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.

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."

Federal Circuit Affirms Dismissal of Declaratory Judgment Counterclaims in Trusopt/Cosopt Case

Merck & Co. v. Apotex, No. 2008-1133 (Fed. Cir. 2008)

In 2005, Hi-Tech Pharmacal became the first company to file a paragraph IV certification relating to Merck's glaucoma drugs Trusopt and Cosopt.  Hi-Tech filed paragraph IV certifications with respect to all three of the Orange Book-listed patents for these drugs:  U.S. Patent Nos. 4,797,413; 6,248,735; and 6,316,443.

In response, Merck sued Hi-Tech for infringing the '413 patent.  Merck did not assert the '735 and '443 patents against Hi-Tech, but instead disclaimed the patents under 35 U.S.C. § 253.  Last year (as reported here), the Federal Circuit affirmed a district court decision in favor of Merck and against Hi-Tech, causing Hi-Tech to be enjoined from marketing its generic versions of Trusopt and Cosopt until October 28, 2008, when the '413 patent (plus six months of pediatric exclusivity) will expire.  Although Hi-Tech lost the case, it retained its 180-day exclusivity on Trusopt and Cosopt due to its paragraph IV certifications against the '735 and '443 patents.

In 2006, Apotex filed its own ANDA for generic versions of Trusopt and Cosopt.  Like Hi-Tech, Apotex included paragraph IV certifications against all three Orange Book-listed patents.  Merck sued Apotex for infringing the '413 patent and Apotex counterclaimed for a declaratory judgment of noninfringement and invalidity of the '735 and '443 patents (notwithstanding that Merck had disclaimed them).  Apotex agreed to be bound by the results of Hi-Tech's appeal to the Federal Circuit on the '413 infringement issue, and thus, like Hi-Tech, became enjoined until October 28, 2008.  On November 15, 2007 (as reported here), the district court dismissed Apotex's counterclaims relating to the '735 and '443 patents for lack of subject matter jurisdiction.  Recently, in an opinion released August 21st, the Federal Circuit affirmed the dismissal.

The Federal Circuit observed that Apotex pursued its counterclaims under the "theory that if it can obtain a final judgment in its favor (invalidity or non-infringement) on these patents, such a judgment would act as a forfeiture trigger should Hi-Tech fail to market its generic version of Cosopt within 75 days of the date of Apotex's final judgment."  According to the court, "since Hi-Tech is enjoined from marketing its generics any time before October 28, 2008, Apotex asserts that a final judgment of invalidity or noninfringement as to the '735 and '443 patents obtained on or before August 14, 2008 would create a forfeiture of exclusivity for Hi-Tech and would allow Apotex to market its competing generic immediately upon final approval of its ANDA."

The Federal Circuit applied the standard for declaratory judgment jurisdiction enunciated in MedImmune:  the dispute must be "definite and concrete, touching the legal relations of parties having adverse legal interests; . . . real and substantial, and admit of specific relief through a decree of a conclusive character, as distinguished from an opinion advising what the law would be upon a hypothetical state of facts."  Here, the court found that as a practical matter, it could not provide any realistic relief:  "Even with prompt action by this panel, the final judgment sought by Apotex cannot be provided in time to be meaningful."  Accordingly, the court concluded, "the dispute presented does not 'admit of specific relief through a decree of a conclusive character' and, thus, does not present a justiciable case or controversy."

District Court Denies Early Motion For Rule 11 Sanctions in Ritalin LA Case

Celgene and Novartis v. KV Pharm., No. 07-4819 (D.N.J. 2008)

KV Pharmaceutical filed an ANDA for a generic version of Ritalin LA (methylphenidate HCl extended-release capsules) with paragraph IV certifications to Celgene's U.S. Patent Nos. 5,837,284 and 6,635,284.  Apparently KV made an offer of confidential access to its ANDA, but Celgene and Novartis (which markets Ritalin LA) declined it.  Last October, within 45 days of receiving notice of KV's paragraph IV certifications, Celgene and Novartis sued KV for infringing the two patents.

Earlier this year, KV filed a motion for sanctions under Rule 11 on grounds that Celgene and Novartis "failed to make a reasonable inquiry into their infringement claims before filing suit."  KV sought dismissal of the suit, plus costs and attorney fees.  KV's motion relied on Q-Pharma, Inc. v. Andrew Jergens Co., 360 F.3d 1295 (Fed. Cir. 2004), which states, "In the context of patent infringement actions, we have interpreted Rule 11 to require, at a minimum, that an attorney interpret the asserted patent claims and compare the accused device with those claims before filing a claim alleging infringement."

