Pantoprazole Sodium (Protonix) patent issues: Jury decision favorable to innovator; final decision pending

The generic player Teva (announced in a press release here ) about ongoing patent litigation and jury’s decision on Pantoprazole Sodium (Protonix) formulation.

The Jury appointed by US district Court for the district of New Jersey has opined on April 23, 2010 that innovator Nycomed’s ( who licensed the molecule’s patents to wyeth, now part of Pfizer) compound patent US4758579 (Expiry: Jan 19, 2011), which covers Pantoprazole as product is valid and infringed by generic players. Now, the court's final verdict is keenly awaited by pharma experts.

As per Teva’s press release, the Court has reserved decision on the issue of what, if any, effect to give to the jury's determinations in connection with the obviousness-type double patenting defenses, which Teva has argued is to be decided by the Court. A decision by the District Court judge independent of today's jury verdict would be sufficient to invalidate the patent.

As per USFDA database, 3 generic players have final approval for this formulation:

1) Teva: ANDA approved on Aug 2, 2007

2) Sun Pharma: ANDA approved on Sep 10, 2007

3) Kudco Ireland: ANDA approved on Mar 17, 2009

Background of the case

The generic players Teva filed ANDA on this product in April, 2004, the other generic players like Sun filed ANDA with invalidation grounds against product patent in March 1, 2005 and June 25, 2005, respectively. Subsequently, innovator applied for preliminary injunction to stop generic players from marketing generic version in New Jersey District Court. As per preliminary injunction opinion of the district court, court opined that patent is vunerable to invalidation based on strong prior art documents produced by generic players.

Generic player Teva launched Pantoprazole in 2007 and Sun launched in 2008. Further, to affect sale of generic players, innovator launched authorized generic version through Prasco in 2007.

Also, innovator appealed against district court's decision in U.S. Court of Appeals for the Federal Circuit (CAFC). During appeal, the U.S. Court of Appeals for the Federal Circuit (CAFC) unanimously affirmed the ruling by US district Court for the district of New Jersey

The district court and CAFC denied innovator Altana preliminary injunction based on strong invalidity argument in the light of following prior art:

1) US4255431: product patent on Omeprazole which discloses various structural features for optimal Proton pump inhibitory (PPI) activity

2) US4555518 : Disclosed 18 Proton Pump Inhibitors (PPI) compounds and compund number 12 exhibit structural similarity with Pantoprazole. Further, compound 12 differ from pantoprazole in terms of difference in substituents at 3 position of pyridine ring. Pantoprazole has methoxy group while compound 12 of ‘518 patent contains methyl group.

3) Article by Sachs, Brysnon and ‘431 patent on PPI which shows various structural features for optimal PPI activity like Benzimidazole ring, pyridine ring, methyl sulfinyl groups. Also, these articles describe that methoxy group at pyridine ring lowers Pka value (to about 4) of PPI and exhibit optimal PPI activity.Based on above elements district court opined the vulnerability of ‘579 on obviousness standards and denied preliminary injunction. Subsequently, Altana appealed in CAFC based on following points:

1. District court’s failure to take into account an accused infringer’s clear and convincing burden to prove invalidity

2. District Court’s selection of compound 12 (US4555518) as lead compound

3. District court’s interpretation of Sachs (George Sachs, Pump Blockers and Ulcer disease, 310 New Eng J. Med. 785 (1984), which discloses that substitution of methyl substituent with methoxy substituent in pyridine ring enhances proton pump inhibitory actions.

3. District court’s interpretation of Brysnon articles (Dr A Bryson, The ionization constants of 3-substituted pyridines, substituted quinolines and 4-substituted isoquinolines J. Am. Chem. Soc. 82, 4871 (1960), which discloses the effect of various substituents at 3 position of pyridine ring.

Further, the CAFC upheld (in May, 2009) District court’s decision and opined that elements considered by lower court while denying preliminary injunction were correct.

During ongoing full trial in New Jersey District Court, the jury found patent valid and infringed. Importantly, court’s final decision is pending which will provide more clarity w.r.t techno-legal arguments held during trial.

