
• Essential Requirements of the Clinical Trials Processes
• Patent & IP Overview:  Hatch-Waxman, the Patenting Process, and More
• Drugs, Biological Products:  Labeling
• Non-Patent Exclusivity
• Bioequivalence:  What Patent Lawyers Need to Know
• Follow-On (Comparable or Biosimilar) Biologics

At the Chicago conference, I'll be speaking about Hatch-Waxman litigation.  At the Boston conference, I'll be speaking about non-patent exclusivity.

Orange Book Blog readers can save $400 off registration fees by citing "THE MEDIA PARTNER DISCOUNT."

For more information or to register, click here for the Chicago conference and click here for the Boston conference.

Supreme Court Denies Cert Petition in Lovenox Case

Aventis Pharma v. Amphastar and Teva, S. Ct. Appeal No. 08-937 (2009)

The Supreme Court on Monday denied Aventis Pharma's cert petition in a long-running dispute with generic biopharmaceutical manufacturer Amphastar.  In its petition, Aventis had asked the Court to review a Federal Circuit decision affirming the unenforceability of its patent on Lovenox.  In particular, Aventis asked the Court to overturn the Federal Circuit's "sliding scale" doctrine-–the doctrine that treats the two prongs of the inequitable conduct inquiry (materiality and intent) as inversely related to each other.  The doctrine allows a court to infer that a patentee has acted with deceptive intent if the defendant can show that the alleged misconduct is highly material.

Amphastar and co-defendant Teva opposed Aventis's petition.  First, they suggested that the "sliding scale" doctrine merely reflects the court's routine use of circumstantial evidence.  When alleged misconduct is highly material, they asserted, the circumstantial evidence of deceptive intent is stronger.  Second, Amphastar and Teva argued that Aventis had bypassed the opportunity to question the "sliding scale" doctrine because it never properly raised the issue during its Federal Circuit appeal.  Aventis responded that the Court could still entertain the issue because the Federal Circuit's opinion demonstrated that the appellate panel had relied on the "sliding scale" standard in reaching its decision.

While the petition was pending, the Federal Circuit began pulling back the reins a bit on the "sliding scale" doctrine.  Last month, Judge Linn wrote a stinging concurrence in Larson Mfg. v. Aluminart Prods, criticizing the doctrine.  Earlier this month, Judge Moore (a member of the panel that heard the Aventis case) seemed to question the "sliding scale" doctrine in Ariad v. Eli Lilly.

Perhaps the Supreme Court believed that the Federal Circuit was in the process of correcting itself on this issue.  Or maybe the Supremes did not want to grant cert on an issue that the petitioner had largely ignored in its earlier appeal.  In any event, the "sliding scale" doctrine remains intact.

BRIEFS:

• Aventis Petition for Writ of Certiorari
• Amphastar Brief in Opposition
• Teva Brief in Opposition
• Aventis Reply Brief

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.

Federal Circuit Affirms Extension of 30-Month Stay Against Teva's Generic Evista

Eli Lilly & Co. v. Teva Pharms. USA, Inc., No. 2009–1071 (Fed. Cir. 2009)

Under the Hatch-Waxman Act, final FDA approval of an ANDA is automatically stayed for thirty months when a patent owner files suit for patent infringement within 45 days of receiving a Paragraph IV notice letter.  The purpose of the stay is to allow the parties to litigate the patent infringement claims while the ANDA filer pursues FDA approval of its generic drug.  Pursuant to 21 U.S.C. § 355(j)(5)(B)(iii), a district court may shorten or lengthen the thirty–month stay if "either party to the action failed to reasonably cooperate in expediting the action."

Today, in a 2–1 decision authored by Judge Rader and joined by Chief Judge Michel, the Federal Circuit affirmed a district court order extending the thirty-month stay of FDA approval of Teva's ANDA for generic Evista (raloxifine hydrochloride) tablets.  Eli Lilly markets Evista for the treatment and prevention of postmenopausal osteoporosis.  Evista accounted for $1.075 billion in sales in 2008.