On July 22nd, the district court denied KV's motion with prejudice.  According to the court, "The pre-filing requirements stated in Q-Pharma make sense only in the context of a typical patent infringement case, and not in the context of a Hatch-Waxman case."  The court reasoned:  "In Q-Pharma, the act of infringement alleged in the complaint was the sale of the infringing product.  ...  Here, in contrast, the act of infringement alleged in the complaint is the filing of an ANDA--not the manufacture or sale of the product."

The court further observed:

If this Court were to grant KV's motion, it would put pharmaceutical patent owners in an untenable position.  After receipt of notification of an ANDA application for a generic pharmaceutical, the patent owner would need to conduct what is likely to be a highly technical infringement analysis, make the decision to file suit, and then do so, all within 45 days, or face dismissal as a sanction under Rule 11.  This would be difficult for patent owners to accomplish and would have the effect of frustrating the purpose of the Hatch-Waxman scheme.

In conclusion, the court explained its decision to deny KV's motion with prejudice:  "Because KV's motion is premised on an erroneous application of Federal Circuit law, and because this Court finds the record before it sufficient to determine that Celgene's pre-filing investigation of the allegation that KV infringed Celgene's patents by filing ANDA No. 79-004 was reasonable under the circumstances, it is appropriate not only to deny this motion prior to full briefing, but to deny it with prejudice."

More:

• District Court opinion
• KV brief in support
• Celgene letter in opposition
• KV reply letter

Federal Circuit Affirms Validity and Enforceability of Eisai's Compound Patent on Aciphex

Eisai v. Dr. Reddy's and Teva, Nos. 2007-1397, -1398 (Fed. Cir. 2008)

Patents on chemical compounds are holding up well to obviousness arguments in the Federal Circuit, even after KSR.  In an opinion released today, the Federal Circuit affirmed the nonobviousness of rabeprazole, the active ingredient in Aciphex.  This follows a decision last year affirming the nonobviousness of pioglitazone, the active ingredient in Actos.

Eisai's U.S. Patent No. 5,045,552 claims rabeprazole and its salts.  Rabeprazole is in a class of drugs known as proton pump inhibitors, which suppress gastric acid production in the stomach.  Aciphex (rabeprazole sodium) is indicated for the treatment of duodenal ulcers, heartburn, and associated disorders, and accounts for over $1 billion of Eisai's annual sales.

Dr. Reddy's stipulated to the validity of the '552 patent (relying on inequitable conduct arguments instead), but Teva challenged its validity, arguing that a combination of three prior art references rendered the claims of the '552 patent obvious:  (1) European Patent No. 174,726, claiming lansoprazole; (2) U.S. Patent No. 4,255,431, claiming omeprazole; and (3) an article by Brandstrom et al., entitled "Structure Activity Relationships of Substituted Benzimidazoles".

The Federal Circuit began by summarizing its recent chemical obviousness jurisprudence:

Where, as here, the patent at issue claims a chemical compound, the analysis of the third Graham factor (the differences between the claimed invention and the prior art) often turns on the structural similarities and differences between the claimed compound and the prior art compounds.  Obviousness based on structural similarity thus can be proved by identification of some motivation that would have led one of ordinary skill in the art to select and then modify a known compound (i.e., a lead compound) in a particular way to achieve the claimed compound.  In keeping with the flexible nature of the obviousness inquiry, the requisite motivation can come from any number of sources and need not necessarily be explicit in the art.  Rather, it is sufficient to show that the claimed and prior art compounds possess a sufficiently close relationship to create an expectation, in light of the totality of the prior art, that the new compound will have similar properties to the old.

With respect to the prior art, the Federal Circuit made the following observations:  (1) Rabeprazole and lansoprazole are structurally similar--the two compounds differ only at the 4-position on the pyridine ring, where lansoprazole contains a fluorinated substituent; (2) "omeprazole is structurally farther afield from rabeprazole than is lansoprazole"; and (3) "rabeprazole, lansoprazole, and omeprazole are all Brandstrom core structure compounds," a class of anti-ulcerative compounds.

Thus, the Federal Circuit stated, "one of skill in this art may have considered [lansoprazole] a candidate for a lead compound in the search for anti-ulcer compounds."  However, according to the court, "the EP '726 reference teaches at best that the fluorinated substituent of lansoprazole provides a special path to achieving lipophilicity, and the record "shows no discernible reason for a skilled artisan to begin with lansoprazole only to drop the very feature, the fluorinated substituent, that gave this advantageous property."  The court concluded that one of skill in the art would not have considered such a modification to be "an identifiable, predictable solution."

Addressing Teva's suggestion that another compound might have served as a lead compound, the Federal Circuit observed that "Teva alone selected lansoprazole as the anchor for its obviousness theory."  Moreover, according to the court, "post-KSR, a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound.  Teva cannot create a genuine issue of material fact on obviousness through the unsupported assertion that compounds other than lansoprazole might have served as lead compounds."