Sumatriptan and Naproxen (Treximet) 85 mg+500 mg Tablets: Innovator Pozen and generic player Teva settled patent litigation

Innovator Pozen (announced in a press release here) and generic player Teva settled patent litigation w.r.t generic version of the migraine treatment Sumatriptan and Naproxen (Treximet) 85 mg+500 mg Tablets.

Innovator Pozen has strong patent portfolio on this formulation. The listed patent has claims on method of use, formulation and pharmacokinetic properties of the combination

Both parties were in litigation at U.S. District Court for the Eastern District of Texas w.r.t following patents:

US6,060,499 (Expiry: Aug 14, 2017) : Which covers a method for treating a migraine patient by administering a 5-HT agonist, the improvement which comprises: concomitantly administering to said patient a long-acting, non-steroidal, anti-inflammatory drug (LA-NSAID) in an amount that, together with said 5-HT agonist, is effective to reduce migraine relapse or produce longer lasting efficacy compared to the administration of said 5-HT agonist in the absence

US6,586,458 (Expiry: Aug 14, 2017): Which covers a method of treating a patient for migraine headache, comprising: (a) administering a 5-HT agonist to said patient, wherein said 5-HT agonist is a triptan; and (b) administering a long-acting, non-steroidal, anti-inflammatory drug (LA-NSAID) to said patient, wherein said LA-NSAID has a pharmacokinetic half-life of at least 4 hours and a duration of action of at least 6 hours; wherein: (i) said 5-HT agonist and said LA-NSAID are concomitantly administered in unit dosage form; and (ii) the respective amounts of said 5-HT agonist and said LA-NSAID administered to said patient are sufficient to produce longer lasting efficacy compared to the administration of said 5-HT agonist in the absence of said LA-NSAID or the administration of said LA-NSAID in the absence of said 5-HT agonist.

US7,332,183 (Expiry: Aug 14, 2017): Which covers a multilayer pharmaceutical tablet comprising naproxen and a triptan and, wherein: a) substantially all of said triptan is in a first layer of said tablet and substantially all of said naproxen is in a second, separate layer; and b) said first layer and said second layer are in a side by side arrangement such that the dissolution of said naproxen occurs independently of said triptan.

Under the terms of the Settlement Agreement, litigation against Teva will be dismissed without prejudice from the consolidated litigation currently pending in the United States District Court for the Eastern District of Texas against Teva, Par Pharmaceutical, Inc., Alphapharm Pty Ltd., and Dr. Reddy's Laboratories, Inc., but will agree to be bound by the outcome of such litigation or any resulting settlements with third parties.

Repaglinide (Prandin) tablets: CAFC refused to change patent use code

In a dispute between innovator Novo Nordisc and generic player Caraco on patent Use code listed for following Orange book listed patent on antidiabetic formulation Repaglinide tablets:

US6,677,358 (Expiry: Jun 12, 2018): which covers use of Repaglinide in combination with Metformin

The CAFC has refused to correct patent use code boundary.

The dispute is due to following patent use cod listed for ‘358 patent:
1) U-968: A METHOD FOR IMPROVING GLYCEMIC CONTROL IN ADULTS WITH TYPE 2 DIABETES MELLITUS
2) U-546:USE OF REPAGLINIDE IN COMBINATION WITH METFORMIN TO LOWER BLOOD GLUCOSE

Innovator has earlier listed the use code U-546, which was narrow in terms of use coverage and generic player Caraco filed section viii (generic player would not market product for the patented indication) against this patent, however, innovator changed this use code to the broad U-968. The revised use code covers all approved uses of Repaglinide:
1) Use of Repaglinide as monotherapy
(2) Use of Repaglinide in combination with Metformin
(3) Use of Repaglinide in combination with thiazolidinediones

As the revised use code covers all approved uses of Prandin, USFDA refused to accept Sec viii statement of Caraco and directed them to revise the patent certification.

Caraco challenged Novo’s use code change in an FDC Act §505(j)(5)(C)(ii)(I) directing Novo to correct the listed patent information w.r.t use code, which is broad in comparison to the patent claims.