Thirteen patents are currently listed in the Orange Book for Evista, with expiration dates ranging from 2012 to 2017.  On May 16, 2006, Teva notified Lilly of its Paragraph IV certifications on at least some of the patents.  Lilly sued Teva on June 29, 2006, alleging that Teva's ANDA infringed four method patents.  Thus, the 30–month stay was originally set to expire on November 16, 2008.  The district court scheduled trial to begin on March 9, 2009.

In February 2007, Lilly amended its complaint to assert that Teva infringed three more patents--U.S. Patent Nos. 6,458,811; 6,797,719; and 6,894,064--covering raloxifene particle size and formulations.  On July 8, 2008, Teva amended its ANDA to include a new particle-size measuring methodology for the raloxifene in its generic drug product.  Shortly thereafter, Lilly filed a motion to extend the thirty-month stay, arguing that Teva "failed to reasonably cooperate in expediting the action . . . as evidenced by Teva's last-minute alteration of its proposed drug product and its multiple delays in producing critical discovery . . . [which have] adversely affected Lilly's infringement case and trial preparation."

The district court granted Lilly's motion and extended the thirty-month stay by about four months, to March 9, 2009.  In an order dated October 29, 2008, the court stated:

In light of the fact that Teva has recast its product more than eighteen months after it provided the original sample to Lilly and only eight months before trial is set to commence, we find that, in preparation for trial, Lilly is entitled to have sufficient opportunity to identify the nature and composition of the raloxifene product as Teva intends for it to be sold.

In its decision today, the Federal Circuit concluded that the district court did not abuse its discretion:

In making this determination, the record contained sufficient evidence, not based on clearly erroneous factual findings, upon which the district court rationally based its decision.  The court relied on the evidence in the record that Teva altered its proposed generic raloxifene hydrochloride tablets late in the litigation.  Specifically, Teva changed the particle size manufacturing specification of its active pharmaceutical ingredient and the method of measuring the particle size.  Teva then delivered its changed samples to Lilly past the court’s August 18, 2008, discovery deadline.

Judge Prost dissented, writing that "the district court never made any finding related to the statutory standard, i.e., whether Teva reasonably cooperated in expediting the action."  Moreover, she stated that "the consequences of the majority opinion are of particular importance here" because "this court has not previously provided any guidance to the district courts as to what qualifies as a 'failure to reasonably cooperate in expediting the action.'"  She concluded, "To affirm in this case is to effectively eliminate the statutorily required finding, and to prematurely terminate the development of appropriate standards governing modification under 21 U.S.C. § 355(j)(5)(B)(iii)."

According to the FDA website, Teva's ANDA for generic Evista is tentatively approved.  As a result of today's decision, final approval of Teva's remains stayed until March 9, 2009, when trial is set to begin in the Southern District of Indiana.  According to the district court's order of October 29, 2008, Teva previously "informed Lilly that it will launch its generic raloxifene hydrochloride upon expiration of the statutory stay."

RELATED READING:

• Dow Jones
• Patently-O

Sanofi and BMS Prevail Over Apotex in Plavix Appeal

Sanofi-Synthelabo et al. v. Apotex, No. 2007-1438 (Fed. Cir. 2008)

In an opinion released last Friday, the Federal Circuit affirmed the decision of the U.S. District Court for the Southern District of New York, following a 2007 bench trial, that Sanofi's U.S. Patent No. 4,847,265 is not invalid for anticipation or obviousness.  The '265 patent covers clopidogrel bisulfate, the active ingredient in Sanofi and Bristol-Myers Squibb's blockbuster heart medication Plavix.  A botched settlement of the case in 2006 led to Apotex's at-risk launch of its generic Plavix, followed by a preliminary injunction against Apotex, and ultimately the departure of executives from BMS.

Claim 3 of the '265 patent is directed to clopidogrel bisulfate:  "Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer."  Apotex stipulated to infringement and argued that claim 3 is invalid as anticipated by and obvious over Sanofi's U.S. Patent No. 4,529,596, which describes the racemate that includes clopidogrel.