In addition to affirming the validity of the '552 patent, the Federal Circuit affirmed its enforceability, rejecting arguments that Eisai committed inequitable conduct.

Dr. Reddy's and Teva alleged that Eisai misled the Patent Office in five ways:

1. failing to disclose Eisai's own co-pending '013 application, which claimed the "ethyl homolog" of rabeprazole;
2. withholding rejections from the '013 application's prosecution that also would have been applicable to the '552 patent's prosecution;
3. failing to disclose the prior art "Byk Gulden patent";
4. submitting a misleading declaration to the examiner of the '552 patent; and
5. concealing lansoprazole from the examiner.

The Federal Circuit affirmed the district court's findings that the materiality of the '013 application was "low"; that there was insufficient evidence that Eisai intended to deceive the Patent Office by failing to disclose the rejections made during prosecution of the '013 application; that the Byk Gulden patent was cumulative with other references disclosed to the Patent Office; that Eisai did not intend to deceive the Patent Office by submitting the "misleading declaration" during prosecution of the '552 patent; and that lansoprazole was not material to the patentability of rabeprazole.

Affirming the district court on all counts, the Federal Circuit concluded, "In a series of thoughtful, thorough opinions, the district court carefully explained its reasoning with respect to both obviousness and inequitable conduct."

RELATED READING:

• Eisai press release
• Reuters story
• OBB post on SJ of no inequitable conduct (15 May 07)
• OBB post on SJ of validity (31 Oct 06)

OBB News Briefs

• Teva announced Friday that it is acquiring Barr Pharmaceuticals for $7.5 billion plus $1.5 billion in debt.  For more:  AP; Reuters; WSJ.
• Zentiva, the Czech generic drug maker, announced Friday that it rejected a takeover bid from Sanofi-Aventis.  Sanofi already owns 25% of the company.
• Meanwhile, the WSJ Health Blog recently reported that the CEOs of GSK and Roche have no interest in getting into the generics business.
• FDA Law Blog recently reported on two interesting USPTO decisions denying Patent Term Extension requests under 35 U.S.C. § 156.  In both cases, AstraZeneca was the applicant:  July 8 (Symbicort); July 16 (Prilosec OTC).
• On July 16, Impax and Wyeth announced a settlement of their litigation over Impax's generic version of Effexor XR.  Under the agreement, Impax may launch its capsule formulation of Effexor XR on June 1, 2011, and possibly as early as January 1, 2011.
• On July 11, Momenta Pharmaceuticals announced the filing of an ANDA with a paragraph IV certification for a generic version of Copaxone, Teva's $500 million multiple sclerosis drug.  According to Pharmalot, Teva's CEO is not concerned.
• The Baltimore Sun recently reported that the brand-name pharmaceutical industry has been successfully pushing legislation at the state level requiring pharmacists to inform doctors or get their permission before substituting a generic drug for a brand-name drug.
• The FDA announced on July 9 that it is revising the way it communicates to drug companies when a marketing application cannot be approved as submitted.  CDER will no longer issue "approvable" or "not approvable" letters.  For more:  Pharmalot; WSJ Health Blog.
• The WSJ Health Blog had an interesting post recently about a report from the HHS Inspector General, finding that FDA typically takes longer than the 180 days allowed under law to review a generic drug application.
• The Mircera case between Amgen and Roche is attracting a great deal of attention, particularly because of the "public interest" factor of the injunction analysis.  Patent Docs reported that BIO filed an amicus brief with the Federal Circuit.  Pharmalot has more on the case.
• Insmed recently announced that it has developed a biosimilar version of Amgen's Neupogen, a $1 billion drug for the treatment of Neutropenia.  Pharmalot has more.

Federal Circuit Vacates Dismissal of Delaratory Judgment Counterclaims in Fosamax Case as Moot

Merck & Co. v. Apotex, No. 2007-1362 (Fed. Cir. 2008)

Fosamax (alendronate sodium) is one of the all-time best-selling drugs for the treatment and prevention of osteoporosis, with over $3 billion in U.S. sales last year.  Merck listed ten patents in the Orange Book for Fosamax:  U.S. Patent No. 4,621,077, which claims a method of inhibiting bone resorption by administering alendronate sodium; U.S. Patent No. 5,994,329, which claims other methods of use; and eight other patents on formulations and methods.

In 1999, Teva filed an ANDA for a generic version of Fosamax, with paragraph IV certifications to all ten Orange Book-listed patents.  Teva was the first ANDA filer, earning 180-day exclusivity.  According to Teva's approval letter, a district court upheld the validity of the '077 and '329 patents and dismissed the cases with respect to the other patents-in-suit.  The Federal Circuit affirmed the validity of the '077, but, in a January 2005 opinion, held two claims of the '329 patent to be invalid for obviousness.