On September 24, 2009, the U.S. District Court for the Eastern District of Michigan directed innovator Novo Nordisk to change the use code from broad U-968 to narrow U-546. Court directed innovator to file the changes with USFDA with in 20 days, however, innovator appealed in CAFC, which reversed the lower court's decision. The court decided that as per FDC Act §505(j)(5)(C)(ii)(I), the innovator can correct erroneous patent listing or expiry date of the patent but not the use code.
The Judge Dyk was not in agreement with Judge Radar and Judge Clevenger and dissented against this opinion.
Related news by:

Kurt R. Kast of FDA Law Blog Here
Aaron Barkoff of Orange Book Blog here

Omeprazole + Sodium Bicarbinate (Zegerid) Capsules and oral suspension: Innovator Santarus’ key patents declared invalid by US court

In a significant decision, the U.S. District Court for the District of Delaware has declared the Orange Book listed patents of innovator Santarus (who has got licensed on the patents from University of Missouri) for Omeprazole + Sodium Bicarbinate (Zegerid) 20 mg; 1.1 g and 40 mg ;1.1 g Capsules and 20 mg/PACKET;1.68 g/PACKET and 40 mg/PACKET;1.68 g/PACKET powder for oral suspension were declared invalid due to obviousness in the light of prior publications. The following Orange Book listed patents were opposed by the generic player Par Pharma and court declared the patent invalid:

US6,489,346 (Expiry: Jul 16, 2016): Invalid due to Obviousness
US6,645,988 (Expiry: Jul 16, 2016): Invalid due to Obviousness
US 6,699,885 (Expiry: Jul 16, 2016): Invalid due to Obviousness
US6,780,882 (Expiry: Jul 16, 2016): Listed for suspension only, Invalid due to Obviousness
US7,399,772(Expiry: Jul 16, 2016): Invalid due to lack of written description as per 35 USC 112
Earlier, generic player Par filed ANDA with Para IV in 2007 for capsules and oral suspension. Subsequently, innovator sued Par for the infringement of above patents.

The patent invalidty attack of Par (in the light of well searched and debated arguments) resulted into invalidation of above key patents. Also, court found that the patent are not invalid due to inequitable conduct and refused attorney fees to Par.

As per press release by innovator (Here), Santarus is currently assessing the potential timing and impact of launch of a generic version of ZEGERID. Par has not yet received final FDA approval for any of its ANDA submissions, and Santarus is not aware of any other companies that have submitted ANDAs for generic versions of ZEGERID. As a result, the timing of a launch of a generic version of ZEGERID is uncertain.

Losartan (Cozaar) and Losartan + HCTZ (Hyzaar): Teva launched generic version

The generic player M/S Teva Pharma announced (in a press release Here ) that the U.S. Food and Drug Administration (USFDA) has granted final approval for the Company's generic versions of innovator Merck's antihypertensive Losartan (Cozaar) 25 mg, 50 mg and 100 mg tablets and Losartan + HCTZ (Hyzaar) 100+ 12.5, 50+12.5, 100 + 25 mg tablets.

Importantly, company is first to file on these products and USFDA has awarded 180-day Hatch-Waxman statutory exclusivity to market these products to Teva. Also, generic players Roxane, Torrent and Mylan have got final approval for Losartan + HCTZ (Hyzaar) 100 +12.5 mg tablets (no exclusivity on this strength).

Also, generic player Sandoz has launched authorized generic of this product.

As per USFDA database, these generic players have got final approval on Apr 6, 2010 after the expiry of compound patent US5153197, which covered Losartan as product.

Teva has got 180 days exclusivity challenge by challenging US5608075 (Expiry: Sep 4, 2009), which covers various polymorphic forms of Losartan Potassium. After Teva's ANDA filing, innovator Merck filed patent delisting request on '075 patent. However, Teva opposed this delisting and after a long legal battle with USFDA (full of twists ), Teva got exclusivity on this product. Also, generic players Roxane and Apotex challenged USFDA decision of grant of FTF 180 days exclusivity to Teva.