For anticipation, Apotex argued that the '596 patent describes not only the racemate ("PCR 4099"), but also its addition salts and enantiomeric forms.  The district court found that although the racemate is in the prior art, the dextrorotatory enantiomer and salt in claim 3 of the '265 patent are not described, either explicitly or inherently, in any reference.  The court reasoned that the '596 patent would not have guided a person of ordinary skill in the art to either the dextrorotatory enantiomer of PCR 4099 or its bisulfate salt.  On appeal, according to the Federal Circuit, Apotex argued that the district court "erred in law, and that it suffices that the reference shows the specific racemate PCR 4099 and states that the compounds in the reference have enantiomers and that the enantiomers are included in the invention."

The Federal Circuit, however, explained in its opinion that Apotex's view "is not the correct view of the law of anticipation, which requires the specific description as well as enablement of the subject matter at issue.  To anticipate, the reference must not only disclose all elements of the claim within the four corners of the document, but must also disclose those elements arranged as in the claim."  Distinguishing the classic cases of In re Petering (CCPA 1962) and In re Schaumann (CCPA 1978), the court stated, "PCR 4099 is shown in the references as one of several compounds with desirable biological properties, but the district court did not clearly err in finding that the reference disclosure would not have led one of ordinary skill to recognize either an explicit or inherent disclosure of its dextrorotatory enantiomer, as well as the bisulfate salt."  Similarly, consistent with Forest Labs v. Ivax, the court discerned no clear error in the district court's finding that the asserted prior art does not enable one to separate the enantiomers of PCR 4099 without undue experimentation.

With respect to obviousness, the district court "held that the unpredictable and unusual properties of the dextrorotatory enantiomer, and the therapeutic advantages thereby provided, weighed in favor of nonobviousness, and that Apotex had not met its burden of establishing otherwise."  On appeal, Apotex argued "that the only features of clopidogrel bisulfate arguably not explicit in the prior art -- the separation of the dextro- from the levorotatory enantiomer and its preparation as a bisulfate salt -- required no more than well-known chemical techniques."  Apotex cited known examples of other chiral compounds that exhibit stereoselectivity and that even if some experimentation was required, upon separation of the enantiomers, "routine testing would have revealed the favorable allocation of properties in the dextrorotatory isomer."

In affirming the district court's holding of nonobviousness, the Federal Circuit cited numerous instances where Apotex's expert witnesses appeared to admit the unexpected properties of clopidogrel.  For example, according to the court, Sanofi determined that the enantiomers of PCR 4099 had the "rare characteristic of 'absolute stereoselectivity':  the dextrorotatory enantiomer provided all of the favorable antiplatelet activity but with no significant neurotoxicity, while the levorotatory enantiomer produced no antiplatelet activity but virtually all of the neurotoxicity.  The experts for both sides agreed that while it was generally known that enantiomers can exhibit different biological activity, this degree and kind of stereoselectivity is rare, and could not have been predicted."  In addition, "the experts of both parties agreed that whether a pharmaceutically suitable crystalline salt will form from a particular acid-base combination is unpredictable."  Moreover, "here Sanofi presented evidence that the prior art taught away from the use of sulfuric acid with an enantiomer, for strong acids could encourage re-racemization."

When Apotex launched its generic version of Plavix in 2006, it was able to ship a six-month supply of its generic drug before the district court preliminarily enjoined further sales.  Thus, potential damages could run into the billions of dollars.  Accordingly, it would not be surprising for Apotex to appeal the Federal Circuit decision to the Supreme Court.

RELATED READING:

• Sanofi/BMS press release
• Apotex press release
• Bloomberg article
• Previous OBB posts:  8/8/06 (Apotex launches at-risk); 12/10/06 (Fed. Cir. affirms preliminary injunction); 6/19/07 (district court trial decision); 4/27/08 (Apotex sues to recover 180-day exclusivity)

Federal Circuit Affirms $16.8 Million Award of Fees to Takeda in Pioglitazone Case

Takeda v. Mylan and Alphapharm, Nos. 2007-1269, -1270 (Fed. Cir. 2008)

In an opinion released Monday, the Federal Circuit affirmed a district court decision granting $16.8 million for attorney fees, expenses and expert fees to Takeda for baseless paragraph IV certification letters and litigation misconduct by Mylan and Alphapharm in ANDA litigation involving Actos (pioglitazone).  We previously reported on the district court decision here; and on the Federal Circuit briefing here.