Apotex filed an ANDA for generic Fosamax sometime later, with a paragraph III certification to the '077 patent and paragraph IV certifications to the other nine Orange Book-listed patents.  Merck sued Apotex for infringement and Apotex counterclaimed for invalidity and noninfringement.  Following discovery, Merck granted Apotex a covenant not to sue and moved to dismiss the case.

Apotex opposed the motion, arguing that as long as it was blocked by Teva's 180-day exclusivity, there was an Article III case or controversy and thus it should be allowed to pursue its counterclaims.  Apparently, Apotex aimed to trigger Teva's exclusivity by obtaining an early "court decision."  Apotex further argued that dismissal might not lift the automatic 30-month stay of FDA approval of Apotex's ANDA.  However, the district court granted Merck's motion to dismiss (click here for opinion), based largely on the covenant not to sue.  Apotex appealed to the Federal Circuit.

The Federal Circuit issued its opinion this morning.  The court began its analysis by noting that "depending on the circumstances, a justiciable Article III controversy may continue to exist between a patentee drug company and a Paragraph IV ANDA filer in the context of the Hatch-Waxman Act even after the patentee drug company has granted the Paragraph IV ANDA filer a covenant not to sue," citing its decision in Caraco v. Forest earlier this year.  The court continued:

This case, however, has been rendered moot by two factual developments that were brought to this court's attention after oral argument.  First, the FDA decided to treat the thirty-month stay on Apotex's ANDA as dissolved once the district court dismissed this case.  Second, the first Paragraph IV filer (i.e., Teva) triggered its 180-day exclusivity period . . . by marketing its generic drug on or about February 6, 2008.  As a result, Apotex no longer suffers a delay in entering the market under either the thirty-month stay provision or the 180-day exclusivity provision that is traceable to Merck and redressible by a court judgment.  Indeed, Apotex's only remaining delay in entering the market is the balance of Teva's 180-day exclusivity period, which expires on or about August 5, 2008.

Thus, the Federal Circuit vacated the district court's dismissal of Apotex's counterclaims as moot.

AstraZeneca Wins Seroquel Case on Summary Judgment; Teva and Sandoz to Appeal

AstraZeneca v. Teva Pharms. USA and Sandoz, No. 05-5333 (D.N.J. 2008)

On July 1st, the U.S. District Court for the District of New Jersey granted AstraZeneca's motion for summary judgment that its patent on quetiapine fumarate, the active ingredient in Seroquel, is not unenforceable for inequitable conduct.  The decision disposed of the last remaining issue in the case, as Teva and Sandoz, which are challenging the patent, had already conceded infringement and validity.

The district court's opinion explains that Seroquel, which is indicated for the treatment of schizophrenia and bipolar disorder, is in a class of drugs known as "atypical antipsychotics."  According to the opinion, early ("typical") antipsychotic medications were plagued by undesirable side effects, including acute dyskinesias (uncontrollable muscle movements).  In 1985, Astra scientists discovered quetiapine, which showed reduced potential to cause dyskinesias, and in 1989 Astra was issued U.S. Patent No. 4,879,288 on the compound.

Teva and Sandoz offered four arguments for the unenforceability of the '288 patent:

• Astra misrepresented and/or omitted material information concerning certain prior art compounds in its prosecution of the '288 patent;
• In response to a request by the patent examiner, Astra falsely asserted that generating data regarding a particular prior art compound would have been "very expensive";
• Astra deceived the PTO by representing that a record reference taught that a particular compound was a typical antipsychotic; and
• Astra failed to disclose to the PTO the death of a cebus monkey during testing of quetiapine.

The district court rejected each of these arguments, concluding that the information allegedly withheld or misrepresented by Astra during prosecution of the '288 patent was not sufficiently material to support a finding of inequitable conduct.

In addition, the court rejected as a "facile argument" the defendants' suggestion that a trial is necessary "in order for the parties to present expert testimony and to allow the court to make credibility determinations with respect to fact witnesses."  According to the court, "there are no credibility determinations to be made here; the prosecution record speaks for itself.  Moreover, experts engaging in hindsight cannot change the facts and circumstances of the patent application process that occurred two decades ago."

Seroquel is Astra's best-selling drug, with global sales of $4 billion last year (accounting for 10% of Astra's revenues) and annual U.S. sales of $3.5 billion.  Teva and Sandoz have announced their intention to appeal the district court's decision to the Federal Circuit.  The '288 patent is currently set to expire in 2011, though pediatric exclusivity could extend Astra's protection until 2012.

RELATED READING:

• AstraZeneca press release
• International Herald-Tribune
• Reuters
• Wall St. Journal
• WSJ Health Blog