The brand products had combined annual sales of approximately $1.6 billion in the United States, based on IMS sales data.

For an excellent review on court cases and Teva’s dispute with USFDA, you can refer to Mr. Kurt R. Kast’ FDA Law Blog Here .

Seasonique: Teva Receives Favorable Court Decision

Innovator Teva Pharma announced (in a press release Here ) that the U.S. District Court for the District of Nevada has granted Teva's Motion for Summary Judgment with respect to the validity of U.S. Patent No. 7,320,969. In March 2008, Duramed, now Teva Women's Health, brought suit in the District of Nevada against Watson alleging infringement of Teva's patent as a result of Watson's filing of an Abbreviated New Drug Application (ANDA) for Seasonique®. The ANDA sought approval to market a generic version of Seasonique in the U.S. before the patent expires on January 30, 2024. Teva's motion sought judgment on the remaining liability issue in the case, as Watson had previously conceded infringement of Teva's patent. Since the Court granted Teva's motion in its entirety, trial is unnecessary. Separate litigation is pending in the United States District Court for the District of New Jersey with respect to Mylan/Famy Care's and Lupin's ANDAs for Seasonique. Teva is currently analyzing the impact of this decision on those cases.

Oxaliplatin (Eloxatin): Teva Settled patent Litigation with innovator Sanofi & Debipharm

Jerusalem, April 1, 2010 - Teva Pharma announced (announced in a press release Here )
today that patent infringement litigation pertaining to Teva's generic version of sanofi-aventis and Debiopharm's Oxaliplatin (Eloxatin) has been dismissed by the United States District Court for the District of New Jersey pursuant to a settlement between the parties. The settlement, which provides for a full release of Teva, includes an injunction prohibiting Teva from selling its oxaliplatin injection product and a license to reenter the market at a later point in time. Teva anticipates continued sales of its oxaliplatin injection at least through June 30, 2010, and will resume shipping additional units August 9, 2012, subject to acceleration under certain contingencies.

Gemcitabine (Gemzar®): Teva Provides Update on patent Litigation

Jerusalem, April 1, 2010 Teva Pharma announced (announced in a press release Here ) today that the U.S. District Court for the Southern District of Indiana issued a decision yesterday on two patents for Gemcitabine (Gemzar®); the compound patent expiring on November 15, 2010, and a method of use patent expiring on May 7, 2013. As to the method of use patent, the Court denied Lilly's request for an injunction on the grounds that the Eastern District of Michigan had previously found that patent invalid. Lilly has appealed that decision and oral argument is scheduled for May 7, 2010. Teva believes it is first-to-file on that patent and thus will be able to launch a generic version of Gemzar with 180-days Hatch Waxman exclusivity when the compound patent (which the Court found valid) expires or is held invalid on appeal.

Teva Provides Update on Generic Temodar®

Jerusalem, March 17, 2010 - Teva Pharma announced (in a press release Here) today that the parties to the patent litigation regarding Barr's U.S. generic version of Schering's Temodar® have entered into an agreement pending resolution of Schering's appeal to the Federal Circuit of the U.S. District Court's decision holding the '291 Patent unenforceable. Under the terms of the agreement, subject to limited exceptions, Teva will only market a generic product should the Federal Circuit uphold the District Court's decision. Furthermore, the agreement grants Teva the right to commence selling its generic product as of August 2013, during the period of Schering's pediatric exclusivity.

Teva To Acquire Ratiopharm

Jerusalem, Israel, March 18, 2010 - Teva Pharmaceutical Industries Ltd. announced (in a press release Here) that it has entered into a definitive agreement to acquire ratiopharm, Germany's second largest generics producer and the sixth largest generic drug company worldwide, for an enterprise value of 3.625 billion euro. The transaction is subject to certain conditions including relevant regulatory approvals. On a pro forma basis, the combined company would have had 2009 revenues of $16.2 billion. Teva expects to complete the transaction by year-end 2010.

(Source: Press Release of M/S Teva)