With respect to Alphapharm, the Federal Circuit observed that the district court "methodically examined a number of shortcomings in Alphapharm's Paragraph IV letter, which were made obvious by Alphapharm's 'constantly shifting set of arguments,' that supported the finding that the certification was baseless."  The court concluded that "the district court correctly found that Alphapharm's filing would amount to litigation misconduct supporting an exceptional case finding if it were 'baseless' and if it 'failed to present even a prima facie case of invalidity in filing the paragraph IV certification.'"

With respect to Mylan, the Federal Circuit stated, "Mylan's invalidity argument in its certification letter appears even more baseless than Alphapharm's."  Moreover, the court concluded, "the finding that Mylan engaged in litigation misconduct was well-supported and explained by the district court."  According to the court, "We do not find persuasive Mylan's argument that the district court took issue with the mere fact that Mylan changed its theory of invalidity and then lost.  Rather, the court determined that Mylan's initial certification letter was completely baseless and that the claims Mylan offered as substitutes were similarly frivolous."

The Federal Circuit was similarly unimpressed with the "chilling effect" argument put forward by Alphapharm and Mylan and supported by an amicus brief from GPhA:  namely, that a high fee award would deter paragraph IV ANDA filings.  The court stated, "It is clear from the district court's opinion that it was not faulting Alphapharm or Mylan for the act of filing an ANDA that challenged the pioglitazone patent, nor did it limit the filers to the theories raised in their certification letters.  Rather, the district court found the case exceptional based on the specific circumstances involved in this case, viz., baseless certification letters compounded with litigation misconduct."

Finally, the Federal Circuit affirmed the specific amount awarded by the district court, as well the "allocation of two-thirds of the fee burden to Mylan because it acted as lead defense counsel for discovery of the obviousness claims and then added considerably to the complexity of the case with an untimely assertion of an inequitable conduct claim."

FTC Roundtable, "Competition Issues Involving Follow-On Biologic Drugs," Washington, November 21

The Federal Trade Commission is hosting a roundtable entitled "Competition Issues Involving Follow-On Biologic Drugs," Friday, November 21, at its headquarters in Washington.  Speakers include industry leaders, government officials, outside counsel and others.

The agenda includes the following presentations:

• Welcoming remarks, FTC Commissioner Pamela Jones Harbour
• Opening remarks, Rachel Behrman, FDA: "How Do Biologic Drugs Differ from Small Molecule Drugs?"
• "Likely Market Effects of Follow-On Biologic Drug Competition," a panel discussion moderated by Michael Wroblewski and Elizabeth Jex, FTC
• "Likely Competitive Effects of Reference Product Regulatory Exclusivity," moderated by Michael Wroblewski and Christopher Garmon, FTC
• "Biotechnology Patent Issues," moderated by Suzanne Michel and Suzanne Drennon, FTC
• "Likely Competitive Effects of Follow-On Biologic Regulatory Incentives," moderated by Michael Wroblewski and Elizabeth Jex, FTC
• "Patent Dispute Resolution Processes," moderated by Michael Wroblewski and Suzanne Drennon, FTC

In advance of the roundtable, over a dozen organizations have submitted comments to the FTC, including BIO, GPhA, and PhRMA.

A live webcast of the event will be offered.  For more information, please visit the FTC website.

ACI "Paragraph IV On Trial" Conference, New York, November 19-20

American Conference Institute is presenting its first-ever "Paragraph IV On Trial" Conference, November 19-20 in New York.  This is a unique conference, with the format of a mock trial in a Hatch-Waxman case.

ACI states:  "Structured as an actual trial based on an ANDA filing involving a compound and a formulation patent, our experienced faculty of patent litigators will conduct live demonstrations of direct and cross examinations, as you witness an entire, detailed, Paragraph IV trial, beginning with the banging of the gavel and concluding with closing statements."

After each direct and cross examination, a panel of judges and in-house counsel will provide commentary.

For more information or to register, please visit the conference website.

Orange Book Blog readers can save $200 by using registration code "S".